Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication IMBRUVICA is a kinase inhibitor indicated for the treatment of: Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) ( 1.1 ). Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion ( 1.2 ). Adult patients with Waldenström’s macroglobulinemia (WM) ( 1.3 ). FDA label
Also known as Ibrutinib, IMBRUVICA®, Next-line ibrutinib, BTK Inhibitor PCI-32765, CRA-032765, GDC-0199, venetoclax, Bruton's tyrosine kinase inhibitor PCI-32765
PCI-32765 · 105 trials · 154 indications
Proportion of MRD negative patients at month15 based on the intention-to-treat population (ITT population), that is the number of MRD negative patients divided by the number of the ITT population. MRD negativity is defined as \<1 CLL-cell among 10,000 leukocytes analyzed \[0.01%\], i.e. \< 10-4. Primary outcome measure for the comparison of GVe vs. SCIT
Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines \[2008\]), or death from any cause, whichever occurs first. Primary outcome measure for the comparison GIVe vs. SCIT
TLS is defined per Howard criteria that require a clinical intervention per independent review committee (IRC) assessment during the venetoclax ramp-up period in previously untreated participants with chronic lymphocytic leukemia (CLL) achieving a medium tumor burden with creatinine clearance (CrCl) of at least 80 ml/min or low tumor burden (regardless of CrCl level) after debulking therapy.
Hyperkalemia (potassium \>6.0 mmol/L) is defined per Howard criteria that require a clinical intervention per IRC assessment during the venetoclax ramp-up period in previously untreated participants with CLL achieving a medium tumor burden with CrCl of at least 80 ml/min or low tumor burden (regardless of CrCl level) after debulking therapy.
Time from randomization to the first occurrence of progression or relapse (determined using standard iwCLL guidelines), or death from any cause, whichever occurs first
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above.
DLTs are any of the hematologic, nonhematologic toxicities, adverse events (AEs) occurring following administration of venetoclax as described in the protocol and evaluated by the Investigator and the sponsor.
DLTs are hematologic toxicities consisting of any Grade ≥ 3 neutropenia or thrombocytopenia lasting more than 7 days and nonhematologic toxicities as described in the protocol and evaluated by the Investigator and the Sponsor. In addition, AEs that lead to omitting \> 20% of the scheduled dose within the cycle is considered as a DLT unless clearly related to underlying disease. Treatment delay due to toxicity lasting greater than 14 days since the last dose of Venetoclax is also considered a DLT.
per the RECIL criteria
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either reasonable possibility or no reasonable possibility. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs/TESAEs) are defined as any event that began or worsened in severity after the first dose of study drug. For more details on adverse events please see the Adverse Event section.
The composite complete remission rate is defined as the percentage of participants with complete remission (CR) or complete remission with incomplete blood count recovery (CRi) at any time during the study as assessed by the investigator. Response was based on bone marrow results and hematology values according to the modified International Working Group (IWG) criteria for AML: CR: Absolute neutrophil count (ANC) \> 10\^3/μL (1,000/μL), platelets \> 10\^5/μL (100,000/μL), red blood cell (RBC) transfusion independence, and bone marrow with \< 5% blasts CRi: Bone marrow with \< 5% blasts, and absolute neutrophils of ≤ 10\^3/μL or platelets ≤ 10\^5/μL
PFS is defined as the time in days from subject randomization to the date of the first documented progressive disease (PD) or death due to any cause, whichever occurs first.
Low tumor burden is defined as absolute lymphocyte count (ALC) \< 25 × 10\^9 /L and all lymph nodes \< 5 cm per computed tomography (CT) scans.
Complete remission rate is defined as the percentage of participants achieving complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: * Peripheral blood lymphocytes \<4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly * Absence of disease or constitutional symptoms (unexplained fevers \>38°C, drenching night sweats, ≥10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \>1500/μL * Platelets \>100,000/μL * Hemoglobin \>11.0 g/dL * Bone marrow at least normocellular for age, \<30% lymphocytes CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.
TLS events are defined as follows: * Clinical TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) with the following exceptions: * For the purpose of TLS assessment during the Safety Run-in Period, only those increases in serum creatinine \> 1.0 mg/dL from pre-treatment baseline will be considered clinical TLS. * In participants with renal dysfunction at baseline (CrCl \< 60 mL/min), clinical TLS is defined as the presence of laboratory TLS plus either seizures, cardiac dysrhythmia, or death. * Laboratory TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) for laboratory TLS, that does not resolve within 72 hours despite protocol required management.
DLT: any Grade (Gr) 3 or higher non-TLS adverse event (AE) at least possibly related to study drug occurring during the DLT assessment period with the following clarifications: Non-Hematologic DLTs: Gr ≥3 nausea, vomiting or diarrhea uncontrolled despite maximum medical supportive care and persisting \>5 days; Gr 3 fatigue persisting \>7 days; Gr 3 infection is not a DLT, however an infection with lifethreatening consequences or requiring urgent intervention (Gr 4) was considered a DLT; Treatment delay of any study drug \>7 days for toxicity. Hematologic DLTs: Gr 3 neutropenia is not a DLT, however, Gr 4 neutropenia (ANC \<500/mm\^3) lasting for \> 7 days is a DLT; Gr 3 or 4 neutropenia complicated by fever ≥38.5°C or infection; Gr 4 thrombocytopenia (\<25,000/mm\^3) that persists for \> 7 days; Gr 3 or 4 thrombocytopenia associated with Gr 2 or greater bleeding; Gr 3 anemia is not a DLT, however, Gr 4 anemia is a DLT; Treatment delay of any study drug \>7 days for hematologic toxicity.
AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).
PFS is defined as the time from the date of randomization to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.
CR rate is defined as the percentage of participants with a CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
CR and CRi was calculated based on current International Working Group (IWG) criteria. CR is defined as absolute neutrophil count \>10\^3/ microliter (mcL), platelets \>10\^5/mcL, red cell transfusion independence, and bone marrow with \<5% blasts. CRi is defined as bone marrow with less than 5% blasts, and absolute neutrophils of ≤10\^3/mcL or platelets ≤10\^5/mcL. Percentages are rounded off to whole number at the nearest decimal.
PFS is the time from the date of randomization to the date of the first documented evidence of disease progression (based on the Revised Response Criteria for Malignant Lymphoma \[Cheson 2014, Lugano Classification\]) or death from any cause, whichever occurs first. Participants who initiated subsequent anticancer therapy or missed two or more consecutive overall disease assessments were censored as described in the SAP. Estimated by Kaplan-Meier method.
EORTC QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items and a score ranging from 0 to 100 is calculated. A higher score on the global health status/quality of life scale indicates a better level of functioning, and positive changes from baseline indicate improvement. A change of 5 - 10 points is considered a small change, and a change of 10 - 20 points is considered a moderate change.
Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes. CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.
PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of PD or death from any cause. Disease progression was characterized by at least one of the following: 1) \>/= 50% increase in the absolute number of circulating lymphocytes to at least 5\*10\^9/L, 2) Appearance of new palpable lymph nodes (\> 15 mm in longest diameter) or any new extra-nodal lesion; 3) \>/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) \>/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.
PFS was defined as time from the date randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
PFS was defined as the time from date randomization to date of first IRC-confirmed disease progression (PD) assessed according to the modified VIth International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria (National Comprehensive Cancer Network \[NCCN\] 2014) or death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. As the median PFS was not reached in the Ibrutinib + Rituximab arm at the time of the analysis, Kaplan Meier landmark estimate of the PFS rate at 54 months (that is, the estimated percentage of participants with PFS at Month 54) is presented.
PFS is defined as the time from the date of randomization to the date of disease progression determined by the investigator or date of death from any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to disease progression (PD) or death. Estimated by Kaplan-Meier method.
The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS Progressive disease according to 2008 IWCLL guidelines was defined as: * Group A * Lymphadenopathy, increase ≥50% * Hepatomegaly, increase ≥50% * Splenomegaly, increase ≥50% * Blood lymphocytes, increase ≥ 50% over baseline * Group B * Platelets counts, decrease of ≥ 50% from baseline secondary to CLL * Hemoglobin, decrease of \> 2 g/dL from baseline secondary to CLL
The primary objective of this study was to evaluate the efficacy of ibrutinib compared to ofatumumab based on independent review committee (IRC) assessment of progression-free survival (PFS) according to 2008 IWCLL guidelines.
The (CRMRD-+CR+CRi+MLFS) shows non-inferiority of venetoclax with azacitidine when compared with historical controls who received induction chemotherapy.
Will be defined as the rate of complete remission (CR) plus CR with incomplete count recovery (CRi).
Reduction of BCR::ABL1 stem cells measured by quantitative genomic PCR in bone marrow after venetoclax administration.
MRD evaluation performed by 8 colours flow cytometry analysis in the bone marrow
CR / VGPR 12 months after randomization
CRc is defined as achievement of complete remission (CR), CR with partial hematologic recovery (CRh) or CR with incomplete blood count recovery (CRi) after induction (or re-induction). The CRc rate will be computed on the safety set and presented with a point-estimate and exact binomial 95% confidence interval (CI). CRc will also be modeled with univariable logistic regressions, applied to the efficacy set, to determine if any baseline patient or disease feature is correlated with clinical response.
Will be defined as \< 1 x 10\^-4 by ClonoSEQ in the peripheral blood, after 12 cycles of combined venetoclax plus zanubrutinib assessed by ClonoSEQ. Will be calculated separately in each cohort among all eligible patients who start any amount of study drug, and the 95% exact confidence interval will be provided with the estimated rate.
Will be defined at \< 1 x 10\^-4 by ClonoSEQ in the peripheral blood, after 24 cycles of combined venetoclax plus zanubrutinib. Will be calculated separately in each cohort among all eligible patients who start any amount of study drug, and the 95% exact confidence interval will be provided with the estimated rate.
Major response is defined as participants with a best overall response of complete response (CR), very good partial response (VGPR) or partial response (PR) per independent review committee (IRC) assessment according to International Workshop on Waldenstrom macroglobulinemia (WM) (IWWM)-11 criteria in participants with Immunoglobulin M (IgM) \>= 500 mg/dL at screening.
Major response is defined as participants with a best overall response of CR, VGPR or PR per IRC assessment according to IWWM-11.
Complete Response (CR) rate is defined as the proportion of participants achieving CR during study treatment. CR is defined based on RECIL criteria.
Evaluation will be done with a bone marrow aspirate, cytogenetics, metabolic imaging, study of MRD by NGS and flow-cytometry and SWAT SCORE
Rate of BM-uMRD is defined by negative MRD in the bone marrow by flow cytometry at a sensitivity of 10\^-4. The Clopper Pearson method is used to estimate the 95% two-sided confidence interval (CI) of the rate of BM-uMRD.
Determination of dose-limiting toxicities within the first two cycles of treatment
Bone marrow assessments will be performed at least at screening, at the end of cycle 1, after cycle 4 and after cycle 6 resp. end of treatment (EOT). Criteria for disease status / response assessment follow the ELN-2022 recommendations .
OR is defined as the percentage of participants achieving a best response of partial remission (PR), nodular partial remission (nPR), complete remission with incomplete marrow recovery (CRi), or complete remission (CR). Disease assessments will be based on the 2018 International Workshop for Chronic Lymphocytic Leukemia (iwCLL) criteria for tumor response.
CR rate is defined as the percentage of participants achieving a best response of CR or CRi.
CR rate is defined as the percentage of participants achieving a best response of CR or CRi.
Complete response rate (CRR), defined as the percentage of participants achieving a best overall response of complete response (CR) per the Revised Criteria for Response Assessment for Malignant Lymphoma following the Lugano classification (Cheson 2014), assessed by an Independent Review Committee (IRC).
Proportion of patients with VGPR to therapy within 24 cycles of therapy initiation. (VGPR is \>90% reduction in serum IgM from baseline)
Respiratory failure is defined as a clinical diagnosis of respiratory failure and initiation of one of the following therapies: endotracheal intubation and mechanical ventilation; OR extracorporeal membrane oxygenation; OR high-flow nasal cannula oxygen delivery (i.e., reinforced nasal cannula delivering heated, humidified oxygen with fraction of delivered oxygen ≥ 0.5 and flow rates of ≥ 30 L/min); OR non-invasive positive pressure ventilation; OR clinical diagnosis of respiratory failure with initiation of none of these measures only when clinical decision-making is driven solely by resource limitation.
ORR is defined as the percentage of participants achieving complete remission (CR), CR with incomplete bone marrow recovery (CRi), or partial remission (PR) as their best response per investigator assessment based on the T-PLL consensus criteria 2019. CR: All of the following response criteria must be met: Group A: * all lymph nodes \< 1 cm; * spleen \< 13 cm; * no constitutional symptoms; * circulating lymphocyte count \< 4 × 10\^9/L; * bone marrow T-PLL cells \< 5% of mononuclear cells; * no other specific site involvement Group B: * platelets ≥ 100 × 10\^9 /L; * hemoglobin ≥ 11.0 g/dL; * neutrophils ≥ 1.5 × 10\^9 /L. CRi: All of the CR response criteria in Group A met; at least 1 parameter in Group B not achieved, unrelated to T-PLL, but related to drug toxicity. PR: At least 2 of the parameters in Group A and 1 parameter in Group B need to improve if previously abnormal. If only 1 parameter of both Groups A and B is abnormal prior to therapy, only 1 parameter needs to improve.
VGPR or better response rate is defined as the proportion of participants with documented VGPR or better (sCR, CR. or VGPR) based on IMWG criteria.
CR or better response is defined as the percentage of participants with documented response of CR or better (stringent complete response \[sCR\] or CR) based on IMWG criteria.
TTR is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of first documented response of PR or better.
DOR is defined as the number of days from the participant's date of first documented response (PR or better) to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first.
TTP is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of first documented PD or death due to MM, whichever occurs first.
Response will be assessed by the revised Lugano. Will compute estimates of response, along with corresponding confidence intervals, using appropriate exact methods that take into account the 2-stage design.
Defined as the number of participants who achieve CR according to National Comprehensive Cancer Network (NCCN) Guidelines for Acute Lymphoblastic Leukemia (ALL), Version 2.2015
VGPR or better response rate is defined as the percentage of participants with documented VGPR or better based on IMWG criteria.
ORR is defined as the percentage of participants with a documented PR or better based on IMWG criteria.
Complete response or better rate is defined as the percentage of participants with documented CR or better based on IMWG criteria.
DFS is defined as time from randomization date to MRD-positive relapse, or disease progression per investigator assessment (per 2008 International Workshop for Chronic Lymphocytic Leukemia \[IWCLL\] criteria \[Halleck et al\]) or death from any cause, whichever occurred first. 1-year DFS estimated using Kaplan-Meier method at 12 months landmark time.
CR/CRi rate is defined as the percentage of participants achieving a best overall response of complete response (CR), CR with incomplete blood count recovery (CRi) per 2008 IWCLL criteria (halleck et al.) on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurred earlier.
The primary efficacy endpoint of this study is mPFS. Progression free survival is defined as the time from the date of first dose of study treatment to confirmed disease progression or death from any cause, whichever occurs first.
CMR: a score 1 (no uptake above background), 2 (uptake less than or equal to \[\<=\] mediastinum), or 3 (uptake less than \[\<\] mediastinum but \<=liver) with or without a residual mass on PET 5-point scale (5-PS), for lymph nodes and extralymphatic sites with no new lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. Assessment was performed by an IRC according to Lugano classification using PET scan. 95% confidence interval (CI) for percentage of responders was calculated using Clopper-Pearson method.
To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.
ORR is defined as the proportion of subjects who achieved complete response (CR), partial response (PR). Response criteria are as outlined in the International Working Group Criteria for NHL, Cheson (2007), with disease assessments performed by an independent review committee (IRC). Per Cheson: CR is defined as disappearance of all evidence of disease. PR is defined as regression of measurable disease and no new sites.
Number of subjects achieving the best overall responses of CR or PR prior to the initiation of the next line of antineoplastic therapy as assessed by investigator per the Cheson et al, 2007 criteria. Target lesions are measured by CT, unless MRI is used as the assessment modality for lesions in anatomical locations not amenable to CT. CR is defined as the disappearance of all evidence of disease. PR is defined as \>=50% decrease in the sum of the product of the diameters of up to 6 largest dominant masses.
The clinical benefit response (CBR) rate, defined as the proportion of subjects who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) as assessed by the modified International Myeloma Working Group (IMWG) response criteria
The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator.
The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator. CR is a complete disappearance of all disease, no new lesions, lymph nodes must have regressed and be PET negative, spleen and liver should not be palpable and without nodules, and bone marrow must be negative. PR is a \>/= 50% decrease in the sum of the product of diameters of the target lesions, and \>/= 50% decrease of splenic and hepatic nodules from baseline, no new lesions and no increase in the size of liver, spleen or non-target lesions.
Subjects were to receive ibrutinib once daily at the dose level the subject was receiving in the parent study until disease progression or unacceptable toxicity. The study included Screening, Treatment (from the first dose until study drug discontinuation), and Follow-up Phases.
Evaluation of Dose-limiting toxicity (DLT) to determine the optimal dose level in terms of both toxicity and safety for venetoclax + azacitidine
Response assessment performed according to modified IWG (International Working Group) 2006 criteria for myelodysplastic syndrome and to European Leukemia Net criteria for acute myeloid leukemia
To determine the maximum tolerated dose (MTD of venetoclax given in combination with regimen-prescribed chemotherapy. The MTD is defined as the dose level associated with observed DLTs in \<33% of enrolled subjects
To determine the Recommended Phase 2 Dose (RP2D) of venetoclax given in combination with regimen-prescribed chemotherapy. The RP2D is defined either as the MTD or maximum dose tested should MTD not be reached.
All grade 2 or higher adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAE v5 criteria. Incidence is the number of patients experiencing at least one treatment-related grade 2 or higher AE of any type during the time of observation.
Describe the incidence and severity of calaspargase pegol-related toxicities in subjects with relapsed/refractory ALL/LBL per collected Adverse Events using CTCAE v5 criteria.
The maximum tolerated dose of Ibrutinib and Venetoclax as determined by number of DLTs observed. • If 0/3 DLT is observed, dose escalation will continue to the next upper dose level. • If ≥ 2/3 DLTs are observed, then the dose finding procedure will be terminated. • If 1/3 DLT is observed, then 3 additional patients will be enrolled in the same dose level. If no DLT is observed from the additional 3 patients, then dose escalation will continue to the next upper dose level. If any DLT is observed from the 3 additional patients, then the previously lower dose will be chosen as the MTD and the dose finding procedure will be terminated.
Number of participants on the recommended phase II dose level 2, with a partial or complete response, as determined by the revised Lugano Response Criteria for Non-Hodgkin Lymphoma,
Descriptive analysis of highest dose of venetoclax that did not cause a dose limiting toxicity with toxicity type based CTCAE vs 5.0 criteria.
The MTD will be determined based on the rate of dose-limiting toxicities (DLTs). Adverse events will be categorized and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Will be selected based on the overall tolerability of the regimen, but will not exceed the MTD.
Prostate Cancer Working Group (PCWG)3 will be used to evaluate PSA response and progression as well as progression on bone scans. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used to assess response and progression for nodal and visceral metastasis. The Kaplan-Meier product-limit estimator will be used.
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications. In order to be declared a dose-limiting toxicity, an adverse experience must be determined related (definitely, probably, or possibly) to study drug. Point estimates and 95% exact confidence intervals will be reported for all patients in the safety set as well as in subgroups defined by whether or not a patient received blinatumomab consolidation therapy.
Adverse events will be graded and categorized according to the Common Terminology Criteria for Adverse Events version 5.0. Point estimates and 95% exact confidence intervals will be reported.
The number of participants with end Block 1 minimal residual disease \<0.01% by flow cytometry
The recommended Phase 2 dose (RP2D) of venetoclax in combination with a) high-dose cytarabine and navitoclax will be the dose at which 0 or 1 of 6 treated patients experience a dose limiting toxicity.
The recommended Phase 2 dose (RP2D) of venetoclax in combination with b) blinatumomab will be the dose at which 0 or 1 of 6 treated patients experience a dose limiting toxicity. RP2D is 240mg/m2 which was delivered for 21 days.
The highest dose of the drug combination that does not cause unacceptable side effects as assessed by protocol-specified DLT criteria.
Defined as the partial response (PR) and complete response (CR) rate, according to the Lugano criteria.
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above.
Maximum Plasma Concentration (Cmax) of Venetoclax.
Time to Cmax (Tmax) of Venetoclax.
Area Under the Plasma Concentration-time Curve over time from time 0 to 48 hours (AUC0-48).
Unbound Fraction (fu) of Venetoclax in Plasma.
Dialysis Clearance (CLdialysis) is calculated in participants undergoing hemodialysis in Period 1.
Unbound fraction pre-dialysis (fu,predialysis) of venetoclax in plasma is calculated in participants undergoing hemodialysis in Period 1.
Unbound fraction post-dialysis (fu,postdialysis) of venetoclax in plasma is calculated in participants undergoing hemodialysis in Period 1.
Determine the rate of subjects who experience a dose limiting toxicity and the maximum tolerable dose
MTD was determined by testing increasing doses up to 600mg orally daily on dose escalation cohorts 1 to 3 with 3 to 6 participants each. MTD reflects the highest dose of drug where fewer than 33% of subjects experience a dose limiting toxicity (DLT). DLT is defined as an adverse event related (possible, probably, or definite) to Venetoclax and/or Gemtuzumab fulfilling one of the following criteria: Hematologic toxicity: treatment-related grade 3 or worse neutropenia and/or thrombocytopenia due to bone marrow hypocellularity present at the end of cycle one (day 28) with an additional 28 days allowed for count recovery (i.e. present at day 56); Note: patients who enter the study with grade 3 or worse cytopenias will not be evaluable for hematologic DLT. Non-hematologic toxicity: any grade 3 or worse treatment-related toxicity occurring within the first 56 days.
The RPTD of co-administered venetoclax and gilteritinib will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data.
Modified CRc rate is defined as the proportion of participants with documented complete response (CR) + CR with partial blood count recovery (CRp) + CR with incomplete blood count recovery (CRi) plus Morphologic Leukemia-Free State (MLFS) based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML).
To determine a safe and tolerable dose of venetoclax that can be given in combination with standard induction therapy to patients with newly diagnosed AML.
To determine a safe and tolerable dose of venetoclax and that can be given with a cycle of high dose cytarabine in consolidation after achievement of remission with induction therapy at the established MTD of venetoclax.
Time to maximum plasma concentration (Tmax) of venetoclax
Clearance (CL) of alvocidib
Area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) post-dose of alvocidib
Maximum plasma concentration (Cmax) of venetoclax
Half-life (t1/2) of alvocidib
Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of venetoclax.
Maximum plasma concentration (Cmax) of alvocidib.
Area under the plasma concentration-time curve from time zero to time t (AUCt) post-dose alvocidib.
RPTD will be determined using available safety and pharmacokinetics data upon completion of the dose escalation phase.
Highest dose of ibrutinib from Phase 1 (420, 560, or 840 mg by mouth daily) that had fewer than two dose-limiting toxicities in its respective cohort
To define the clinical benefit rate (CBR = CR \[complete response\] + PR \[partial response\] + SD \[stable disease\] \> 6 months) of ibrutinib plus trastuzumab in patients with HER2-amplified, T-DM1-pretreated MBC
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study.
A DLT is any Grade 3 or higher non-hematologic adverse event (AE) with exceptions outlined in the protocol.
Venetoclax RPTD is the dose determined based on adverse event reporting and dose-limiting toxicity information from all participants.
To determine the maximum tolerated dose (MTD) of venetoclax in combination with chemotherapy in patients with newly diagnosed Acute Lymphoblastic Leukemia (ALL)
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine
Maximum plasma concentration (Cmax) of azacitidine
Time to Cmax (peak time, Tmax) for venetoclax
Area under the plasma concentration-time curve from Time 0 to infinite time.
Time to Cmax (peak time, Tmax) for azacitidine
AUC over a 24-hour dose interval (AUC\[0-24\]) for venetoclax
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax
Terminal elimination half-life (t\[1/2\]) for azacitidine
The RPTD of venetoclax \[co-administered venetoclax and azacitidine\] will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data \[upon completion of the dose escalation phase\].
AUC over a 24-hour dose interval (AUC\[0-24\]) for venetoclax.
Complete remission rate will be defined as the proportion of participants who achieved a complete response per the International Working Group (IWG) 2006 criteria for Myelodysplastic Syndromes (MDS).
If a maximum tolerated dose (MTD) is reached, the RPTD of budigalimab will not be a dose higher than the defined MTD, and will be selected based on the type(s) and occurrence(s) of dose limiting toxicities which occur in addition to the MTD. If a MTD is not reached, then the RPTD will be defined based on the safety and other available data.
MTD will be defined at the highest dose level at which less than 2 of 6 subjects or less than 33% of (if cohort is expanded beyond 6) participants experience a dose limiting toxicity.
Terminal phase elimination half-life (t1/2) of Budigalimab
Maximum Serum Concentration (Cmax) of Budigalimab
Time to maximum plasma concentration of Budigalimab
Area Under the Plasma Concentration-time Curve from time 0 to last measurable concentration (AUCt) of Budigalimab
The safety and tolerability of a single dose of Budigalimab in combination with Rovalpituzumab Tesirine will be assessed in patients with advanced small cell lung cancer (SCLC) to determine the RPTD and schedule for the combination.
The safety and tolerability of Budigalimab in combination with venetoclax will be assessed in patients with metastatic Non-Small Cell Lung Cancer (NSCLC) to determine the RPTD for the combination.
Maximum Serum Concentration (Cmax) for Venetoclax
Area Under the Plasma Concentration-time Curve from time 0 to time 0 to 24 hours post-dose (AUC(0-24)) of Venetoclax
Time to maximum plasma concentration of of Venetoclax
An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
A DLT was defined as any Grade 3 (severe) or higher non-hematologic or Grade 4 (life-threatening) hematologic adverse event (AE) occurring during the DLT observation period that was considered to be at least possibly related to the study treatment (ibrutinib or drug combination).
PFS is defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease (PD) or date of death from any cause, whichever occurs first, regardless of the use of subsequent anti-cancer treatment. PD was defined in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.
ORR is defined as the percentage of participants who have a best response of partial response (PR) or complete response (CR) to therapy in accordance with RECIST 1.1 criteria. CR: The disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Normalization of tumor marker level, if relevant. All lymph nodes must be non-pathological in size (\< 10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
The response criteria is measured based on the revised criteria for malignant lymphoma described by the International Working Group for NHL (Cheson 2014).
Dose-limiting toxicities (DLTs) were determined during cycle 1 of the dose-escalation phase and defined as Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 grade 4 (life threatening requiring urgent intervention) or 5 (resulted in death) toxicity, excluding adverse events commonly caused by AML (eg, neutropenia, fever). Hematologic DLT was defined as failure of platelet recovery to 25 × 10\^9/L or greater and absolute neutrophil count (ANC) to 0.5 × 10\^9/L or greater within 14 days of the last dose of venetoclax in the absence of residual AML.
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
The time at which the maximum plasma concentration (Cmax) is observed.
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
The time at which the maximum plasma concentration (Cmax) is observed.
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator rated the severity of each AE according to the CTCAE Version 4.0 and the following: Grade 1: The AE is transient and easily tolerated (mild). Grade 2: The AE causes discomfort and interrupts usual activities (moderate). Grade 3: The AE causes considerable interference with usual activities and may be incapacitating (moderate to severe). Grade 4: The AE is life threatening requiring urgent intervention. Grade 5: The AE resulted in death. The investigator assessed each event as either having a reasonable possibility or no reasonable possibility of being related to the use of study drug. Treatment-emergent events are defined as events that began or worsened in severity after the first dose of study drug.
Collect all adverse events at each visit
The proportion of participants with response (e.g., partial, complete response) using IWCLL (International Workshop on Chronic Lymphocytic Leukemia) criteria for CLL participants will be computed for all participants with active disease at baseline (in the opinion of the investigator).
Number of participants with dose-limiting toxicities as a measure of safety profile to determine recommended dose of ibrutinib
Overall Response Rate is defined as the proportion of subjects who achieved complete response (CR) or partial response (PR). Response criteria are based on NIH cGVHD Response assessment (Pavletic 2006; Measurement of Therapeutic Response, ASBMT Web site).
Part-1: To determine the maximum tolerated dose (MTD) of the combination of ibrutinib and lenalidomide with dose adjusted EPOCH-R
Part 2 - Overall Response rate will be defined as the proportion of subjects who achieve either a Complete Response or a Partial Response according to the international Working Group Response Criteria for NHL as assessed by investigator.
MTD is defined as the highest dose Level at which =\< 1 of 6 patients experienced a DLT.
The dose levels of lenalidomide were explored, and dose escalation of lenalidomide followed the 3+3+3 dose escalation schema. A Dose Level Review Committee evaluated safety data following completion of each dose observation period of the Phase 1b portion.
An adverse event (AE) is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A serious AE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization \> 24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. AEs that started or worsened during the treatment-emergent period and all possibly related or related AEs were considered TEAEs. Related events were those that were considered possibly related or related to study drug per investigator's judgment. Events were graded per the national Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03: Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life-threatening; grade 5=death.
The ORR was defined as the percentage of participants who achieve either a partial response (PR) or complete response (CR), according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (Cheson 2014), as assessed by the investigator in response-evaluable population. The 95% confidence interval (CI) was calculated using the exact method.
DLTs in this study were defined as specific adverse events (AEs) occurring during the DLT observation window: 1) Grade 4 neutropenia not responsive to granulocyte colony stimulating factors (G-CSF) lasting more than 14 days; 2) Grade 3 or 4 febrile neutropenia with fever lasting longer than 4 days; 3) Grade 4 thrombocytopenia resulting in bleeding, or that did not improve to Grade \</=2 within 3 weeks; 4) Clinical tumor lysis syndrome (TLS) defined by the presence of laboratory TLS and one or more clinical manifestations related to the electrolyte abnormalities; 5) Grade 4 infusion-related reactions (IRRs) secondary to rituximab or obinutuzumab despite appropriate premedication and administration rate; 6) All other Grades 3, 4, or 5 AEs persisting for more than 2 weeks with or without treatment with some exceptions.
Overall response rate is defined as the percentage of participants with documented best overall response of Partial Response (PR) or better (PR, Very good partial response \[VGPR\], Complete response \[CR\], or Stringent complete response \[sCR\]) per 2016 standard International Myeloma Working Group (IMWG) criteria.
The percentage of participants with documented best overall response of Very Good Partial Response (VGPR) or better (VGPR, Complete response \[CR\], or Stringent complete response \[sCR\]) per 2016 standard International Myeloma Working Group (IMWG) criteria was computed.
Number of dose-limiting toxicities observed in the first 6 participants enrolled in treatment Groups 1 and 2
Number of participants who had experienced at least one treatment emergent AEs.
| Arm | Type | Description |
|---|---|---|
| Standard chemoimmunotherapy (SCIT) | ACTIVE_COMPARATOR | Patients up to age 65: 6 cycles (q28d) of Fludarabine + Cyclophosphamide + Rituximab (FCR) Patients older than 65 years: 6 cycles (q28d) of Bendamustine + Rituximab (BR) |
| Rituximab + Venetoclax (RVe) | EXPERIMENTAL | 6 cycles (q28d) of RVe + 6 cycles (q28d) of Venetoclax (alone) |
| Obinutuzumab + Venetoclax (GVe) | EXPERIMENTAL | 6 cycles (q28d) of GVe + 6 cycles (q28d) of Venetoclax (alone) |
| Obinutuzumab + Ibrutinib + Venetoclax (GIVe) | EXPERIMENTAL | 6 cycles (q28d) of GIVe + 6 cycles (q28d) of Ibrutinib plus Venetoclax. Administration of ibrutinib will be continued for a maximum of 36 months or until MRD negativity, start of new anti-CLL therapy or inacceptable toxicity, whatever occurs first. |
| Arm A: Control Arm without Venetoclax | ACTIVE_COMPARATOR | During Cycle 1 (42-day-cycles), participants will receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 1-5. Gemtuzumab 3 mg/m\^2 will be given on Day 6 (only for participants with CD33 expression on leukemia blasts). During Cycle 2 participants will receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 1-5. After Cycle 2 participants are assessed for HSCT or azacitidine maintenance therapy. |
| Arm B: Experimental Arm with Venetoclax | EXPERIMENTAL | During Cycle 1 (42-day-cycles), participants will receive 300 mg adult dose equivalent of venetoclax once on Day 1 followed by 600 mg adult dose equivalent of venetoclax on Days 2-21. Participants will also receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 8-12. Gemtuzumab 3 mg/m\^2 will be given on Day 13 (only for participants with CD33 expression on leukemia blasts). During Cycle 2, participants will receive 600 mg adult dose equivalent of venetoclax on Days 1-21. Participants will receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 1-5. After Cycle 2 participants are assessed for HSCT or azacitidine maintenance therapy in combination with venetoclax. |
| Arm A: Venetoclax + Obinutuzumab | EXPERIMENTAL | Participants will receive venetoclax in combination with obinutuzumab, with a 5 week venetoclax ramp up. |
| Arm B: Venetoclax + Acalabrutinib | EXPERIMENTAL | Participants will receive venetoclax in combination with acalabrutinib, with a 5 week venetoclax ramp up. |
| Arm C: Venetoclax + Acalabrutinib | EXPERIMENTAL | Participants will receive venetoclax in combination with acalabrutinib, with a modified venetoclax ramp up A. |
| Arm D: Venetoclax + Acalabrutinib | EXPERIMENTAL | Participants will receive venetoclax in combination with acalabrutinib, with a modified venetoclax ramp up B. |
| I (Ibrutinib) | EXPERIMENTAL | Ibrutinib p.o. will be administered until occurrence of unacceptable toxicity, progression of CLL or end of trial, whichever occurs first. |
| VG (Obinutuzumab + Venetoclax) | EXPERIMENTAL | 12 cycles (q 28d): Obinutuzumab i.v. + Venetoclax p.o. will be administered for 6 cycles, followed by 6 additional cycles of Venetoclax alone |
| VI (Venetoclax + Ibrutinib) | EXPERIMENTAL | 15 cycles (q 28d): Ibrutinib p.o. + Venetoclax p.o. will be administered for a total of 12 cycles with a prior Ibrutinib monotherapy lead-in of 3 cycles |
| Venetoclax + Low-Dose Cytarabine (LDAC) | EXPERIMENTAL | Participants will receive venetoclax once daily (QD) on days 1 through 28 plus LDAC QD on days 1 through 10 during the 28-day treatment cycles. |
| Arm 1: Venetoclax + Azacitidine (AZA) | EXPERIMENTAL | Participants will receive venetoclax once daily (QD) (Days 1-14) in combination with AZA QD (7 days of the first 9 days) of each 28 day cycle. |
| Arm 2: Placebo + Azacitidine | ACTIVE_COMPARATOR | Participants will receive placebo once daily (QD) (Days 1-14) in combination with AZA QD (7 days of the first 9 days) of each 28 day cycle. |
| Part 1: Dose Confirmation | EXPERIMENTAL | Participants will receive venetoclax once daily (QD) (Days 1-28) for up to 24 cycles, azacitidine (AZA) QD on Days 1-5 of each 28 day cycle for up to 6 cycles. |
| Part 3 (Dose Finding): Dose Escalation | EXPERIMENTAL | Participants will receive venetoclax QD for up to 24 cycles, AZA QD on Days 1 to 14 of each 28-day cycle for up to 24 cycles to determine recommended phase 3 dose (RPTD). |
| Part 3 (Dose Finding): Safety Expansion | EXPERIMENTAL | Participants will receive venetoclax QD for up to 24 cycles, AZA QD on Days 1 to 14 of each 28-day cycle for up to 24 cycles at the RPTD. |
| Ibrutinib/Rituximab | EXPERIMENTAL | All subjects meeting eligibility criteria will receive rituximab: 375 mg/m\^2 on days 1, 8, 15 and 22 on cycle 1. |
| Ibrutinib/Placebo | PLACEBO_COMPARATOR | Ibrutinib capsules (140 mg each) will be dosed at 560 mg once daily on a 28-day cycle on a continuous basis. Placebo capsules will be similarly dosed at 4 capsules daily. |
| Venetoclax | EXPERIMENTAL | Venetoclax at the same dose administered to each subject during the previous study in which they were enrolled. |
| Venetoclax 400 mg + azacitidine 75 mg | EXPERIMENTAL | Participants received venetoclax orally daily for 28-day cycles, for a maximum of 6 cycles, beginning on Cycle 1 Day 1. The venetoclax dosing ramp-up schedule was 100 mg on Cycle 1 Day 1, 200 mg on Cycle 1 Day 2, and 400 mg on Cycle 1 Days 3 -28 and 400 mg daily for each 28-day cycle thereafter. Azacitidine (75 mg/m\^2) was administered subcutaneously or intravenously per investigator's choice and institutional practice for 7 days beginning on Day 1 of each 28-day cycle. |
| Venetoclax 400 mg + decitabine 20 mg | EXPERIMENTAL | Participants received venetoclax orally daily for 28-day cycles, for a maximum of 6 cycles, beginning on Cycle 1 Day 1. The venetoclax dosing ramp-up schedule was 100 mg on Cycle 1 Day 1, 200 mg on Cycle 1 Day 2, and 400 mg on Cycle 1 Days 3 -28 and 400 mg daily for each 28-day cycle thereafter. Decitabine (20 mg/m\^2) was administered intravenously per investigator's choice and institutional practice for 5 days beginning on Day 1 of each cycle. |
| Arm 1 VenDex | EXPERIMENTAL | Venetoclax administered orally once daily (QD) plus dexamethasone administered orally once every week (Q1W) for each 28-day cycle. |
| Arm 2 PomDex | ACTIVE_COMPARATOR | Pomalidomide administered orally once daily (QD) on Days 1 - 21 for each 28-day cycle plus dexamethasone administered orally once every week (Q1W) for each 28-day cycle. |
| Obinutuzumab | EXPERIMENTAL | Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. |
| Obinutuzumab/bendamustine | EXPERIMENTAL | Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m\^2 ) was to be administered to those with nodes or nodal mass \> 10 cm, or with del(11q) and \> 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. |
| Safety Run-in | EXPERIMENTAL | Participants with a low or high risk of TLS enroll into the open-label Safety Run-in Period to receive concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramp up to a target dose of 400 mg once daily over a 5-week period. |
| Randomization Phase: Ibrutinb + Venetoclax | EXPERIMENTAL | Participants randomized to ibrutinib and venetoclax for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax is discontinued after 104 weeks of treatment, regardless of response assessment. |
| Randomization Phase: Ibrutinib + Placebo | PLACEBO_COMPARATOR | Participants randomized to ibrutinib and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo is discontinued after 104 weeks of treatment, regardless of response assessment. |
| Treatment-naive Open-label Arm | EXPERIMENTAL | Participants are treated with ibrutinib 560 mg and venetoclax 400 mg, administered using the 5-week ramp-up schedule. |
| Venetoclax + Low Dose Cytarabine (LDAC) | EXPERIMENTAL | Venetoclax 600 mg orally every day (QD) plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle. |
| Placebo + LDAC | PLACEBO_COMPARATOR | Matching placebo to venetoclax orally QD plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle. |
| Ibrutinib + Prednisone | EXPERIMENTAL | Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for cytochrome P450 \[CYP\] inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses. |
| Placebo + Prednisone | PLACEBO_COMPARATOR | Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses. |
| Group 1 and Group 2: Placebo + Azacitidine 75 mg/m^2 | PLACEBO_COMPARATOR | Participants enrolled under original protocol and enrolled during or after protocol amendment 1 received venetoclax-matching placebo, orally, every day (QD), from Day 1 to Day 28 of each 28 day cycle along with azacitidine 75 mg/m\^2, subcutaneously (SC) or intravenously (IV), QD for 7 days from Day 1 of each 28-day cycle until documented disease progression, unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation (whichever occurred first). |
| Group 1 and Group 2: Venetoclax 100 mg/200 mg/400 mg + Azacitidine 75 mg/m^2 | ACTIVE_COMPARATOR | Participants enrolled under original protocol and enrolled during or after protocol amendment 1 received venetoclax 100 mg, once orally, on Day 1 of Cycle 1 followed by venetoclax 200 mg, once orally, on Day 2 of Cycle 1 and venetoclax 400 mg, orally, QD, on Day 3 to Day 28 of each 28 day cycle along with azacitidine 75 mg/m\^2, SC or IV, QD for 7 days from Day 1 of each 28-day cycle until documented disease progression, unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation (whichever occurred first). |
| Open Label China Cohort: Venetoclax 400 mg + Azacitidine 75 mg/m^2 | ACTIVE_COMPARATOR | Participants received venetoclax 400 mg, orally, QD, from Day 1 to Day 28 of each 28 day cycle along with azacitidine 75 mg/m\^2, SC, QD for 7 days from Day 1 of each 28-day cycle until documented disease progression, unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation (whichever occurred first). |
| (Arm A) ibrutinib + rituximab | EXPERIMENTAL | Participants to receive 560mg of ibrutinib once daily and rituximab 375mg/m\^2 weekly x4 with maintenance. |
| (Arm B) placebo + rituximab | PLACEBO_COMPARATOR | Participants to receive placebo once daily and rituximab 375mg/m\^2 weekly x4 with maintenance. |
| Venetoclax + Bortezomib and Dexamethasone | EXPERIMENTAL | Cycles 1-8: Venetoclax 800 mg orally every day (QD) on Days 1 - 21 plus bortezomib 1.3 mg/m\^2 subcutaneously or IV on Days 1, 4, 8 \& 11 and dexamethasone 20 mg orally on Days 1, 2, 4, 5, 8, 9, 11 \& 12; Cycles 9 and beyond: Venetoclax 800 mg orally every day (QD) on Days 1 - 35 plus bortezomib 1.3 mg/m\^2 subcutaneously or IV on Days 1, 8, 15 and 22 and dexamethasone 20 mg orally on Days 1, 2, 8, 9, 15, 16, 22 and 23 |
| Placebo + Bortezomib and Dexamethasone | PLACEBO_COMPARATOR | Cycles 1-8: Placebo (to match venetoclax 100 mg tablet) 800 mg orally every day (QD) on Days 1 - 21 plus bortezomib 1.3 mg/m\^2 subcutaneously or IV on Days 1, 4, 8 \& 11 and dexamethasone 20 mg orally on Days 1, 2, 4, 5, 8, 9, 11 \& 12; Cycles 9 and beyond: Placebo (to match venetoclax 100 mg tablet) 800 mg orally every day (QD) on Days 1 - 35 plus bortezomib 1.3 mg/m\^2 subcutaneously or IV on Days 1, 8, 15 and 22 and dexamethasone 20 mg orally on Days 1, 2, 8, 9, 15, 16, 22 \& 23 |
| Ibrutinib | ACTIVE_COMPARATOR | Ibrutinib daily in combination with: Nab-paclitaxel and gemcitabine |
| Placebo | PLACEBO_COMPARATOR | Placebo daily in combination with: Nab-paclitaxel and gemcitabine |
| Safety Run-in Obinutuzumab + Venetoclax | EXPERIMENTAL | Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days. |
| Obinutuzumab + Chlorambucil | EXPERIMENTAL | Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days. |
| Obinutuzumab + Venetoclax | EXPERIMENTAL | Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days. |
| IBR + OB | EXPERIMENTAL | Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity. |
| CLB + OB | EXPERIMENTAL | Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity. |
| Randomized Study (Ibrutinib + Rituximab) | EXPERIMENTAL | Ibrutinib: 420 mg (3 capsules x 140 mg) orally administered daily beginning from Day 1. Rituximab: 375 mg/m\^2 intravenous (IV) per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval. |
| Randomized Study (Placebo + Rituximab) | EXPERIMENTAL | Placebo: 3 capsules of placebo orally administered daily beginning from Day 1. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval. |
| Open-Label Substudy (Ibrutinib) | EXPERIMENTAL | Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1. |
| Chlorambucil | EXPERIMENTAL | Participants who received chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) Days 1 and 15 of 28-day cycle up to 12 cycles in Study 1115. In Study 1116, participants had the option to crossover to next-line ibrutinib 420 mg/day after disease progression (PD). |
| Ofatumumab (Arm A) | ACTIVE_COMPARATOR | An anti-CD20 monoclonal antibody |
| ibrutinib (Arm B) | EXPERIMENTAL | A Bruton Tyrosine Kinase Inhibitor |
| Azacitidine and Venetoclax | EXPERIMENTAL | Azacitidine will be given intravenously for 7 days. Venetoclax will be given orally. The patient will start out with 100mg and progress to 600mg. Once 600mg is reached, the patient will stay at this dose until the 28 day cycle is finished. |
| Treatment (azacitidine, decitabine, venetoclax) | EXPERIMENTAL | Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7 (for patients with prior decitabine use), or decitabine IV on days 1-5 (for patients with prior azacitidine), and venetoclax PO daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| FCR | ACTIVE_COMPARATOR | FCR : * rituximab (R): 375 mg/m² IV D1 cycle 1 and 500 mg/m² IV D1 cycles 2 to 6. * fludarabine (F): 40 mg/m² orally, D2 to D4 - cycles 1 to 6. * cyclophosphamide (C): 250 mg/m² orally, D2 to D4 - cycles 1 to 6. |
| venetoclax and ibrutinib (I+VEN) | EXPERIMENTAL | * ibrutinib: 420 mg/d orally, continuously from Month 1 to the end of treatment, either Month 15 or Month 27 * venetoclax: stepwise weekly dose ramp-up beginning at Month 4 from a starting dose of 20 mg/d to the final dose of 400 mg/d (20, 50, 100, 200 and then 400 mg) over a 5 weeks, and then 400 mg/d continuously from Month 5 to the end of treatment, either Month 15 or Month 27. |
| Venetoclax / Rituximab | EXPERIMENTAL | Cycle 1 (28-days cycle) Stepwise dose escalation of Venetoclax in all patients with a target dose of xy mg/d QD PO. Day 1-7: Venetoclax xy mg/d QD PO Day 8-14: Venetoclax xy mg/d QD PO Day 15-28: Venetoclax xy mg/d QD PO Cycle 2-12: Day 1: Rituximab 375 mg/m2 IV Day 1-28: Venetoclax xy mg/d QD PO |
| Dexamethasone / Rituximab / Cyclophosphamide | ACTIVE_COMPARATOR | Cycle 1-6: Day 1: Dexamethasone 20 mg PO Day 1: Rituximab 375 mg/m2 IV Day 1-5: Cyclophosphamide 100 mg/m2 BID PO |
| Treatment (venetoclax, cladribine, cytarabine, azacitidine) | EXPERIMENTAL | See Detailed Description |
| Cohort I (SOC zanubrutinib, venetoclax) | EXPERIMENTAL | Patients receive SOC zanubrutinib PO QD or BID per physician discretion on days 1-28 of each cycle. Starting with cycle 4, patients also receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 15 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, bone marrow biopsy and aspiration, and CT or MRI throughout the study. |
| Cohort II (SOC zanubrutinib, venetoclax) | EXPERIMENTAL | Patients receive SOC zanubrutinib PO QD or BID per physician discretion on days 1-28 of each cycle. Starting with cycle 4, patients also receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, bone marrow biopsy and aspiration, and CT or MRI throughout the study. |
| Venetoclax Monotherapy | EXPERIMENTAL | Participants will receive venetoclax at doses ramping up to the target dose, as part of the approximately 28 month study duration. |
| Rituximab + Venetoclax | EXPERIMENTAL | 33 participants will be enrolled and will complete study procedures as follows: * Baseline visit with screening assessments, scans, and tumor and bone marrow biopsies. * Induction Period: * CT/MRI scans at week 4. * Weeks 1 - 4: Predetermined dose of Rituximab 1x weekly. * Weeks 5 - 8: Predetermined dose of Venetoclax 1x daily. * Maintenance Period: * CT/MRI scan on weeks 12, 36, 60, 84, and then every 6 months after week 96. * Predetermined dose of Venetoclax 1x daily for up to week 96, then once every 6 months. * Predetermined dose of Rituximab 1x weekly at weeks 12, 24, 36, and 48. * End of Treatment Visit: CT/MRI scan, tumor biopsy, and bone marrow biopsy. * Follow up: In-clinic visit at 1 year after finishing study drugs. |
| Single interventional arm | EXPERIMENTAL | For each 28 days-cycle of treatment : * venetoclax 400mg/day orally after a ramp-up period of 3-days * tagraxofusp starting at the end of the venetoclax ramp-up period i.e. at day 4 for twelve 28-days cycles, 12 μg/kg body weight administered as an intravenous infusion over 15 minutes, once daily, on days 1-3 of each cycle |
| CLL/SLL patients on ibrutinib monotherapy for ≥ 6 months | EXPERIMENTAL | - |
| CLL/SLL patients on zanubrutinib monotherapy for ≥ 6 months | EXPERIMENTAL | - |
| CLL/SLL patients on acalabrutinib monotherapy for ≥ 6 months | EXPERIMENTAL | - |
| CLL/SLL patients on orelabrutinib monotherapy for ≥ 6 months | EXPERIMENTAL | - |
| Azacidine+Venetoclax | EXPERIMENTAL | Azacitidine will be administered subcutaneously at the standard dose of 75 mg/m²/d either on days 1-7 or using a 5-2-2 schedule of the 28 day-cycles. Patiens will be exposed to Venetoclax during the first 7 or 14 days of the 28 day-cycles (number of days of Venetoclax determined during the safety run-in phase). At cycle 1, Venetoclax will be given orally with 3-day ramp-up, at 100 mg on day 1, 200 mg on day 2 and 400 mg on days 3 to 7 or 14 of the cycle. At all subsequent cycles, Venetoclax will be given orally at 400 mg on days 1 to 7 or 14 of the cycle. Treatment duration will be 24 months. |
| VEN+AZA-5 | EXPERIMENTAL | Azacitidine (AZA) 75 mg/m2, d1-5 of each 28 day cycle (SC) in combination with Venetoclax (VEN): 400 mg daily (orally) |
| Cohort 1 - venetoclax + obinutuzumab | EXPERIMENTAL | Participants will receive venetoclax + obinutuzumab for six 28-day cycles followed by venetoclax for six 28-day cycles. |
| Cohort 2 - venetoclax + obinutuzumab | EXPERIMENTAL | Participants will receive venetoclax + obinutuzumab for six 28-day cycles followed by venetoclax for eighteen 28-day cycles. |
| Venetoclax + Obinutuzumab (V+G) | EXPERIMENTAL | Participants will receive venetoclax + obinutuzumab for twelve 28-day cycles. |
| Venetoclax + Ibrutinib (V+I) | EXPERIMENTAL | Participants will receive venetoclax + ibrutinib for fifteen 28-day cycles. |
| Ibrutinib + Venetoclax | EXPERIMENTAL | Participants will receive Ibrutinib Dose A + Venetoclax in various doses until a target dose is reached, for up to 104 weeks, followed by Ibrutinib monotherapy. |
| Ibrutinib and Venetoclax | EXPERIMENTAL | The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. * Ibrutinib will be administered at a predetermined dose, once daily for 28 days * TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment) * Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up during cycle 2. |
| Ibrutinib 420 mg + SOC | EXPERIMENTAL | 420 mg ibrutinib administered once daily as three hard gelatin capsules (140 mg each) with approximately 240 mL of water for up to 28 days and supportive care (standard-of-care, SOC) |
| Placebo + SOC | PLACEBO_COMPARATOR | Three hard gelatin placebo capsules administered once daily with approximately 240 mL of water for up to 28 days and supportive care (standard-of-care, SOC) |
| Venetoclax + Ibrutinib | EXPERIMENTAL | Participants received 400 mg venetoclax orally once a day after a 5-day ramp-up and 420 mg ibrutinib orally once a day for up to 2 years or until progressive disease, intolerability, or they became eligible for stem cell transplantation after achieving complete remission. |
| Arm A, Part 1a: VenDd Dose Escalation | EXPERIMENTAL | Venetoclax (Ven) various doses administered orally, once daily (QD) in combination with daratumumab (D) (1800 mg subcutaneous injection (preferred) or 16 mg/kg intravenous \[IV\]) administered in accordance with prescribing information and dexamethasone (d) (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol). |
| Arm B, Part 1b: VenDd Dose Expansion | EXPERIMENTAL | Venetoclax at a dose determined by the dose-escalation phase, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol). |
| Arm D, Part 2a: VenDVd Dose Escalation | EXPERIMENTAL | Venetoclax at various doses administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection \[preferred\] or IV) Cycles 1-8, Days 1, 4, 8 and 11), and dexamethasone (oral or IV) 20 mg Cycles 1 - 3, Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 20 mg Cycles 4-8, Days 1,2,4,5,8,9,11 and 12; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) Cycle 9+. |
| Arm E, Part 2b: VenDVd Dose Expansion | EXPERIMENTAL | Venetoclax at dose determined by the dose-escalation phase, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection) Cycles 1-8, Days 1, 4, 8 and 11, and dexamethasone (oral or IV) 20 mg Cycles 1 - 3, Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 20 mg Cycles 4-8, Days 1,2,4,5,8,9,11 and 12; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) Cycle 9+. |
| Arm F: VenDd Dose Expansion | EXPERIMENTAL | Venetoclax at a pre-determined dose, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol). |
| Arm G: VenDd Dose Expansion | EXPERIMENTAL | Venetoclax at a pre-determined dose, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol). |
| Arm H: DVd Dose | ACTIVE_COMPARATOR | Daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection) Cycles 1-8: Days 1, 4, 8 and 11, and dexamethasone (oral or IV) 20 mg on Cycles 1 - 3: Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) on Cycles 4-8: Days 1,2,4,5,8,9,11 and 12; 20 mg monthly for Cycles 9+: Day 1 |
| Treatment (ibrutinib, obinutuzumab) | EXPERIMENTAL | Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive obinutuzumab intravenously (IV) on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Beginning 2 months after cycle 6, patients with stable disease will continue to receive obinutuzumab every 2 months for a total of 12 doses. After completion of study treatment, patients are followed up monthly for 1 year, every 3-6 months for 4 years, and then annually for up to 2 years. |
| Cohort 1: Venetoclax | EXPERIMENTAL | Participants with 17p deletion status will receive various doses of venetoclax once daily (QD). |
| Cohort 2: Venetoclax | EXPERIMENTAL | Participants who have failed a B-Cell Receptor Signaling Pathway Inhibitor (BCRI) therapy and who have also failed, or were unable to receive chemoimmunotherapy (CIT) irrespective of 17p status will receive various doses of venetoclax once daily (QD). |
| Treatment (ibrutinib, blinatumomab) | EXPERIMENTAL | INDUCTION THERAPY: Patients receive ibrutinib PO QD on days 1-49 of course 1 and days 1-42 of course 2, and blinatumomab IV on days 8-35 of course 1 and days 1-28 of course 2 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: Patients with CR/CRi after Induction Therapy receive ibrutinib PO QD on days 1-42 and blinatumomab IV on days 1-28. Treatment repeats every 42 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Venetoclax + Carfilzomib + Dexamethasone | EXPERIMENTAL | Part 1: Evaluate the safety and pharmacokinetic profiles while providing information to determine the appropriate doses of venetoclax and carfilzomib (VenKd) to be used in the VenKd combination in approximately 18 participants. The dose levels are Venetoclax 400 mg or 800 mg; Carfilzomib 20/27 mg/m2, 20/70 mg/m2, and/or 20/56 mg/m2; Dexamethasone 40 mg Part 2: Further evaluate the safety and efficacy profile of the VenKd combination selected after completion of Part 1 in approximately 22 additional participants. Participants may discontinue Kd but may continue receiving venetoclax once daily (QD) as monotherapy. Part 3: Further evaluation of the efficacy of the VenKd combination after completion of Part 1 and Part 2 in 7 additional participants. Part 4, An additional 65 participants t(11;14) positive will receive varying doses of the VenKd combination or carfilzomib and dexamethasone |
| Fixed Duration (FD) Cohort: Open Label Ibrutinib + Venetoclax | EXPERIMENTAL | Participants receive 420 mg of single-agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until disease progression or unacceptable toxicity. |
| MRD Cohort/Confirmed Undetectable MRD (uMRD): Randomized to Ibrutinib (Blinded) | EXPERIMENTAL | Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD are randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, disease progression (PD), or unacceptable toxicity. After MRD-positive relapse or disease progression (PD) by iwCLL criteria, participants can reintroduce 400 mg venetoclax with a 5-week ramp up. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. |
| MRD Cohort/Confirmed uMRD: Randomized Placebo (Blinded) | PLACEBO_COMPARATOR | Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD are randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity. If MRD-positive relapse or PD is confirmed after restaging per iwCLL criteria, participants can first reintroduce oral daily ibrutinib with the option of subsequently reintroducing 400 mg venetoclax with a 5-week ramp up, if subsequent disease relapse per iwCLL criteria occurs after ibrutinib reintroduction. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. |
| MRD Cohort/uMRD Not Confirmed: Randomized to Ibrutinib (Open-Label) | EXPERIMENTAL | Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. In case of confirmed PD after restaging per iwCLL criteria, participants can continue ibrutinib and reintroduce venetoclax treatment. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. |
| MRD Cohort/uMRD Not Confirmed: Randomized Ibrutinib + Venetoclax (Open-Label) | EXPERIMENTAL | Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase. |
| Ibrutinib+ Bortezomib+ Dexamethasone | EXPERIMENTAL | - |
| Obinutuzumab, Ibrutinib, Venetoclax | EXPERIMENTAL | Obinutuzumab i.v.: Cycle 1 (3000 mg), Cycle 2-6 (1000 mg) Ibrutinib (tablet): Cycle 1-15 (420 mg daily) Venetoclax (tablet): Cycle 1 (last 7 days 20 mg daily), Cycle 2 (ramp up 50 mg to 400 mg) Cycle 3-12 (400 mg daily) |
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | EXPERIMENTAL | Participants will receive venetoclax no more than 600 milligrams (mg) orally once daily continuously along with rituximab 375 milligrams per square meter (mg/m\^2) intravenous (IV) infusion on Day 1 of 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of the 28-day cycle. Safety run-in will continue until first 9 participants complete the safety observation window of 28 days. Participants will continue receiving the same treatment as decided for Arm B. |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | EXPERIMENTAL | Participants will receive venetoclax 800 mg orally once daily for 1 year along with rituximab 375 mg/m\^2 IV infusion on Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 4, 6, 8, 10, and 12. Each cycle will be of 28 days. |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | EXPERIMENTAL | Participants will receive venetoclax at doses decided from safety run-in orally once daily continuously for 1 year along with rituximab 375 mg/m\^2 IV infusion on Day 1 of each 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles. |
| Chemotherapy-Containing Cohort: Arm C (BR) | ACTIVE_COMPARATOR | Participants will receive rituximab 375 mg/m\^2 IV infusion on Day 1 of each 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles. |
| ABT-199 after ibrutinib therapy | EXPERIMENTAL | Participants with ibrutinib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 593 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. |
| ABT-199 after idelalisib therapy | EXPERIMENTAL | Participants with idelalisib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 1023 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. |
| ABT-199 after ibrutinib therapy: Expansion Cohort | EXPERIMENTAL | Participants with ibrutinib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 622 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants enrolled into the Expansion Cohort with bulky disease at study entry who were non-responders or those who showed signs of clinical progression after completing the ramp up to 400 mg either by clinical disease assessment or by CT/MRI scan between Week 6 to Week 12 may have been permitted to escalate venetoclax to a daily dose of 600 mg. |
| ABT-199 after idelalisib therapy: Expansion Cohort | EXPERIMENTAL | Participants with idelalisib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 1189 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants enrolled into the Expansion Cohort with bulky disease at study entry who were non-responders or those who showed signs of clinical progression after completing the ramp up to 400 mg either by clinical disease assessment or by CT/MRI scan between Week 6 to Week 12 may have been permitted to escalate venetoclax to a daily dose of 600 mg. |
| Main Study Arm 1 | EXPERIMENTAL | Subjects enrolled into this arm will receive ibrutinib continuously until disease progression or unacceptable toxicity. In addition, subjects will receive rituximab once weekly for four doses for the first four weeks of study treatment. |
| Exploratory Study Arm 2 | EXPERIMENTAL | Subjects enrolled into this arm will receive ibrutinib continuously as a single agent for the first eight weeks, then ibrutinib concurrently with rituximab once weekly for four doses. After the rituximab treatment, subjects will receive ibrutinib continuously until disease progression or unacceptable toxicity. |
| Cohort 1 | EXPERIMENTAL | PCI-32765 420 mg per day |
| Cohort 2 | EXPERIMENTAL | PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week |
| Cohort 3 | EXPERIMENTAL | PCI-32765 840 mg per day |
| Cohort 4 | EXPERIMENTAL | PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week |
| PCI-32765: 560 mg | EXPERIMENTAL | Treatment Group 1: Subjects received 560 mg of ibrutinib once daily, on a continuous basis. |
| PCI-32765: 840 mg | EXPERIMENTAL | Treatment Group 2: Subjects received 840 mg of ibrutinib once daily, on a continuous basis. |
| Participants received PCI-32765 560 mg daily | EXPERIMENTAL | Participants were enrolled and received 560 mg/day dose, stratified into 2 groups based on prior bortezomib exposure. |
| PCI-32765 | EXPERIMENTAL | - |
| venetoclax + azacitidine +/- donor lymphocyte infusion | EXPERIMENTAL | Venetoclax + azacitidine +/- donor lymphocyte infusion (maximum 12 cycles). Venetoclax: on D1 to D14 of 28 days cycle ; Phase I: 4 dose levels: 50, 100, 200, 400 mg/d, starting dose at 100 mg ; Phase II: dose defined in the phase I. Azacitidine 75 mg/m²/d or 50 mg/m²/d (if allohematopoietic stem cell transplantation relapse \< 4 months) x 5 days (on D1 to D5 of 28 days cycle). |
| Cohort A | EXPERIMENTAL | For Part 1, participants will receive: * Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 14-20 people will participate in Part 2 (Dose Expansion) of this cohort Treatment cycle is approximately 28 days for up to 4 cycles * Venetoclax-once daily on predetermined days per protocol * Azacitidine-once daily on predetermined days per protocol * Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician |
| Cohort B | EXPERIMENTAL | Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) with an underlying genetic condition that increases their risk for developing treatment-related toxicities. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 6 people will participate in Part 2 (Dose Expansion) of this cohort. * Venetoclax-once daily on predetermined days per protocol * Azacitidine-once daily on predetermined days per protocol * Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician |
| Cohort C | EXPERIMENTAL | Patients with relapsed/refractory acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL) or acute leuekmai of ambiguous lineage. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 12 people will participate in Part 2 (Dose Expansion) of this cohort. Cohort C: Treatment cycle is approximately 32 days for one cycle and will be a single treatment cycle: Dosage, duration and timings as outlined in protocol. * Venetoclax * Dexamethasone * Vincristine * Doxorubicin * Dexrazoxane * Calaspargase pegol ---Short acting Erwinia preparations (recombinant or native Erwinia asparaginase) may be used for participants with known pegaspargase or calaspargase pegol allergy * Cytarabine * Methotrexate * Hydrocortisone * Leucovorin- \*Cytarabine, Methotrexate, Hydrocortisone and Leucovorin may be given more frequently if leukemia/lymphoma cells are detected in spinal fluid), |
| Phase I - Dose Level 0 | EXPERIMENTAL | Ibrutinib (capsule) - 420mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase I - Dose Level 1 | EXPERIMENTAL | Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase I - Dose Level 2 | EXPERIMENTAL | Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 600mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase I - Dose Level 3 | EXPERIMENTAL | Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 800mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase II Dose | EXPERIMENTAL | The Phase II dose will be the maximum tolerated dose as determined in the Phase I portion. |
| Venetoclax + Inotuzumab Ozogamicin with Dexamethasone | EXPERIMENTAL | Phased 28 day treatment cycles with lead in: Lead In Cycle: Dose escalated venetoclax 1x daily for days 1-3 with and Dexamethasone daily for days 1-3 lead in, 7 days total. Induction Cycle 1: Dose escalated venetoclax 1x daily for days 1-21, Dexamethasone daily for days 1-4, Inotuzumab ozogamicin on days 1, 8, and 15 Induction Cycle 2: Dose escalated venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15 Consolidation Cycles: Up to 5 cycles of dose escalated Venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15 |
| Treatment (venetoclax, selinexor) | EXPERIMENTAL | Patients receive venetoclax PO QD on days 1-28. Patients with DLBCL receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Venetoclax naïve AML patients receive selinexor on days 8, 15, and 22 of cycle 1, followed by days 1, 8, 15, and 22 of subsequent cycles. Venetoclax refractory AML patients receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Treatment (CLAG-M, venetoclax) | EXPERIMENTAL | Patients will receive induction with granulocyte colony-stimulating factor on days 0-5 (if peripheral white blood cell count is less than 20,000/uL), cladribine on days 1-5, cytarabine on 1-5, and mitoxantrone on days 1-3. Patients also receive venetoclax orally (PO) on days 1-14. Treatment repeats every 28-35 days for up to 2 induction cycles including mitoxantrone, and up to 4 consolidation cycles without mitoxantrone in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and/or aspiration, and blood sample collection throughout the study. |
| Treatment (venetoclax, enzalutamide) | EXPERIMENTAL | Patients receive venetoclax PO QD and enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Treatment (prednisone, dasatinib, venetoclax, rituximab) | EXPERIMENTAL | See detailed description |
| Block 1 | EXPERIMENTAL | All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine) |
| Block 2 | EXPERIMENTAL | Block 2a Therapy: Patients receive intervention according to the Detailed Description section with the following: Venetoclax, Navitoclax, Dexamethasone, Cytarabine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, IT MHA, Radiation Block 2b Therapy: Patients receive intervention according to the Detailed Description section with the following: Venetoclax, Blinatumomab, Dexamethasone, Dasatinib, IT MHA Following Block 2 of therapy, late (≥36 months from diagnosis) first relapse B-ALL who are MRD negative after Block 1 will continue chemotherapy using adapted R3 intensification, interim, and continuation therapies. Patients receive intervention according to the Detailed Description section with the following: Methotrexate, Mercaptopurine, IT MHA, Leucovorin, Dexamethasone, Vincristine, Cyclophosphamide, Etoposide, Cytarabine, Dasatinib, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Radiation |
| Dose Escalation Copanlisib + Venetoclax | EXPERIMENTAL | Phase 1 * Dose escalation will occur using a 3+3 design * Copanlisib will be administered IV on days 1, 8 and 15 in 28 day cycle * Venetoclax will be administered orally daily for each 28-day cycle. During cycle 1, a venetoclax dose ramp-up is performed in the outpatient setting |
| Recommended phase II dose (RP2D) Copanlisib + Venetoclax | EXPERIMENTAL | Patients will be treated with copanlisib in combination with venetoclax, administered at the Recommended phase II dose (RP2D). |
| Group 1: Participants With Normal Renal Function | EXPERIMENTAL | Participants with normal renal function will receive single dose of venetoclax on Day 1. |
| Group 2: Participants With End Stage Renal Disease | EXPERIMENTAL | Participants with end stage renal disease (ESRD) will receive single dose of venetoclax on Period 1 Day 1 and Period 2 Day 1 (Each period is 3 days separated by 7-day washout period). |
| Treatment | EXPERIMENTAL | Cycle 1 of Treatment will be Decitabine days 1-10 plus Venetoclax ramp up on days 1-3 followed by Venetoclax target dose on days 4-21 Cycle 2 of Treatment will be Decitabine days 1-10 plus Venetcolax target dose days 1-21 During maintenance Decitabine on days 1-5 plus Venetoclax days 1-21 |
| Gemtuzumab Ozogamicin(GO) + Venetoclax | EXPERIMENTAL | Gemtuzumab Ozogamicin(GO) + Venetoclax |
| Phase 1/2 | EXPERIMENTAL | Part A: Subjects ≥1 to \<12 years of age with moderate or severe cGVHD after failure of 1 or more lines of systemic therapy, will receive oral ibrutinib once daily to determine Recommended Pediatric Equivalent Dose (RPED). Part A Continuation: Subjects participating in Part A may continue receiving daily ibrutinib until the RPED is determined, at which time their dose may be adjusted to the RPED. Part B: Subjects ≥1 to \<12 years of age( upper age limit is \< 22 years) with moderate or severe cGVHD after failure of 1 or more lines of systemic therapy or with newly diagnosed moderate or severe cGVHD will be dosed at the RPED. Subjects ≥12 will be given 420mg orally ibrutinib once daily. |
| Dose Escalation Venetoclax + Gilteritinib | EXPERIMENTAL | Different combinations of dose levels for venetoclax in combination with gilteritinib will be administered to determine the recommended phase 2 dose (RPTD). |
| Dose Expansion Venetoclax + Gilteritinib | EXPERIMENTAL | Participants will receive venetoclax in combination with gilteritinib at the dose determined in dose escalation portion. |
| Venetoclax+Daunorubicin+Cytarabine | EXPERIMENTAL | * Venetoclax administered orally on days 1 to 11 daily * Daunorubicin administered intravenously on days 2-4 * Cytarabine administered on days 2-8 by continuous IV infusion |
| Venetoclax + Alvocidib | EXPERIMENTAL | Venetoclax administered orally once daily (QD) and Alvocidib administered as an intravenous infusion on Days 1, 2, and 3 for all 28-day treatment cycles. Different combinations of dose levels for venetoclax and alvocidib may be explored. |
| Trastuzumab plus Ibrutinib 560 mg | EXPERIMENTAL | In Phase I, starting dose of Ibrutinib will be 560 mg orally per day. 3 patients will be enrolled first. If none of these have DLTs, 3 new patients will be enrolled at the next higher Ibrutinib dose level (840 mg orally per day). If 1 of these 3 patients have a DLT, expand this arm to 6 patients. If 2 or more of these 6 patients have a DLT, enroll 3 patients in lower dose lever (420 mg). |
| Trastuzumab plus Ibrutinib 840 mg | EXPERIMENTAL | If no patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this higher dose is tolerated. |
| Trastuzumab plus Ibrutinib 420 mg | EXPERIMENTAL | If 2 or more patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this lower dose is tolerated. |
| Phase II- Trastuzumab plus Maximum Tolerated Dose | EXPERIMENTAL | Maximum tolerated dose from Phase I will be used here in Phase II. |
| Venetoclax with or without chemotherapy | EXPERIMENTAL | Venetoclax administered orally once daily (QD) with various doses and dosing regimens with or without chemotherapy at the discretion of the investigator. Allowed chemotherapy regimens as outlined in the study protocol. |
| Venetoclax + Chemotherapy | EXPERIMENTAL | * Venetoclax is administered orally once daily for 21 days in each cycle * Standard Chemotherapy will be administered every 28 days |
| Venetoclax monotherapy (Cohort 1) | EXPERIMENTAL | - |
| Venetoclax + azacitidine (Cohort 2) | EXPERIMENTAL | - |
| Safety Expansion (Cohort 3) | EXPERIMENTAL | - |
| Venetoclax + Azacitidine | EXPERIMENTAL | - |
| ABBV-181 plus Venetoclax | EXPERIMENTAL | Venetoclax will be taken once daily beginning 7 days prior to cycle 1 and continuing daily for a 28 day cycle and ABBV-181 will be administered every 4 weeks. |
| ABBV-181 | EXPERIMENTAL | ABBV-181 will be administered at escalating dose levels in 28-day dosing cycles (2 doses per cycle). Based on available safety, pharmacokinetic, and pharmacodynamic data from the dose-escalation part of the study, participants will be enrolled in dose-expansion cohorts to further evaluate ABBV-181 at a dose level which is at or below the Maximum tolerated dose (MTD). In the Monotherapy Expansion portion of the study, ABBV-181 will be administered in 28-day dosing cycles at either 1 dose per cycle or 2 doses per cycle. Based on available safety, PK and PD data from the single agent dose-escalation part of the study, a dose for ABBV-181 will be selected to evaluate in combination with Rovalpituzumab Tesirine or venetoclax. |
| ABBV-181 plus Rovalpituzumab Tesirine | EXPERIMENTAL | Rovalpituzumab Tesirine will be given once every six weeks times two doses and ABBV-181 will be administered every 3 weeks. |
| Cohort 1: Renal Cell Carcinoma (RCC) | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of everolimus to determine the recommended phase 2 dose (RP2D) of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in phase 1b in combination with everolimus. |
| Cohort 2: Urothelial Carcinoma (UC) | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of paclitaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with paclitaxel. |
| Cohort 3: Gastric Adenocarcinoma (GA or GC) | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of docetaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive docetaxel at the RP2D determined in Phase 1b in combination with docetaxel. |
| Cohort 4: Colorectal Adenocarcinoma (CRC) | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of cetuximab to determine RP2D of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with cetuximab. |
| Cohort 5: Urothelial Carcinoma (UC) Ibrutinib | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels to determine the RP2D of ibrutinib.(The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b. |
| Cohort 6: Urothelial Carcinoma (UC) With Pembrolizumab | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of pembrolizumab to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with pembrolizumab. |
| Phase 1b/ 2: Follicular lymphoma expansion cohort | EXPERIMENTAL | In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 explored in cohort 1 and followed a 6+3 dose de-escalation design. Phase 2 used the phase 1b starting dose. |
| Phase 1b/ 2: Diffuse large B-cell lymphoma expansion cohort | EXPERIMENTAL | In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 explored in cohort 1 and followed a 6+3 dose de-escalation design. Phase 2 used the phase 1b starting dose. |
| Phase 1b | EXPERIMENTAL | In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 will be explored and will follow a 6+3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), Breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma). |
| Phase 2 | EXPERIMENTAL | Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), Breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results. |
| Phase 1: 600 mg Venetoclax + LDAC | EXPERIMENTAL | Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg (Day 2) and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received low-dose cytarabine (LDAC; 20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. |
| Phase 1: 800 mg Venetoclax + LDAC | EXPERIMENTAL | Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 100 mg (Day 2) and increased up to 800 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. |
| Phase 2: 600 mg Venetoclax + LDAC | EXPERIMENTAL | Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. |
| Arm A (Phase 1) | EXPERIMENTAL | Step-up doses of venetoclax to the designated cohort dose administered in participants with relapsed or refractory (R/R) Non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) |
| Arm B (Phase 1) | EXPERIMENTAL | Step-up doses of venetoclax to the designated dose administered in participants with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) |
| Arm C (Phase 1) | EXPERIMENTAL | Step-up doses of venetoclax to the designated dose with the addition of azacitidine administered in participants with acute myeloid leukemia (AML) |
| Arm D (Phase 2) | EXPERIMENTAL | Step-up doses of venetoclax to the designated dose with the addition of rituximab in participants with R/R CLL |
| Phase 1b: Dose Level 1 | EXPERIMENTAL | Subjects receive daily dose of 420 mg of Ibrutinib capsules |
| Phase 1b: Dose Level 2 | EXPERIMENTAL | Subjects receive daily dose of 280 mg of Ibrutinib capsules |
| Phase 1b: Dose Level 3 | EXPERIMENTAL | Subjects receive daily dose of 140 mg of Ibrutinib capsules |
| Part 1: Dose Level 1 | EXPERIMENTAL | Ibrutinib 560 mg PO + DA-EPOCH-R |
| Part 1: Dose Level 2 | EXPERIMENTAL | Ibrutinib 560 mg (PO) +lenalidomide 15 mg (PO) + DA-EPOCH-R |
| Part 1: Dose Level 3 | EXPERIMENTAL | Ibrutinib 560 mg (PO) +lenalidomide 20 mg (PO) + DA-EPOCH-R |
| Part 1: Dose Level 4 | EXPERIMENTAL | Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R |
| Part 2: RP2D | EXPERIMENTAL | Recommended Phase 2 Dose(RP2D): Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R |
| Treatment (enzyme inhibitor, chemo, monoclonal antibody) | EXPERIMENTAL | Patients receive BTK inhibitor PCI-32765 PO QD on days 1-28. Patients also receive rituximab IV on day 1 and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may continue receiving BTK inhibitor PCI-32765 PO in the absence of disease progression or unacceptable toxicity. |
| Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1) | EXPERIMENTAL | Ibrutinib 560 mg administered orally (PO) once daily (QD) beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered intravenously (IV) on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1) | EXPERIMENTAL | De-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 10 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+) | EXPERIMENTAL | Re-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2) | EXPERIMENTAL | Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3) | EXPERIMENTAL | Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 2: Enrolled at Lenalidomide Dose 20 mg | EXPERIMENTAL | Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 2: Enrolled at Lenalidomide Dose 25 mg | EXPERIMENTAL | Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| 1L CLL BR+V | EXPERIMENTAL | Participants with first-line (1L)/previously untreated CLL were administered escalating doses of venetoclax (V) in combination with fixed dose bendamustine and rituximab (BR). Participants received six 28-day cycles of BR+V. Participants with 1L CLL received 6 months of single-agent venetoclax for a total of 1-year treatment duration. Single-agent venetoclax could be extended if there was detectable minimal residual disease (MRD) in the bone marrow and/or partial response (PR) after 1 year of treatment and upon the request of the treating physician. |
| 1L CLL BG+V | EXPERIMENTAL | Participants with first-line (1L)/previously untreated CLL were administered escalating doses of venetoclax (V) in combination with fixed dose bendamustine and obinutuzumab (BG). Participants received six 28-day cycles of BG+V. Participants with 1L CLL received 6 months of single-agent venetoclax for a total of 1-year treatment duration. Single-agent venetoclax could be extended if there was detectable minimal residual disease (MRD) in the bone marrow and/or partial response (PR) after 1 year of treatment and upon the request of the treating physician. |
| R/R CLL BR+V | EXPERIMENTAL | Participants with relapsed/refractory (R/R) CLL were administered escalating doses of venetoclax (V) in combination with fixed dose bendamustine and rituximab (BR). Participants received six 28-day cycles of BR+V. Participants with R/R CLL continued single-agent venetoclax until disease progression, death, or unacceptable toxicity. |
| Phase 1 - Dose Finding | EXPERIMENTAL | Ibrutinib PO 560mg + Carfilzomib IV 20/27mg/m2 + Dexamethasone PO 20mg |
| Phase 2b - Main Study | EXPERIMENTAL | Ibrutinib PO 560mg + Carfilzomib IV 20/36mg/m2 + Dexamethasone PO 20mg |
| Phase 2b - Sub-study | EXPERIMENTAL | Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg |
| Dose-Finding: Schedule A: Relapsed/Refractory CLL | EXPERIMENTAL | All 4 cohorts will begin venetoclax administration after the ramp-up period of 5 weeks. In 4 cohorts of participants with relapsed/refractory CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule A, venetoclax will be introduced before obinutuzumab. Schedule A will be explored prior to Schedule B. |
| Dose-Finding: Schedule B: Relapsed/Refractory CLL | EXPERIMENTAL | In 4 cohorts of participants with relapsed/refractory CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule B, venetoclax will be introduced after obinutuzumab. Schedule A will be explored prior to Schedule B. |
| Dose-Finding: Schedule A: Previously Untreated CLL | EXPERIMENTAL | All 4 cohorts will begin venetoclax administration after the ramp-up period of 5 weeks. In 4 cohorts of participants with previously untreated CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule A, venetoclax will be introduced before obinutuzumab. Schedule A will be explored prior to Schedule B. |
| Dose-Finding: Schedule B: Previously Untreated CLL | EXPERIMENTAL | In 4 cohorts of participants with previously untreated CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule B, venetoclax will be introduced after obinutuzumab. Schedule A will be explored prior to Schedule B. |
| Safety Expansion: Relapsed/Refractory CLL | EXPERIMENTAL | In participants with relapsed/refractory CLL a recommended dose of venetoclax will be administered in combination with obinutuzumab in the safety expansion stage. Schedule A or B will be used for the expansion cohort after a review of available safety data from the dose finding stage. |
| Safety Expansion: Previously Untreated CLL | EXPERIMENTAL | In participants with previously untreated CLL a recommended dose of venetoclax will be administered in combination with obinutuzumab in the safety expansion stage. Schedule A or B will be used for the expansion cohort after a review of available safety data from the dose finding stage. |
| Phase 1: Venetoclax 300 mg | EXPERIMENTAL | Participants in the dose-escalation cohort received 300 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. |
| Phase 1: Venetoclax 600 mg | EXPERIMENTAL | Participants in the dose-escalation cohort received 600 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. |
| Phase 1: Venetoclax 900 mg | EXPERIMENTAL | Participants in the dose-escalation cohort received 900 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. |
| Phase 1: Venetoclax 1200 mg | EXPERIMENTAL | Participants in the dose-escalation cohort received 1200 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. |
| Phase 1 Safety Expansion: Venetoclax 1200 mg | EXPERIMENTAL | Participants in the safety expansion cohort received 1200 mg of venetoclax daily on Days 1 - 21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. |
| Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | EXPERIMENTAL | Participants with t(11;14) translocation multiple myeloma received daily venetoclax at a dose of 800 mg (no lead-in period) on Days 1- 21 of each cycle concomitant with weekly dexamethasone at a dose of 40 mg (20 mg for those aged ≥ 75 years). |
| Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | EXPERIMENTAL | The Phase 2 cohort further explored the efficacy of venetoclax in combination with dexamethasone in relapsed or refractory participants with t(11;14) translocation multiple myeloma. Participants received daily venetoclax at a dose of 800 mg (no lead-in period) on Days 1- 21 of each cycle concomitant with weekly dexamethasone at a dose of 40 mg (20 mg for those aged ≥ 75 years). |
| PCI-32765 plus fludarabine/cyclophosphamide/rituximab (FCR) | EXPERIMENTAL | - |
| PCI-32765 plus bendamustine/rituximab (BR) | EXPERIMENTAL | - |
| Group 1 | EXPERIMENTAL | In Group 1, PCI-32765 420 mg PO was administered daily for 1 cycle (28 days) before the start of ofatumumab IV dosing |
| Group 2 | EXPERIMENTAL | In Group 2, PCI-32765 420 mg PO daily was initiated concomitantly with ofatumumab IV (PCI-32765 initiated on Day 2 of Cycle 1) |
| Group 3 | EXPERIMENTAL | In Group 3, two cycles of ofatumumab IV were administered prior to the start of PCI-32765 420 mg PO daily |
| Name | Type | Description |
|---|---|---|
| Fludarabine | DRUG | Fludarabine i.v.: cycles 1-6: 25 mg/m², d1-3, q28d |
| Cyclophosphamide | DRUG | Cyclophosphamide i.v.: cycles 1-6: 250 mg/m², d1-3, q28d |
| Rituximab | BIOLOGICAL | Rituximab i.v. (before chemotherapy): cycle 1: 375 mg/m², d0; cycles 2-6: 500 mg/m², d1; q28d |
| Bendamustine | DRUG | Bendamustine i.v.: cycles 1-6: 90mg/m², d1-2, q28d |
| Venetoclax | DRUG | Venetoclax p.o. (ramp-up: dose escalation until final dose is reached) cycle 1: 20 mg (2 tabl. at 10 mg), d22-28, q28d cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28, q28d cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28, q28d |
| Obinutuzumab | BIOLOGICAL | Obinutuzumab i.v. cycle 1: 100 mg, d1; 900 mg, d1(2); 1000 mg, d8+15, q28d cycles 2-6: 1000 mg, d1, q28d |
| Ibrutinib | DRUG | Ibrutinib p.o. cycles 1-12: 420 mg, d1-28, q28d cycles 13-36: 420 mg, d1-28, q28d |
| Cytarabine | DRUG | Intravenous (IV) infusion |
| Gemtuzumab Ozogamicin | DRUG | Intravenous (IV) infusion |
| Azacitidine | DRUG | Intravenous (IV) infusion or subcutaneous injection |
| Acalabrutinib | DRUG | Oral: Tablet |
| Placebo | DRUG | Tablet; Oral |
| Decitabine | DRUG | The decitabine infusion was prepared and administered per the package insert and given intravenously, per institutional practice. |
| Pomalidomide | DRUG | capsule, oral |
| Dexamethasone | DRUG | oral, locally available form |
| Placebo Oral tablet to match Venetoclax | DRUG | Administered orally once daily |
| Prednisone | DRUG | Prednisone administered daily |
| Ibrutinib Oral Capsule | DRUG | Ibrutinib 560mg administered orally daily |
| Bortezomib | DRUG | Bortezomib (subcutaneous injection \[preferred\] or IV) was given following administration of venetoclax or placebo in Cycles 1 -8 on Days 1, 4, 8 and 11, and for Cycles 9 and beyond, on Days 1, 8, 15 and 22 and was to be administered per the prescribing information. The route of administration was to stay the same during the study. |
| Placebo for venetoclax | DRUG | Participants self-administered placebo tablets by mouth QD in combination with bortezomib. Placebo was to be given before other agents administered on the same day, if applicable. Each placebo dose was to be taken all at one time with approximately 240 mL of water within 30 minutes after completion of breakfast or the subject's first meal of the day. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed. On days that pre-dose PK sampling was required, dosing occurred at the clinic to facilitate PK sampling. |
| Gemcitabine | DRUG | - |
| Nab-paclitaxel | DRUG | - |
| Chlorambucil | DRUG | Chlorambucil 0.5 milligrams per kilogram (mg/kg) orally at Day 1 and Day 15 at of each 28 day cycle for 12 cycles. |
| Next-line ibrutinib | DRUG | Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily |
| ofatumumab | DRUG | The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks) |
| venetoclax and ibrutinib (I+VEN) | DRUG | The treatment will start with ibrutinib alone for 3 months (lead-in phase) from Month 1 to Month 3 and then venetoclax will be added from Month 4 with an initial ramp-up period. The total duration of treatment with (I+VEN) will depend on the response achieved at Month 9: * if BM MRD at M9 \< 0.01%, the treatment with (I+VEN) will be continued for 6 additional months until Month 15 and stopped then. MRD will be assessed at Month 15 (PB), Month 21 (PB) and Month 27 (PB and BM) * if BM MRD at M9 ≥ 0.01%, the treatment with (I+VEN) will be continued for 18 additional months until Month 27 and stopped then, whatever the results of MRD assessments that will be performed at the same time points as above. |
| FCR | DRUG | All patients will receive 6 cycles of FCR administered at 4 weeks intervals (D1 = D29) from Month 1 to Month 6. 6 cycles of FCR will be administered at 4 weeks intervals (D1 = D29) from Month 1 to Month 6. |
| Venetoclax; Rituximab | DRUG | Combination of venetoclax and rituximab |
| DRC | DRUG | Combination of Dexamethasone / Rituximab / Cyclophosphamide |
| Biospecimen Collection | PROCEDURE | Undergo blood sample collection |
| Bone Marrow Aspiration | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Bone Marrow Biopsy | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Cladribine | DRUG | Given IV |
| Echocardiography | PROCEDURE | Undergo ECHO |
| Lumbar Puncture | PROCEDURE | Undergo LP |
| Multigated Acquisition Scan | PROCEDURE | Undergo MUGA |
| Questionnaire Administration | OTHER | Ancillary studies |
| Computed Tomography | PROCEDURE | Undergo CT |
| Magnetic Resonance Imaging | PROCEDURE | Undergo MRI |
| Zanubrutinib | DRUG | Given PO |
| Tagraxofusp | DRUG | Single interventional arm |
| Venetoclax combined with Ibrutinib | DRUG | All Patients will be treated with venetoclax for 12 cycles after a standard 5-week dose ramp-up, as an add-on to the primary using ibrutinib. After the completion of combination therapy, patients will stop both the ibrutinib and venetoclax then be followed. Each cycle is 28 days. At the start of cycle 0, patients will start venetoclax by 20mg-50mg-100mg-200mg daily in a weekly dose escalation way. The combination of full dose venetoclax (400mg) and ibrutinib will continue for an additional 12 cycles. Venetoclax and ibrutinib will be continued until the completion of cycle 12, start of new CLL-directed therapies, disease progression or unacceptable toxicities, depending on which comes first. Ibrutinib is intended to be admistratered orally 420mg once daily. |
| Venetoclax combined with Zanubrutinib | DRUG | All Patients will be treated with venetoclax for 12 cycles after a standard 5-week dose ramp-up, as an add-on to the primary using zanubrutinib. After the completion of combination therapy, patients will stop both the zanubrutinib and venetoclax then be followed. Each cycle is 28 days. At the start of cycle 0, patients will start venetoclax by 20mg-50mg-100mg-200mg daily in a weekly dose escalation way. The combination of full dose venetoclax (400mg) and zanubrutinib will continue for an additional 12 cycles. Venetoclax and zanubrutinib will be continued until the completion of cycle 12, start of new CLL-directed therapies, disease progression or unacceptable toxicities, depending on which comes first. Zanubrutinib is intended to be admistratered orally 160mg twice daily. |
| Venetoclax combined with Acalabrutinib | DRUG | All Patients will be treated with venetoclax for 12 cycles after a standard 5-week dose ramp-up, as an add-on to the primary using acalabrutinib. After the completion of combination therapy, patients will stop both the acalabrutinib and venetoclax then be followed. Each cycle is 28 days. At the start of cycle 0, patients will start venetoclax by 20mg-50mg-100mg-200mg daily in a weekly dose escalation way. The combination of full dose venetoclax (400mg) and acalabrutinib will continue for an additional 12 cycles. Venetoclax and acalabrutinib will be continued until the completion of cycle 12, start of new CLL-directed therapies, disease progression or unacceptable toxicities, depending on which comes first. Acalabrutinib is intended to be admistratered orally 100mg twice daily. |
| Venetoclax combined with Orelabrutinib | DRUG | All Patients will be treated with venetoclax for 12 cycles after a standard 5-week dose ramp-up, as an add-on to the primary using orelabrutinib. After the completion of combination therapy, patients will stop both the orelabrutinib and venetoclax then be followed. Each cycle is 28 days. At the start of cycle 0, patients will start venetoclax by 20mg-50mg-100mg-200mg daily in a weekly dose escalation way. The combination of full dose venetoclax (400mg) and orelabrutinib will continue for an additional 12 cycles. Venetoclax and orelabrutinib will be continued until the completion of cycle 12, start of new CLL-directed therapies, disease progression or unacceptable toxicities, depending on which comes first. Orelabrutinib is intended to be admistratered orally 150mg once daily. |
| VEN+AZA-5 | DRUG | Up to 6 cycles: Azacitidine (AZA) 75 mg/m2, d1-5 of each 28 day cycle (SC) in combination with Venetoclax (VEN): 400 mg daily (orally) |
| Daratumumab | DRUG | Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) |
| Laboratory Biomarker Analysis | OTHER | Correlative studies |
| Blinatumomab | BIOLOGICAL | Given IV |
| Carfilzomib | DRUG | Carfilzomib lyophilized administered intravenously as a 10 to 30 minute infusion in Cycles 1 and beyond within 30 minutes to 4 hours after dexamethasone dosing. Dose level 1 (K1) Cycle 1: 20 mg/m2 on Days 1 and 2, 27 mg/m2 on Days 8, 9, 15, and 16; Cycles 2 - 12: 27 mg/m2 on Days 1, 2, 8, 9, 15, and 16; Cycles 13 - 18: 27 mg/m2 on Days 1, 2, 15, and 16; Cycles 19 and beyond, for participants that have not previously transitioned to monotherapy: 27 mg/m2 on Days 1, 2, 15, and 16. Dose Level K2: Cycle 1: 20 mg/m2 on Day 1; 70 mg/m2 on Days 8 and 15 Cycles 2 - onward: 70 mg/m2 on Days 1, 8, and 15. Dose Level K3: Cycle 1: 20 mg/m2 on Days 1 and 2; 56 mg/m2 on Days 8, 9, 15, and 16. Cycles 2 - onward: 56 mg/m2 on Days 1, 2, 8, 9, 15, and 16. |
| PCI-32765 | DRUG | - |
| venetoclax + azacitidine +/- donor lymphocyte infusion | DRUG | Venetoclax will be given once daily orally on days 1 to 14 for all cycles. Venetoclax + azacitidine +/- donor lymphocyte infusion (12 cycles maximum) |
| Methotrexate | DRUG | Lumbar Puncture |
| Hydrocortisone | DRUG | Lumbar Puncture |
| Leucovorin | DRUG | Taken Orally or intravenously |
| Vincristine | DRUG | Taken intravenously |
| Doxorubicin | DRUG | Taken intravenously |
| Dexrazoxane | DRUG | Taken intravenously |
| Calaspargase Pegol | DRUG | Taken intravenously |
| Erwinia asparaginase | DRUG | Given as intramuscular injection |
| Inotuzumab Ozogamicin | DRUG | Intravenous infusion |
| Selinexor | DRUG | Given by mouth |
| Mitoxantrone | DRUG | Given IV |
| Recombinant Granulocyte Colony-Stimulating Factor | BIOLOGICAL | Given subcutaneously |
| Enzalutamide | DRUG | Given PO |
| Dasatinib | DRUG | Given PO |
| Bone Marrow Aspiration and Biopsy | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Navitoclax | DRUG | Given oral (PO). |
| Mercaptopurine | DRUG | Given oral (PO). |
| Etoposide | DRUG | Given intravenously (IV). |
| Intrathecal Triples | DRUG | Given Intrathecal (IT). |
| Pegaspargase | DRUG | May be used in place of Calaspargase Pegol where available. Given intravenously (IV) or intramuscularly (IM). |
| Radiation | RADIATION | See detailed description section. |
| Copanlisib | DRUG | Intravenous infusion |
| Gilteritinib | DRUG | tablet, oral |
| Daunorubicin | DRUG | Chemotherapy is most effective at killing cells that are rapidly dividing. |
| Alvocidib | DRUG | Intravenous |
| Trastuzumab | DRUG | 8 mg/kg loading dose (first dose), followed by 6 mg/kg every 3 weeks, administered intravenously (IV) |
| Ibrutinib 560 mg | DRUG | 560 mg by mouth daily |
| Ibrutinib 840 mg | DRUG | 840 mg by mouth daily |
| Ibrutinib 420 mg | DRUG | 420 mg by mouth daily |
| chemotherapy | DRUG | Dexamethasone and/or vincristine and/or pegasparaginase OR cytarabine and/or etoposide and/or pegasparaginase; tyrosine kinase inhibitor; cytarabine OR azacitidine OR decitabine; rituximab and/or dexamethasone and/or vincristine; cyclophosphamide and/or topotecan |
| Standard Chemotherapy | DRUG | Standard treatment of chemotherapy is administered |
| Rovalpituzumab Tesirine | DRUG | Intravenous infusion |
| ABBV-181 | DRUG | Intravenous infusion |
| everolimus | DRUG | Everolimus 10 mg tablets should be taken orally once daily at the same time every day, either consistently with food or consistently without food. Four (4) x 2.5 mg tablets or two (2) x 5.0 mg tablets may be substituted if 10 mg tablet strength is not available. |
| paclitaxel | DRUG | Paclitaxel should be administered as a 60-minute (±10 minutes) infusion. Paclitaxel should be given at a dose level of 80 mg/m\^2, once weekly, in continual 3 weekly cycles. |
| docetaxel | DRUG | Docetaxel administered as a 60 minute infusion (±10 minutes) at a dose level of 60 - 75 mg/m\^2 (according to local institutional standard of care), given continually in 21-day cycles. |
| cetuximab | DRUG | Cetuximab 400 mg/m\^2 administered as a 120-minute IV infusion. The recommended subsequent weekly dose (all other infusions) is 250 mg/m\^2 infused over 60 minutes. |
| pembrolizumab | DRUG | Pembrolizumab 200 mg intravenous (IV) every 3 weeks. |
| MEDI4736 | DRUG | - |
| Durvalumab | DRUG | Anti PDL-1 |
| azacitadine | DRUG | 75 mg/m2 by IV infusion or subcutaneous dosing |
| rituximab / IDEC-C2B8 | DRUG | 375 mg/m2 on Week 6 |
| DA-EPOCH-R | DRUG | Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim |
| Lenalidomide | DRUG | Lenalidomide |
| BTK inhibitor PCI-32765 | DRUG | Given PO |
| bendamustine hydrochloride | DRUG | Given IV |
| pharmacogenomic studies | OTHER | Correlative studies |
| pharmacological study | OTHER | Correlative studies |
Inclusion Criteria: 1. Documented CLL requiring treatment according to iwCLL criteria 2. Age at least 18 years 3. Life expectancy ≥ 6 months 4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements 5. Adequate bone marr...
PCI-32765 is an investigational small molecule being studied in oncology for B-cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic leukemia, and multiple myeloma. Clinical trials have evaluated it in patients with recurrent B-cell lymphoma, chronic lymphocytic leukemia, and relapsed or refractory mantle cell lymphoma.
PCI-32765 is being developed by AbbVie Inc., a biopharmaceutical company traded on the New York Stock Exchange under the ticker ABBV. The company has sponsored clinical trials of the drug across multiple B-cell malignancies.
PCI-32765 is in clinical development. Completed trials include Phase 1 studies in B-cell lymphoma, chronic lymphocytic leukemia, and combination regimens, as well as a Phase 2 study in mantle cell lymphoma. The drug is investigational and has not been reported as approved.
PCI-32765 has been studied in four completed trials. NCT00849654 examined safety in recurrent B-cell lymphoma, NCT01105247 in chronic lymphocytic leukemia, NCT01236391 in relapsed or refractory mantle cell lymphoma, and NCT01292135 combined the drug with FCR or BR regimens in chronic lymphocytic leukemia.
PCI-32765 is the investigational name used in early clinical trials for the drug now known as ibrutinib. The trials listed under PCI-32765, including NCT00849654 and NCT01105247, were early studies of this Bruton's tyrosine kinase inhibitor in B-cell malignancies.
PCI-32765 targets Bruton's tyrosine kinase, an enzyme involved in B-cell receptor signaling. By inhibiting this kinase, the drug is designed to disrupt pathways that support the survival and proliferation of malignant B cells in conditions like chronic lymphocytic leukemia and mantle cell lymphoma.