Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication VENCLEXTA is a BCL-2 inhibitor indicated: For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ( 1.1 ) In combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. FDA label
Also known as ABT-199 (Main Cohort), Venetoclax, GDC-0199, ABT-199 also known as venetoclax, VENCLEXTA, VENCLYXTO
ABT-199 · 75 trials · 95 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.
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.
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.
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.
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.
The (CRMRD-+CR+CRi+MLFS) shows non-inferiority of venetoclax with azacitidine when compared with historical controls who received induction chemotherapy.
Proportion of patients responding according to international working Group on chronic lymphocytic leukemia criteria
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.
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.
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.
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.
The objective remission rate (ORR) was defined as the percentage of participants who achieved complete remission (CR), complete remission with incomplete bone marrow recovery (CRi), or partial remission (PR) per the International Working Group criteria for AML. Complete remission (CR) was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts. Complete remission with incomplete bone marrow recovery (CRi) was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL. Partial remission (PR) was defined as normalization in peripheral blood neutrophil and platelet counts with at least a 50% decrease in blasts persisting in bone marrow versus baseline.
The overall response rate (ORR) is defined as the proportion of participants with an overall response (complete remission \[CR\] + complete remission with incomplete marrow recovery \[CRi\] + nodular partial remission \[nPR\] + partial remission \[PR\]) per the 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute-Working Group (NCI-CWG) criteria as assessed by the Independent Review Committee (IRC) in the first 70 participants treated in the Main Cohort.
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 drug. 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. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.
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.
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.
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.
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).
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.
Electrocardiogram and Multi Gated Acquisition Scan and/or Echocardiogram
Subjects will be monitored for clinical and laboratory evidence of adverse events throughout the study
Chemistry, coagulation, hematology, lymphocyte enumeration, paraproteins, urinalysis, and, if appropriate, viral polymerase chain reaction and viral serologies
Subjects will be monitored for clinical and laboratory evidence of adverse events throughout the study
Body temperature, weight, blood pressure, heart rate
Blood samples for pharmacokinetic (PK) analysis of ABT-199 will be collected at designated timepoints to assess the PK parameters for ABT-199 alone relative to ABT-199 with ketoconazole
Blood samples for pharmacokinetic analysis of ABT-199 will be collected at designated timepoints
ABT-199 will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicities information from all subjects.
Blood samples for pharmacokinetic analysis of ABT-199 will be collected at designated timepoints
Blood samples for pharmacokinetic analysis of ABT-199 will be collected at designated timepoints
ABT-199 will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicities information from all subjects.
Blood pressure, heart rate and body temperature
Hematology, Chemistry, and Urinalysis
ECGs done in triplicate
Cmax
Time to Cmax
the area under the exposure-time curve of ABT-199 extrapolated to infinite time for single doses and up to 24 hrs for multiple doses of ABT-199
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.
Protocol-defined events, which are attributed as having a reasonable possibility of being related to the administration of ABT-199 and/or rituximab, or can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, underlying disease or concomitant medication, will be considered a dose limiting toxicity.
Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, or concomitant medication, will be considered a dose limiting toxicity
Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, or concomitant medication, will be considered a dose limiting toxicity
Adverse event monitoring, vital signs, physical examination, lymphocyte enumeration, 12-lead ECG, 2D echocardiogram/multiple gated acquisition scan (MUGA), and laboratory assessments
Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, or concomitant medication, will be considered a dose limiting toxicity
Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, underlying illness, concurrent illness, or concomitant medication, will be considered a DLT. Dose limiting toxicities of tumor lysis syndrome observed during the lead-in period will be attributed to the lead-in period.
Blood and urine samples for pharmacokinetic analysis of ABT-199 will be collected at designated time points
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
| 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 |
| 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. |
| 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. |
| Bendamustine + GA101 + ABT-199 | EXPERIMENTAL | Bendamustine: 70mg/m² i.v. GA101: 1000 mg i.v. ABT-199: 20 - 400 mg p.o. Possible Re-treatment of the included patients with GA101: 1000 mg i.v. and ABT-199: 20 - 400 mg p.o. |
| 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. |
| 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 |
| 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). |
| 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 |
| ABT199 | EXPERIMENTAL | ABT199 will be administered daily, with 28 consecutive days defined as a treatment cycle for a maximum for 26 cycles |
| 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. |
| ABT-199 | EXPERIMENTAL | Continuous dosing of venetoclax (ABT-199) QD (once daily) beginning with dose-escalation on Week 1 Day 1. Participants received a dose of 20 mg of ABT-199 on Week 1 Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5, 800 mg on Day 6 and QD thereafter. |
| Main Cohort | EXPERIMENTAL | Participants received ABT-199 tablets once daily (QD) orally for up to 79 months. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. |
| Safety Expansion Cohort | EXPERIMENTAL | Participants received ABT-199 tablets once daily (QD) orally for up to 68 months. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. |
| 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), |
| 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 |
| 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. |
| 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. |
| ABT-199 and Ibrutinib Combination | EXPERIMENTAL | Participants will take ABT-199 (dose 100-400 mg) and Ibrutinib (dose 280-560 mg). |
| 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 |
| 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. |
| Arm A (ABT-199 and ketoconazole) | EXPERIMENTAL | - |
| 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. |
| ABT-199 + BTZ/Dex Dose Escalation Cohorts | EXPERIMENTAL | Evaluate the safety and pharmacokinetics profile of ABT-199 administered with standard therapy bortezomib and dexamethasone in a dose escalation scheme in approximately 54 subjects. |
| ABT-199 + BTZ/Dex Safety Expansion Cohort | EXPERIMENTAL | Safety expansion cohort to further evaluate recommended phase two dose (RPTD) of ABT-199 administered with standard therapy bortezomib and dexamethasone in approximately 12 subjects. |
| Single Dose | EXPERIMENTAL | Subjects enrolled in the Single Ascending Dose (SAD) part of the study will receive a single dose of study drug or placebo. (Groups 1, 2, 3, 4, 5 and 6). |
| Multiple Dose | EXPERIMENTAL | Subjects enrolled in the Multiple Ascending Dose (MAD) part of the study will receive multiple doses of study drug or placebo. (Groups 7, 8, 9, 10 and 11) |
| 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). |
| Arm 1 | EXPERIMENTAL | Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL) |
| Arm A (CLL/SLL subjects) | EXPERIMENTAL | Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) subjects |
| Arm B (NHL subjects) | EXPERIMENTAL | Non-Hodgkin lymphoma (NHL) subjects |
| 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 |
| 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. |
| 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. |
| GA101 | DRUG | Induction: Cycle 1: d1: 100mg, d1(or 2): 900mg, d8 \& 15: 1000mg; Cycle 2-6: d1: 1000mg Maintenance: Cycles 1-8 (Duration 12 weeks): d1: 1000mg |
| ABT-199 | DRUG | Induction: Cycle 2: d1-7: 20mg, d8-14: 50mg, d15-21: 100mg, d22-28: 200mg; Cycle 3-6: d1-28: 400mg Maintenance: Cycles 1-8 (Duration 12 weeks): d1-84: 400mg |
| 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) |
| 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. |
| ABT199 | DRUG | Oral BCL-2 antagonist |
| ABT-199 (Main Cohort) | DRUG | Participants received a test dose of ABT-199 of ≤ 20 mg on Week 1 Day 1 of the Lead-In Period. For those with significant electrolyte and/or lymphocyte changes within 24 hours of the first dose, the 20 mg dose was maintained for 7 days with escalation to 50 mg on Week 2 Day 1. If none of the electrolyte and/or lymphocyte changes occurred within 24 hours from ABT-199 20 mg dose administration, the participant was dose-escalated to 50 mg on Week 1 Day 2. After the first dose of 50 mg, if no laboratory abnormalities occurred, the participant remained on the 50 mg dose through Week 1. After receiving the 50 mg dose for approximately 1 week (6 to 7 days), the following dose escalation proceeded with weekly increases in dose: → 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose), as tolerated. |
| ABT-199 (Safety Expansion Cohort) | DRUG | Participants received an initial dose of ABT-199 of 20 mg on Week 1 Day 1 of the Lead-In Period. If one or more electrolyte changes (from the 0 hr measurement prior to dosing) suggestive of laboratory tumor lysis syndrome (LTLS) or clinical TLS (CTLS) occurred within 24 hours of the 20 mg dose, no additional doses were administered until resolution. Upon resolution of laboratory abnormalities, the 20 mg dose was continued through Week 1. If no significant findings suggestive of clinical or laboratory TLS occurred within 24 hours, the 20 mg dose was continued through Week 1 Day 7, and escalated to a dose of 50 mg on Week 2 Day 1. Those who had drug interruptions may have been allowed to escalate to and be maintained at 50 mg for 1 week after they had been on a 20 mg dose for at least 1 week (5 - 7 days). After a week at 50 mg, weekly dose escalations were implemented as follows: 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose) as tolerated. |
| 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 |
| Prednisone | DRUG | Given PO |
| Blinatumomab | BIOLOGICAL | Given IV |
| 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 |
| 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 |
| ABT-199 and Ibrutinib Combination | DRUG | Both are administered orally once daily. |
| azacitadine | DRUG | 75 mg/m2 by IV infusion or subcutaneous dosing |
| rituximab / IDEC-C2B8 | DRUG | 375 mg/m2 on Week 6 |
| Ketoconazole | DRUG | Subjects will be dosed with ABT-199, then dosed with ABT-199 in combination with ketoconazole |
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...
ABT-199 is an investigational small molecule developed by AbbVie Inc. (ticker ABBV) for oncology indications. It has been studied in Phase 2 clinical trials for acute myelogenous leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, non-Hodgkin's lymphoma, and Waldenström macroglobulinemia. It is also known as ABT-199 and Ibrutinib Combination, ABT-199 (Main Cohort), and ABT199.
ABT-199 targets BCL-2, a protein involved in regulating cell death. By inhibiting BCL-2, ABT-199 may promote apoptosis in cancer cells. This mechanism is being investigated in hematologic malignancies such as leukemia and lymphoma.
ABT-199 is being developed by AbbVie Inc., which trades under the ticker ABBV. AbbVie is the sponsor of the clinical trials evaluating ABT-199 in various blood cancers.
ABT-199 is in Phase 2 clinical development. It is an investigational drug and has not been approved by the FDA. The Phase 2 trials have been completed, and no active trials are currently listed.
ABT-199 has been evaluated in several completed clinical trials, including NCT02677324 in Waldenström macroglobulinemia, NCT02419560 in mantle cell lymphoma, NCT02401503 in chronic lymphocytic leukemia, and NCT01994837 in acute myelogenous leukemia. These trials enrolled a total of 380 participants.
Yes, ABT-199 is also known as ABT199, as well as ABT-199 and Ibrutinib Combination and ABT-199 (Main Cohort). These alternative names refer to the same investigational drug.