Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Venetoclax · 46 trials · 53 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
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.
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.
OS is defined as the number of days from the date of randomization to the date of death of any cause, or last known date to be alive.
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
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.
PFS is defined as the number of days from the date the participant was randomized to the date of the first documented progressive disease (PD) as determined by an Independent Review Committee (IRC) or death due to any cause, whichever occurs first. PFS was analyzed by Kaplan-Meier methodology.
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.
Reduction of BCR::ABL1 stem cells measured by quantitative genomic PCR in bone marrow after venetoclax administration.
Will be defined as the rate of complete remission (CR) plus CR with incomplete count recovery (CRi).
The (CRMRD-+CR+CRi+MLFS) shows non-inferiority of venetoclax with azacitidine when compared with historical controls who received induction chemotherapy.
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.
Evaluation will be done with a bone marrow aspirate, cytogenetics, metabolic imaging, study of MRD by NGS and flow-cytometry and SWAT SCORE
Determination of dose-limiting toxicities within the first two cycles of treatment
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.
ORR is defined as the percentage of participants achieving complete remission (CR), CR with incomplete bone marrow recovery (CRi), or partial remission (PR) as their best response per investigator assessment based on the T-PLL consensus criteria 2019. CR: All of the following response criteria must be met: Group A: * all lymph nodes \< 1 cm; * spleen \< 13 cm; * no constitutional symptoms; * circulating lymphocyte count \< 4 × 10\^9/L; * bone marrow T-PLL cells \< 5% of mononuclear cells; * no other specific site involvement Group B: * platelets ≥ 100 × 10\^9 /L; * hemoglobin ≥ 11.0 g/dL; * neutrophils ≥ 1.5 × 10\^9 /L. CRi: All of the CR response criteria in Group A met; at least 1 parameter in Group B not achieved, unrelated to T-PLL, but related to drug toxicity. PR: At least 2 of the parameters in Group A and 1 parameter in Group B need to improve if previously abnormal. If only 1 parameter of both Groups A and B is abnormal prior to therapy, only 1 parameter needs to improve.
VGPR or better response rate is defined as the 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.
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.
An AE 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.
Cmax of venetoclax HME-03.
Tmax of venetoclax HME-03.
β of venetoclax HME-03.
t1/2 of venetoclax HME-03.
AUCt of venetoclax HME-03.
AUCinf of venetoclax HME-03.
An adverse event 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.
Cmax of venetoclax.
Tmax of venetoclax.
AUCt of venetoclax.
AUCinf of venetoclax.
Apparent terminal phase elimination rate constant of venetoclax.
T1/2 of venetoclax.
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.
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
Time to maximum plasma concentration (Tmax) of Venetoclax.
Time to maximum plasma concentration (Tmax) of EE/Levonorgestrel
Maximum plasma concentration (Cmax) of Venetoclax
Maximum plasma concentration (Cmax) of EE/Levonorgestrel
Terminal phase elimination half-life (t1/2) of Venetoclax.
Terminal phase elimination half-life (t1/2) of EE/Levonorgestrel
Area under the plasma concentration-time curve (AUC) from time 0 to time of the last measurable concentration (AUCt) of Venetoclax
Area under the plasma concentration-time curve (AUC) from time 0 to time of the last measurable concentration (AUCt) of EE/Levonorgestrel
AUC from time 0 extrapolated to infinite time (AUCinf) of EE/Levonorgestrel.
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.
Clearance (CL) of alvocidib
Area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) post-dose of alvocidib
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.
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.
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.
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| Venetoclax Monotherapy | EXPERIMENTAL | Participants will receive venetoclax at doses ramping up to the target dose, as part of the approximately 28 month study duration. |
| 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 |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| Stage 1: Sequence 1: Venetoclax | EXPERIMENTAL | Participants will receive commercial venetoclax following a high-fat meal (Regimen A), followed by venetoclax hot melt extrusion-03 (HME-03) dose A following a high-fat meal (Regimen B), followed by venetoclax HME-03 dose B following a high-fat meal (Regimen C), finally followed by venetoclax HME-03 dose A following fasting (Regimen D), as part of the approximately 18 month study duration. |
| Stage 1: Sequence 2: Venetoclax | EXPERIMENTAL | Participants will receive Regimen B, followed by Regimen C, followed by Regimen A, finally followed by Regimen D, as part of the approximately 18 month study duration. |
| Stage 1: Sequence 3: Venetoclax | EXPERIMENTAL | Participants will receive Regimen C, followed by Regimen A, followed by Regimen B, finally followed by Regimen D, as part of the approximately 18 month study duration. |
| Stage 2: Sequence 1: Venetoclax | EXPERIMENTAL | Participants will receive Regimen A, followed by Regimen B, finally followed by Regimen C, as part of the approximately 18 month study duration. |
| Stage 2: Sequence 2: Venetoclax | EXPERIMENTAL | Participants will receive Regimen B, followed by Regimen C, finally followed by Regimen A, as part of the approximately 18 month study duration. |
| Stage 2: Sequence 3: Venetoclax | EXPERIMENTAL | Participants will receive Regimen C, followed by Regimen A, finally followed by Regimen B, as part of the approximately 18 month study duration. |
| Venetoclax Sequence 1 | EXPERIMENTAL | Participants will receive whole venetoclax, followed by crushed venetoclax, and completed with ground venetoclax for a 15 day period. |
| Venetoclax Sequence 2 | EXPERIMENTAL | Participants will receive crushed venetoclax, followed by ground venetoclax, and completed with whole venetoclax for a 15 day period. |
| Venetoclax Sequence 3 | EXPERIMENTAL | Participants will receive ground venetoclax, followed by whole venetoclax, and completed with crushed venetoclax for a 15 day period. |
| Treatment (prednisone, dasatinib, venetoclax, rituximab) | EXPERIMENTAL | See detailed description |
| 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 |
| Ethinyl estradiol/Levonorgestrel and Venetoclax | EXPERIMENTAL | Ethinyl estradiol/levonorgestrel is administered on Period 1 Day 1 and then again on Period 3 Day 1. Venetoclax is administered on Period 2 Day 1 and then daily thereafter. |
| 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. |
| 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. |
| 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). |
| 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 |
| 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. |
| Acalabrutinib | DRUG | Oral: Tablet |
| Cytarabine | DRUG | Subcutaneous Injection |
| Azacitidine | DRUG | Subcutaneous (SC) or Intravenous (IV) injection |
| Placebo | DRUG | Tablet; Oral |
| Decitabine | DRUG | The decitabine infusion was prepared and administered per the package insert and given intravenously, per institutional practice. |
| 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. |
| Dexamethasone | DRUG | Dexamethasone was to be given orally, administered per the prescribing information, the day of bortezomib dosing and the following day, given the protocol-defined dosing window (bortezomib dosing window is ± 1 day) is maintained. If bortezomib was interrupted or a dose is skipped, dexamethasone was to be administered as scheduled per protocol (unless dexamethasone was interrupted due to toxicity). |
| 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. |
| Tagraxofusp | DRUG | Single interventional arm |
| 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. |
| 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 |
| Dasatinib | DRUG | Given PO |
| Prednisone | DRUG | Given PO |
| Blinatumomab | BIOLOGICAL | Given IV |
| Bone Marrow Aspiration and Biopsy | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Lumbar Puncture | PROCEDURE | Undergo lumbar puncture |
| Biospecimen Collection | PROCEDURE | Undergo blood sample collection |
| ethinyl estradiol/levonorgestrel | DRUG | tablet; oral |
| 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 |
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...
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