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 RO5537382, ABT-0199, ABT-199, GDC-0199, RG7601, Venclexta, Venclyxto, 4-(4-((2-(4-Chlorophenyl)-4
Venetoclax · 9 trials · 21 indications
Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (greater than \[\>\] 1.5 centimeters \[cm\]); unequivocal progression of non-target lesion; an increase of greater than or equal to (\>/=) 50 percent (%) compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count \>/=5000 per microliter (mcL), or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of \>/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by \>2 grams per deciliter (g/dL) or to less than \[\<\] 10 g/dL. Percentages are rounded off.
PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; increase of \>/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count \>/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of \>/=50% in platelet or neutrophil count, or hemoglobin level by \>2 g/dL or to \<10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% confidence interval (CI) was computed using method of Brookmeyer and Crowley.
uMRD4 will be assessed using next generation sequencing (NGS) (sensitivity 10\^-4) from PB.
Percent of participants with high and intermediate risk relapsed/refractory CLL who are alive at 1 year. The percent of patients who are alive at one-year (rOS) will be measured by monitoring you in clinic. An rOS of at least 90% will be considered promising whereas the rOS of 75% or less will be considered non-promising.
The study will be continuously monitored for the primary endpoint, RFS, using the method of Thall, Wooten, and Tannir (2005). Will also summarize the posterior distribution of lambda-E (i.e., median RFS) assuming posterior mean and 95% credible interval.
The CRR is defined as the proportion of participants achieving complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) based on 2008 IW-CLL Response Criteria.
The number of participants with dose limiting toxicities for each treatment dose will be used to determine the MTD. Dose limiting toxicity defined as grade 4 neutropenia lasting more than 5 days, any grade febrile neutropenia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with bleeding, other therapy related non-hematologic toxicity of grade 2 or higher that requires discontinuation of therapy, clinical tumor lysis syndrome (TLS), laboratory TLS if the metabolic abnormalities are considered clinically significant by the investigator. All other grade 3 or higher adverse events (AEs) will be considered as DLTs with a few exceptions.
Hematologic ≥VGPR rate defined as proportion of participants achieving VGPR, low serum differential free light chain concentration (dFLC) partial response (PR), or a complete (CR). VGPR is defined as the difference between involved and uninvolved free light chain (FLC) \[dFLC\] \< 40 mg/L. Low dFLC PR is defined as achieving a dFLC\<10 mg/L, low dFLC PR will be considered as a deep hematologic response and included in the ≥VGPR category). CR is defined as negative serum and urine immunofixation electrophoresis along with a serum free light chain ratio that lies within the normal range or skewed towards the non-amyloid forming light chain, as per institutional laboratory values
The overall incidence and severity of all reported adverse events using Common Toxicity Criteria version 5.0.
ORR will be defined as the proportion of patients who had complete remission (CR), partial remission (PR) or marrow CR (mCR), or hematologic improvement (HI) lasting at least 8 weeks. Will estimate the ORR for the combination treatment, along with the 95% credible interval.
Toxicity incidences assessed and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0, will be tabulated by patient cohort.
DLTs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade \>/= 3 adverse event, that was attributed to having a reasonable possibility of being related to the combined administration of venetoclax plus R-CHOP or G-CHOP, that could not be attributed by the investigator to an alternative, clearly identifiable cause such as tumor progression, concurrent illness or medical condition, or concomitant medication and that occurred during the DLT observation period (start of venetoclax treatment through end of Cycle 2) was considered a DLT for dose-escalation purposes. Grade 3 or 4 neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3, resulting in dose delay were considered DLTs.
CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake \</= mediastinum; 3) uptake \< mediastinum but \</= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy
CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake \</= mediastinum; 3) uptake \< mediastinum but \</= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
| Arm | Type | Description |
|---|---|---|
| Bendamustine + Rituximab | ACTIVE_COMPARATOR | Participants will receive bendamustine 70 milligrams per meter square (mg/m\^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 375 mg/m\^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of Cycles 2-6. |
| Venetoclax + Rituximab | EXPERIMENTAL | Participants will be initially placed on a venetoclax 5 weeks ramp-up period, and will receive an initial dose of 20 milligrams (mg) via tablet orally once daily (QD). Then the dose will be incremented weekly up to a maximum dose of 400 mg. Participants will then continue receiving venetoclax 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards, as directed by the investigator, in combination with rituximab 375 mg/m\^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of Cycles 2-6. |
| Bendamustine + Rituximab Crossover Substudy | EXPERIMENTAL | Participants entering the Crossover Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Crossover Day 1 of the Substudy. |
| Venetoclax + Rituximab Re-Treatment | EXPERIMENTAL | Participants entering the Re-Treatment Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Re-Treatment Day 1 of the Substudy. |
| Venetoclax Added to cBTKi (Commercially Prescribed) | EXPERIMENTAL | Participants will receive venetoclax, orally, once daily (QD) with a starting ramp-up dose of 20 milligrams (mg) on Day 1 of Cycle 1 (cycle length= 28 days). The dose will increase weekly; thereafter, treatment will continue with venetoclax at the target dose of 400 mg, QD from Week 5 up to Day 28 of Cycle 12. Participant will discontinue from venetoclax and/or cBTKi after 12 cycles. Participants with detectable measurable residual disease with the presence of less than 1 CLL cell in 10,000 leukocytes (\< 10\^-4) (MRD4) or uMRD4 with partial response (PR) may continue receiving cBTKi-monotherapy (i.e. ibrutinib or acalabrutinib, or zanubrutinib) as previously prescribed by the investigator according to the prescribing label. |
| Venetoclax-Obinutuzumab +/- Acalabrutinib | EXPERIMENTAL | A treatment cycle is defined as 28 consecutive days. Participants with undetectable MRD (uMRD) at 1 year will complete an additional 1 year of VO then stop therapy. Participants with high detectable MRD at 1 year will complete an additional 1 year of VO plus acalabrutinib then stop therapy. Participants with low detectable MRD at 1 year will complete an additional 1 year of VO alone. If this eradicates MRD, they will stop therapy. If there is still residual MRD, they will complete an additional 1 year of IVO then stop therapy. If progression occurs on VO, I will be added and IV will be administered indefinitely. After 2 years, V may be stopped and I continued as monotherapy at investigator discretion. * Infused Study Drug: Obinutuzumab on Days 1, 2, 8, and 15 of Cycle 1 and then on Day 1 of Cycles 1-6 * Oral Study Drugs: Venetoclax daily starting on Cycle 1 Day 22 * Oral Drug: acalabrutinib daily for Days 1-28 (if applicable) |
| Treatment (azacytidine, venetoclax) | EXPERIMENTAL | Patients receive azacitidine SC or IV over 1 hour daily on days 1-5, and venetoclax PO daily on days 1-14. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. |
| VR-EPOCH (Cohort 1) | EXPERIMENTAL | * Standard chemotherapy regimen, DA-EPOCH-R * Chemotherapy cycles will be administered approximately every 3 weeks * Initial venetoclax dose ramp-up will be done in a condensed fashion over approximately 5 days, followed by continuous daily dosing of 400mg |
| VR-CHOP (Cohort 2) | EXPERIMENTAL | * Standard chemotherapy regimen, R-CHOP * Chemotherapy cycles will be administered approximately every 3 weeks * Initial venetoclax dose ramp-up will be done in a condensed fashion over approximately 5 days, followed by continuous daily dosing of 400mg |
| Phase 1: Venetoclax 200 mg | EXPERIMENTAL | Cohort 1: Venetoclax 200 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days) |
| Phase 1: Venetoclax 400mg | EXPERIMENTAL | Cohort 2: Venetoclax 400 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days) |
| Phase 1: Venetoclax 400mg + Dexamethasone 10 mg | EXPERIMENTAL | Cohort 3: Venetoclax 400 mg tablet, once daily and Dexamethasone 10 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days) |
| Phase 1: Venetoclax 400mg + Dexamethasone 20 mg | EXPERIMENTAL | Cohort 4: Venetoclax 400 mg tablet, once daily and Dexamethasone 20 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days) |
| Phase 2: Venetoclax MTD with Dexamethasone | EXPERIMENTAL | Venetoclax MTD (200 mg or 400 mg) with Dexamethasone (10 mg or 20 mg) as determined by the phase I results |
| Phase 2: Control Arm (Investigator's Choice) | ACTIVE_COMPARATOR | Participants will receive one of the following as determined by the investigator: Daratumumab, Pomalidomide, Bendamustine, or Ixazomib (+/- dexamethasone) |
| Treatment (venetoclax, ASTX727) | EXPERIMENTAL | Patients receive venetoclax orally PO QD on days 1-14. Patients also receive ASTX727 PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase) | EXPERIMENTAL | Patient receive venetoclax PO QD on days 1-28. Beginning cycle 2, patients receive lenalidomide PO QD on days 1-21. Patients also receive rituximab IV on days 1, 8, 15, and 22 of cycle 2 and rituximab hyaluronidase (if no significant infusion reaction to rituximab) SC on day 1 of cycles 4, 6, 8, 10, and 12. Patients may receive rituximab IV (instead of rituximab hyaluronidase) on days 1, 8, 15, and 22 of cycles 4, 6, 8, 10, and 12 if the patient requires rituximab IV in the opinion of the treating physician. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. |
| Venetoclax + G-CHOP Arm | EXPERIMENTAL | Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. |
| Venetoclax + R-CHOP Arm | EXPERIMENTAL | Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. |
| Name | Type | Description |
|---|---|---|
| Bendamustine | DRUG | Bendamustine will be administered at a dose of 70 mg/m\^2 via IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles. |
| Venetoclax | DRUG | Venetoclax will be administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during a 5-week ramp-up period. Venetoclax will be continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurs first. R/C Substudy: venetoclax will be administered for 5-week dose ramp-up period to reach the target dose of 400 mg QD. Venetoclax will continue to be administered during the rituximab cycles until disease progression or for a maximum of 2 years from Cycle 1R/C Day 1 of the R/C Substudy. |
| Rituximab | DRUG | Rituximab will be administered at a dose of 375 mg/m\^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m\^2 on Day 1 of Cycles 2-6. R/C Substudy: Following the venetoclax ramp-up period, rituximab will be administered for 6 cycles consisting of a single infusion on the first day of each 28-day cycle. |
| cBTKi Monotherapy | DRUG | Commercially available cBTKi (ibrutinib or acalabrutinib, or zanubrutinib) will be administered in accordance with its prescribing label. |
| Obinutuzumab | DRUG | Intravenous infusion |
| Acalabrutinib | DRUG | Capsule, taken by mouth |
| Azacitidine | DRUG | Given SC or IV |
| DA-EPOCH-R | OTHER | Intensive chemotherapy regiment |
| R-CHOP | OTHER | Intensive chemotherapy regiment |
| Venetoclax Oral Tablet, 200 mg | DRUG | 200 mg oral tablet daily |
| FISH assay | DEVICE | Cytogenetic analysis is intended for evaluation of relapsed/refractory AL amyloidosis using fluorescence in situ hybridization (FISH) using known translocation probes. Bone marrow aspirate (BMA) samples are collected in lavender top (Ethylenediaminetetraacetic acid (EDTA)) or green top (Sodium heparin) tubes. Specimen tubes shall be transported at room temperature to the laboratory on the same day of collection. |
| Venetoclax Oral Tablet, 400 mg | DRUG | 400 mg oral tablet daily |
| Dexamethasone Oral, 10 mg | DRUG | 10 mg oral tablet weekly |
| Dexamethasone Oral, 20 mg | DRUG | 20 mg oral tablet weekly |
| Daratumumab Injection | DRUG | Daratumumab will be administered at a dose of 16 mg/kg by IV infusion once weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, and every 4 weeks thereafter for a maximum of 6 months of therapy. If subcutaneous formulation is available, participants can also receive subcutaneous daratumumab (1800 mg in 15 ml) in the same schedule. |
| Pomalidomide | DRUG | Pomalidomide will be administered at an initial dose of 2 mg per days on days 1-21 every 28 days. |
| Ixazomib | DRUG | Ixazomib will be administered at an initial dose of 4 mg per days on days 1, 8, and 15 every 28 days. |
| Venetoclax MTD with Dexamethasone | DRUG | Venetoclax MTD (200 mg or 400 mg) with Dexamethasone (10 mg or 20 mg) as determined by the phase I results |
| Decitabine and Cedazuridine | DRUG | Given PO |
| Lenalidomide | DRUG | Given PO |
| Rituximab and Hyaluronidase Human | BIOLOGICAL | Given SC |
| Cyclophosphamide | DRUG | Cyclophosphamide 750 milligrams per square meter (mg/m\^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6. |
| Doxorubicin | DRUG | Doxorubicin 50 mg/m\^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6. |
| Vincristine | DRUG | Vincristine 1.4 mg/m\^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6. |
| Prednisone | DRUG | Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6. |
Inclusion Criteria: * Diagnosis of CLL per diagnostic criteria for relapsed or refractory CLL per the international workshop on chronic lymphocytic leukemia (iwCLL) guidelines * Previously treated with 1-3 lines of therapy (example: completed greater than or equal to \[\>/=\] 2 treatment cycles per...
Venetoclax is a small molecule BCL2 inhibitor developed by Roche Holding AG under the ticker RHHBY. It is being studied across several blood cancers and related conditions, including chronic lymphocytic leukemia, acute myeloid leukemia in remission, AL amyloidosis, chronic myelomonocytic leukemia, and non-Hodgkin lymphoma.
Venetoclax is being evaluated in chronic lymphocytic leukemia both as a first-line combination with a covalent Bruton's tyrosine kinase inhibitor and in relapsed or refractory disease combined with obinutuzumab, with or without acalabrutinib. These studies aim to achieve deep durable remissions that may allow patients to stop treatment.
Venetoclax targets BCL2, a protein that helps cancer cells avoid apoptosis. By inhibiting BCL2, Venetoclax promotes programmed cell death in malignant lymphocytes. This mechanism underlies its investigation in B-cell malignancies such as chronic lymphocytic leukemia and non-Hodgkin lymphoma.
Venetoclax is developed by Roche Holding AG, which trades under the ticker RHHBY. Roche is conducting clinical trials of Venetoclax in multiple hematologic conditions, including chronic lymphocytic leukemia, AL amyloidosis, and chronic myelomonocytic leukemia.
Venetoclax is in Phase 1 and Phase 2 clinical development across its studied indications. It is investigational and has not been approved by the FDA for these uses. The trials include Phase 1 studies in AL amyloidosis and chronic myelomonocytic leukemia, and Phase 2 studies in chronic lymphocytic leukemia.
Venetoclax is being studied in several clinical trials, including NCT06524375 for first-line chronic lymphocytic leukemia, NCT05451771 for relapsed or refractory t(11;14) AL amyloidosis, NCT04655755 for high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia, and NCT04560322 for relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.