Triple Combo Therapy for Chronic Lymphocytic Leukemia
Recruiting in Palo Alto (17 mi)
+9 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?
The purpose of this study is to determine the rate of minimum residual disease (MRD) negative response (i.e. the rate of no evidence of disease) of the study drugs, zanubrutinib, obinutuzumab, and venetoclax, given in combination as a treatment for CLL and/or SLL.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you must stop all current medications, but certain medications are restricted. You must stop taking strong or moderate inhibitors or inducers of CYP3A, CYP2C8, CYP2C9, and CYP2C19 within 7 days before the trial. You also cannot take warfarin, immunotherapy, hormone therapy (except contraceptives, hormone replacement, or megestrol acetate), or any therapies for lymphoma/leukemia outside of this study. Additionally, avoid grapefruit, Seville oranges, and star fruit within 3 days before the trial.
What data supports the idea that Triple Combo Therapy for Chronic Lymphocytic Leukemia is an effective treatment?
The available research does not provide any data on the effectiveness of Triple Combo Therapy for Chronic Lymphocytic Leukemia. The studies listed focus on other treatments and conditions, such as lupus nephritis, rheumatoid arthritis, and systemic lupus erythematosus, but do not mention the specific combination of drugs used in Triple Combo Therapy for Chronic Lymphocytic Leukemia.12345
What safety data is available for the triple combo therapy for CLL?
The safety data for the combination of venetoclax (Venclexta, Venclyxto) and obinutuzumab (Gazyva) in treating chronic lymphocytic leukemia (CLL) is primarily derived from the CLL14 trial. This trial showed that the combination had an acceptable tolerability profile, with notable adverse events such as grade 3 or 4 neutropenia, which can be managed with supportive therapy and dose modifications. The incidence of grade 3-4 neutropenia was reported to be between 52.8% and 57.7%. Venetoclax has been shown to be effective and safe in both previously untreated and relapsed/refractory CLL, providing durable responses with a manageable safety profile.678910
Is the drug combination of Obinutuzumab, Venetoclax, and Zanubrutinib a promising treatment for Chronic Lymphocytic Leukemia?
Yes, the combination of Obinutuzumab, Venetoclax, and Zanubrutinib is promising for treating Chronic Lymphocytic Leukemia. Venetoclax, when combined with Obinutuzumab, has shown to significantly improve patient outcomes, such as longer progression-free survival and higher response rates, compared to traditional treatments. This combination is effective and offers a chemotherapy-free option, making it a valuable choice for patients.6791112
Eligibility Criteria
Adults diagnosed with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL), who haven't had systemic therapy for these conditions, can join. They should be in a stable health condition and willing to use effective contraception. People with other active cancers, serious infections, or certain heart/liver diseases cannot participate.Inclusion Criteria
Signed, informed consent
I am 18 years old or older.
I have been diagnosed with CLL, SLL, or MCL according to WHO standards.
See 13 more
Exclusion Criteria
Other: Females who are currently pregnant or breastfeeding, Participation in a separate investigational therapeutic study unless authorized by the investigator
Co-morbidities: Any uncontrolled illness that in the opinion of the investigator would preclude administration of study therapy, Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to Cycle 1, Day 1, Known bleeding diathesis, Prior major surgical procedure within 4 weeks of study, or anticipation of need for a major surgical procedure during the course of the study, Known CNS hemorrhage or stroke within 6 months of the study, History of progressive multifocal leukoencephalopathy (PML), History of HIV infection or active hepatitis B or hepatitis C infection
I haven't had any other cancers or treatments for them in the last 3 years, except for local treatments aimed at cure.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive zanubrutinib and obinutuzumab starting on Cycle 1, with venetoclax added from Cycle 3, over 28-day cycles
8 months
Multiple visits for drug administration and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment, including MRD response classification
4 weeks
Treatment Details
Interventions
- Obinutuzumab (Monoclonal Antibodies)
- Venetoclax (B-cell Lymphoma-2 (BCL-2) Inhibitor)
- Zanubrutinib (Bruton's Tyrosine Kinase (BTK) Inhibitor)
Trial OverviewThe trial is testing the combination of three drugs: Zanubrutinib, Obinutuzumab, and Venetoclax in patients with CLL/SLL. The goal is to see if this drug combo can eliminate all detectable traces of the disease from the body.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: BOVEN regimenExperimental Treatment3 Interventions
Patients will be given zanubrutinib (160mg by mouth BID) and obinutuzumab (1000mg IVPB on Days 1\*, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8) starting on Cycle 1 (28-day cycles). \* On Cycle 1, obinituzumab will be administered in "split dose" at 100mg IVPB on Day 1 and 900mg IVPB on Day 2 in patients at increased risk for IRR (ALC \>25,000 cells/ul or baseline lymph nodes \>5 cm diameter). Venetoclax will be added to the regimen starting on Cycle 3, and will be incorporated into the regimen using the 5-week ramp-up schedule to mitigate the risk of tumor lysis syndrome (beginning at 20mg and gradually increasing to 400mg), and venetoclax will be administered a ta fixed dose level of 400mg by mouth daily of 28-day cycles thereafter.
Obinutuzumab is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Gazyva for:
- Chronic Lymphocytic Leukemia (CLL)
- Follicular Lymphoma
🇪🇺 Approved in European Union as Gazyva for:
- Chronic Lymphocytic Leukemia (CLL)
- Follicular Lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memoral Sloan Kettering MonmouthMiddletown, NJ
Memorial Sloan Kettering WestchesterWest Harrison, NY
Memorial Sloan Kettering Cancer CenterNew York, NY
Memorial Sloan Kettering NassauUniondale, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
Roche-GenentechIndustry Sponsor
BeiGene USA, Inc.Industry Sponsor
Massachusetts General HospitalCollaborator
References
Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. [2022]To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN).
Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial. [2017]To evaluate the efficacy and safety of treatment with ocrelizumab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and an inadequate response to MTX.
Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus. [2020]To investigate the long-term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE.
Longterm clinical and immunological effects of anti-CD20 treatment in patients with refractory systemic lupus erythematosus. [2022]To retrospectively evaluate longterm clinical and immunological effects of anti-CD20 treatment in patients with systemic lupus erythematosus (SLE) with active nephritis or autoantibody-mediated cytopenias refractory to conventional immunosuppressive treatment.
Update on belimumab for the management of systemic lupus erythematosus. [2018]Belimumab is a fully humanised mAb against B lymphocyte stimulator (B-LyS). It is the first biological drug to be licensed and approved by the US FDA and the European Medicines Evaluation Agency for use in combination with standard immunosuppressants in autoantibody-positive systemic lupus erythematosus (SLE). The clinical effectiveness and impact of this drug on lupus morbidity and mortality is evaluated in this review.
Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. [2020]Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia.
Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]Venetoclax (Venclexta®; Venclyxto®) is a first-in-class, oral, selective inhibitor of B cell lymphoma 2 (BCL2). In several countries, including the USA and those of the EU, venetoclax is indicated in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Approval was based on the results of the phase III CLL14 trial in patients with previously untreated CLL and co-existing conditions. In this study, fixed-duration (12 months) targeted treatment with venetoclax + obinutuzumab resulted in significantly longer progression-free survival (PFS; primary endpoint) relative to fixed-duration chemoimmunotherapy with chlorambucil + obinutuzumab. Venetoclax + obinutuzumab was also associated with significantly higher rates of undetectable minimal residual disease (MRD), complete response and overall response than chlorambucil + obinutuzumab. Improvements in clinical outcomes with venetoclax + obinutuzumab were maintained during long-term follow-up, when all patients had been off treatment for ≥ 2 years. No significant between-group difference was observed in overall survival (OS). Venetoclax had an acceptable tolerability profile. Notable adverse events such as grade 3 or 4 neutropenia can be managed with supportive therapy and venetoclax dose modifications. In conclusion, fixed-duration venetoclax + obinutuzumab represents an important chemotherapy-free first-line treatment option for patients with CLL, particularly those who are not fit enough to receive intensive chemoimmunotherapy.
Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. [2022]The time-limited combination of venetoclax and obinutuzumab (VenG) was established by the German CLL Study Group in the CLL14 trial for the upfront management of newly diagnosed chronic lymphocytic leukemia (CLL), showing a superior progression free survival benefit. The incidence of grade 3-4 neutropenia was reported in the range of 52.8%-57.7%. However, patients who develop neutropenia with this combination have yet to be formally characterized in the literature as it has impact on the clinical practice setting.
Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020]Venetoclax (Venclyxto®; Venclexta®) is a first-in-class, oral, selective B cell lymphoma-2 (BCL-2) inhibitor. The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL); the specific indication(s) for venetoclax may vary between individual countries. Venetoclax monotherapy or combination therapy with rituximab was an effective treatment, provided durable responses, and had a manageable safety profile in pivotal clinical trials in adults with RR CLL, including in patients with adverse prognostic factors. In combination with 6 cycles of rituximab, venetoclax (fixed 24 months' treatment) was more effective than bendamustine plus rituximab (6 cycles) in prolonging progression-free survival (PFS) and inducing undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM), with these benefits sustained during 36 months' follow-up. Hence, with its novel mechanism of action and convenient oral once-daily regimen, venetoclax monotherapy or fixed 24-month combination therapy with rituximab represents an important option for treating RR CLL, including in patients with del(17p) or TP53 mutation and those failing a B cell receptor (BCR) inhibitor and/or chemotherapy.
Venetoclax: First Global Approval. [2018]Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.
Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). .
Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. [2022]Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.