Acalabrutinib + Venetoclax for Chronic Lymphocytic Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Fred Hutchinson Cancer Research Center
Must not be taking: Strong CYP3A4 inhibitors
Disqualifiers: Prolymphocytic leukemia, Cardiovascular disease, Gastrointestinal issues, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase II trial is to evaluate the effects of acalabrutinib in combination with venetoclax in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that does not respond to treatment (refractory) or that has come back (recurrent). Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Given acalabrutinib and venetoclax may kill more cancer cells.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs like strong CYP3A4 inhibitors or proton pump inhibitors. It's best to discuss your current medications with the trial team to see if any adjustments are needed.
What data supports the effectiveness of the drug combination Acalabrutinib and Venetoclax for treating Chronic Lymphocytic Leukemia?
Research shows that Venetoclax, when used with other drugs like obinutuzumab, is effective in treating Chronic Lymphocytic Leukemia (CLL), leading to longer periods without disease progression and higher rates of undetectable cancer cells. Acalabrutinib has also been effective in continuous therapy for CLL, suggesting that the combination of these drugs could be beneficial.
12345Is the combination of Acalabrutinib and Venetoclax safe for treating Chronic Lymphocytic Leukemia?
Venetoclax, when used for Chronic Lymphocytic Leukemia, has shown an acceptable safety profile, with manageable side effects like neutropenia (low white blood cell count) and tumor lysis syndrome (a rapid release of cell contents into the blood). Acalabrutinib, when combined with Venetoclax and obinutuzumab, has been studied as a treatment for CLL, suggesting it is generally safe, but specific safety data for the Acalabrutinib and Venetoclax combination alone is limited.
12346How is the drug combination of Acalabrutinib and Venetoclax unique for treating chronic lymphocytic leukemia?
The combination of Acalabrutinib and Venetoclax is unique because it offers a time-limited, minimal residual disease (MRD)-guided approach that aims to achieve deep and lasting remissions in patients with chronic lymphocytic leukemia. This approach is different from continuous therapies and focuses on achieving undetectable MRD, which can lead to better long-term outcomes.
12347Eligibility Criteria
Adults diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma that's resistant to treatment or has returned. They must have had night sweats for over a month, relapsed after at least one therapy, and meet specific health criteria like certain blood cell counts and organ function tests. Pregnant women, those with other active cancers, significant heart issues, absorption problems, recent major surgeries, or infections like hepatitis B/C or HIV cannot join.Inclusion Criteria
Hemoglobin >= 10 g/dL (independent of growth factor or transfusion support within 1 week of screening)
Estimated creatinine clearance of >= 50 mL/min
I have had night sweats for over a month without being sick.
+20 more
Exclusion Criteria
I have been diagnosed with progressive multifocal leukoencephalopathy.
My condition worsened while I was on venetoclax.
You have had a bad reaction or could not tolerate acalabrutinib or venetoclax in the past.
+18 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive acalabrutinib orally twice a day and venetoclax once daily. Acalabrutinib is given alone for the first three 28-day cycles, with venetoclax added from Cycle 4. Treatment repeats every 28 days for up to 26 cycles.
24 months
Monthly visits for 26 cycles
Follow-up
Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 12 weeks and annually for 10 years.
10 years
Participant Groups
The trial is testing the combination of two drugs: Acalabrutinib and Venetoclax in patients whose chronic lymphocytic leukemia or small lymphocytic lymphoma hasn't responded to previous treatments. The goal is to see if this drug combo can better halt cancer growth by blocking enzymes needed for cell growth and killing cancer cells.
1Treatment groups
Experimental Treatment
Group I: Treatment (acalabrutinib, venetoclax)Experimental Treatment7 Interventions
Patients receive acalabrutinib PO BID and venetoclax PO QD on days 1-28. Patients receive acalabrutinib alone for the first three 28 day cycles. Venetoclax is added beginning with Cycle 4. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
Patients also undergo blood sample collection, bone marrow aspiration and biopsy, and CT or MRI throughout the trial.
Acalabrutinib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Calquence for:
- Mantle cell lymphoma
- Chronic lymphocytic leukemia
- Small lymphocytic lymphoma
🇪🇺 Approved in European Union as Calquence for:
- Chronic lymphocytic leukemia
- Small lymphocytic lymphoma
- Mantle cell lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Fred Hutch/University of Washington Cancer ConsortiumSeattle, WA
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Who Is Running the Clinical Trial?
Fred Hutchinson Cancer Research CenterLead Sponsor
Fred Hutchinson Cancer CenterLead Sponsor
AstraZenecaIndustry Sponsor
References
Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. [2021]Both continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax-obinutuzumab are effective for previously untreated chronic lymphocytic leukaemia. We hypothesised that frontline time-limited, minimal residual disease (MRD)-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deep (ie, more patients with undetectable MRD) and durable remissions.
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: 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.
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). .
Impact of Minimal Residual Disease on Progression-Free Survival Outcomes After Fixed-Duration Ibrutinib-Venetoclax Versus Chlorambucil-Obinutuzumab in the GLOW Study. [2023]In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment.
Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. [2020]Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.
Real-world evidence on venetoclax in chronic lymphocytic leukemia: The Italian experience. [2023]Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western world. In Italy, venetoclax was approved for use in patients with CLL as monotherapy in 2017 and in combinations in 2019. As a result of this delayed approval, there are relatively few real-world studies from Italian clinical practice and much of the data are in heavily pretreated patients. We have collected the available studies in Italian routine practice. Three studies confirm the effectiveness and tolerability of this agent in patients with relapsed/refractory CLL and high-risk disease characteristics, many of whom had received prior B-cell receptor signaling treatment. Addition of rituximab to venetoclax produced more complete responses in patients with relapsed/refractory CLL, while higher disease burden and progression while receiving a prior Bruton's tyrosine kinase inhibitor were both associated with poorer outcomes in patients treated with venetoclax. Venetoclax was well-tolerated with low discontinuation rates. No studies of venetoclax plus obinutuzumab for the first-line treatment of patients with CLL were available due to the short time since approval in Italy. Several cohorts addressed the impact of COVID-19 on patient management and outcomes, suggesting that treated patients and those in clinical observation had similar rates of COVID-19-related hospital admission, intensive care unit admission, and mortality. Overall, the responses and tolerance to venetoclax observed in the Italian real-world setting confirm the tolerability and effectiveness of venetoclax regimens in high-risk patients.