Acalabrutinib + Venetoclax ± Obinutuzumab for Chronic Lymphocytic Leukemia

Overseen By William G Wierda

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 26 cycles (approximately 24-28 months)

168 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of medications for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), particularly in high-risk cases or when the disease has returned or resisted previous treatments. The study examines how well acalabrutinib (a targeted therapy) and venetoclax, with or without obinutuzumab, work together to inhibit cancer cell growth and enhance the immune system's ability to fight cancer. Suitable candidates for this trial include those with CLL or SLL who have not responded to other treatments or have a high-risk form of the disease. As a Phase 2 trial, the study measures the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from promising therapies.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot use warfarin or strong CYP3A inhibitors or inducers within 7 days of starting the study drugs. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of acalabrutinib, venetoclax, and obinutuzumab is under testing for safety and effectiveness in treating chronic lymphocytic leukemia (CLL). Previous studies have shown promising results with these drugs. Acalabrutinib and venetoclax have been tested together for other conditions and appear reasonably safe. Obinutuzumab is also considered safe, as it is already approved for certain types of leukemia.

In studies with these combined drugs, most patients have tolerated them well, although some side effects have been reported. Common side effects include mild to moderate issues like headaches, diarrhea, and fatigue. Serious side effects are less common but can include infections and low blood cell counts.

Since this trial is in a later phase, a lot of safety information is already available. Safety is still being closely monitored, but current evidence suggests these treatments are generally well-tolerated. Always consult a doctor to understand the risks and benefits before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Chronic Lymphocytic Leukemia (CLL) because they offer a novel combination of therapies that might enhance treatment effectiveness. Acalabrutinib and venetoclax work together to target cancer cells in different ways, potentially leading to better outcomes than standard treatments like chemoimmunotherapy. Acalabrutinib is a BTK inhibitor that helps block signals needed for cancer cell survival, while venetoclax is a BCL-2 inhibitor that promotes cancer cell death. The addition of obinutuzumab, an antibody targeting CD20, could further boost the immune system's ability to fight cancer cells. This multi-pronged approach could provide more comprehensive control over CLL with potentially fewer side effects compared to traditional therapies.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research has shown that a combination of three drugs—acalabrutinib, venetoclax, and obinutuzumab—can effectively treat chronic lymphocytic leukemia (CLL). In this trial, participants in Arm I will receive acalabrutinib, venetoclax, and obinutuzumab, while those in Arm II will receive acalabrutinib and venetoclax with early obinutuzumab. One study found that this combination reduced the risk of disease progression or death by 58% compared to standard treatments. As a result, more patients remained in remission longer, with their disease not worsening. Acalabrutinib blocks certain enzymes that cancer cells need to grow. Venetoclax targets a protein called BCL-2, which helps cancer cells survive. Obinutuzumab aids the immune system in attacking cancer cells. Together, these treatments have shown promising results in stopping or slowing down CLL. ^{1 2 3 4 6}

Who Is on the Research Team?

William G Wierda, MD, PhD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with high risk, recurrent, or treatment-resistant chronic lymphocytic leukemia or small lymphocytic lymphoma. Participants must have proper liver function, no recent malignancies (with some exceptions), and adequate kidney function. Women of childbearing age must test negative for pregnancy and agree to use contraception; men must also use contraception. Exclusions include active hepatitis C, uncontrolled autoimmune diseases, significant heart issues, certain dietary restrictions like grapefruit consumption, known bleeding disorders, uncontrolled infections, HIV positivity due to drug interactions risks.

Inclusion Criteria

Total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with Gilbert's disease

My white blood cell count is healthy, not due to cancer in my bone marrow.

My condition did not improve after at least one treatment.

Exclusion Criteria

I have an autoimmune condition needing high-dose steroids.

Patient is pregnant or breast-feeding

You have had serious allergic reactions to certain types of medications made from animals or you are known to be allergic to certain animal products.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib and venetoclax, with or without early obinutuzumab, for up to 26 cycles

26 cycles (approximately 24-28 months)

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The study tests the effectiveness of acalabrutinib and venetoclax in combination with or without early obinutuzumab in treating CLL/SLL. Acalabrutinib blocks enzymes needed by cancer cells to grow; venetoclax targets proteins essential for their growth; obinutuzumab is an immunotherapy that may help the immune system attack cancer cells.

How Is the Trial Designed?

Group I: Arm II (acalabrutinib, venetoclax, early obinutuzumab) Experimental Treatment 3 Interventions

Patients receive acalabrutinib PO BID on days 1-28 beginning cycle 2 and venetoclax PO BID on days 1-28 beginning cycle 3. Patients also receive obinutuzumab IV over 4-6 hours on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2-6. Patients who are BM MRD4-positive or in PR receive obinutuzumab IV over 4-6 hours on day 1 cycles 15-20. Treatment repeats every 28 days (or 42 days for cycle 14) for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (acalabrutinib, venetoclax, obinutuzumab) Active Control 3 Interventions

Patients receive acalabrutinib PO BID on days 1-28. Beginning cycle 3, patients receive venetoclax PO BID on days 1-28. Patients who are BM MRD4-positive or in PR also receive obinutuzumab IV over 4-6 hours on days 1, 2, 8, and 15 of cycle 15 and day 1 of cycles 16-20. Treatment repeats every 28 days (or 42 days for cycle 14) for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

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

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 2 study involving 37 patients with chronic lymphocytic leukaemia, the combination therapy of acalabrutinib, venetoclax, and obinutuzumab achieved a complete remission with undetectable minimal residual disease (MRD) in 38% of participants by cycle 16, indicating promising efficacy.

The treatment was generally well tolerated, with the most common serious adverse event being neutropenia, affecting 43% of patients, and no deaths reported during the study, suggesting a favorable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Davids, MS., Lampson, BL., Tyekucheva, S., et al.[2021]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

The maximum-tolerated dose (MTD) of vinorelbine (VRL) administered via continuous infusion (CIV) was established at 8 mg/m2 bolus plus 10 mg/m2/day for 4 days, with manageable toxicity primarily involving neutropenia and some mucositis, but minimal neurotoxicity.

The trial demonstrated that VRL is effective in treating advanced breast carcinoma, with a 36% objective response rate and a median survival duration of 24 months, suggesting that CIV administration may provide a better therapeutic index compared to traditional weekly dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial of continuous infusion vinorelbine for advanced breast cancer. Toussaint, C., Izzo, J., Spielmann, M., et al.[2018]

The study established the maximum tolerated dose (MTD) for the combination treatment NALIRIFOX in patients with metastatic pancreatic ductal adenocarcinoma, with 32 out of 56 patients receiving the MTD, indicating a manageable safety profile despite some patients experiencing severe treatment-related adverse events.

Patients treated with NALIRIFOX showed a median progression-free survival of 9.2 months and overall survival of 12.6 months, suggesting that this treatment regimen may be effective for this difficult-to-treat cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma: A phase I/II study. Wainberg, ZA., Bekaii-Saab, T., Boland, PM., et al.[2021]

In a phase 3 trial involving 432 patients with untreated chronic lymphocytic leukaemia, the combination of venetoclax plus obinutuzumab resulted in significantly longer progression-free survival compared to chlorambucil plus obinutuzumab, with a hazard ratio of 0.31, indicating a strong treatment advantage.

After a median follow-up of 39.6 months post-treatment, patients receiving venetoclax plus obinutuzumab had not yet reached median progression-free survival, while those on chlorambucil plus obinutuzumab had a median of 35.6 months, highlighting the long-term efficacy of the venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Al-Sawaf, O., Zhang, C., Tandon, M., et al.[2020]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

In a phase I trial involving 23 patients with metastatic colorectal cancer, the recommended dose of capecitabine in combination with oxaliplatin and irinotecan was determined to be 1,400 mg/m² daily, with the regimen showing good tolerability overall.

Despite the treatment being well tolerated, the response rate was low, with only 8 patients achieving a partial response, and median progression-free survival and overall survival were 8.0 and 21.9 months, respectively, suggesting the need for further studies with targeted agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin, irinotecan and capecitabine (OCX) for first-line treatment of advanced/metastatic colorectal cancer: a phase I trial (SAKK 41/03). von Moos, R., Roth, A., Ruhstaller, T., et al.[2018]

In a study of 76 patients with metastatic HER2-positive breast cancer, the combination of oral vinorelbine (OV) and trastuzumab showed a median overall survival (OS) of 59 months, significantly better than the 49 months observed with taxanes plus trastuzumab.

While both treatment groups had similar progression-free survival (PFS) rates, OV plus trastuzumab resulted in a longer brain metastases-free survival (BMFS), suggesting that OV is a promising alternative to taxanes for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Taxanes Plus Trastuzumab Compared To Oral Vinorelbine Plus Trastuzumab in HER2-Overexpressing Metastatic Breast Cancer. Bergen, E., Berghoff, AS., Rudas, M., et al.[2020]

In a phase 2 trial involving 70 patients with chronic lymphocytic leukaemia, both 12 cycles of venetoclax consolidation and minimal residual disease-guided consolidation showed similar effectiveness, with around 50% of patients achieving undetectable minimal residual disease in bone marrow after treatment.

While consolidation treatment did not lead to treatment-related deaths, it was associated with a higher incidence of adverse events, particularly infections, indicating that while it may extend treatment duration, it does not significantly improve disease response or reduce relapse risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Kersting, S., Dubois, J., Nasserinejad, K., et al.[2022]

In a retrospective study of 14 patients with chronic lymphocytic leukemia (CLL) treated with the venetoclax and obinutuzumab (VenG) regimen, 73% developed grade 3 or 4 neutropenia, indicating a high incidence of this side effect.

The study suggests that the high rate of neutropenia may be linked to patients having more comorbidities and high-risk disease features, highlighting the need for further research on supportive treatments to manage this side effect and allow for optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. Samuels, C., Abbott, D., Niemiec, S., et al.[2022]

The combination of oral vinorelbine (oVNR) and trastuzumab (T) in treating advanced breast cancer was well tolerated by patients, with an overall response rate of 43% and a clinical benefit rate of 73% over 24 months.

This new regimen allows for less frequent hospital visits (once every three weeks) compared to the traditional intravenous vinorelbine, improving the quality of life for patients while maintaining effective treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing clinical care of patients with metastatic breast cancer: a new oral vinorelbine plus trastuzumab combination. Catania, C., Medici, M., Magni, E., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03836261

NCT03836261 | Study of Acalabrutinib (ACP-196) in ... This randomized, global, multicenter, open-label, Phase 3 study will evaluate the efficacy and safety of AV and AVG versus chemoimmunotherapy (FCR or BR)

2. astrazeneca.com astrazeneca.com/media-centre/press-releases/2024/fixed-duration-calquence-plus-venetoclax-demonstrated-superior-pfs-vs-standard-care-previously-untreated-cll-with-77-of-patients-progression-free-3-years-amplify-phase-iii-trial.html

Fixed-duration Calquence plus venetoclax demonstrated ... Calquence plus venetoclax with obinutuzumab reduced the risk of disease progression or death by 58% versus standard of care in this setting

3. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-02503

Phase II Study of Acalabrutinib, Venetoclax, and ... This phase II study evaluated acalabrutinib, venetoclax, and obinutuzumab (AVO) with duration guided by measurable residual disease (MRD) in a ...

4. news.abbvie.com news.abbvie.com/2025-07-29-AbbVie-Submits-for-U-S-FDA-Approval-of-Combination-Treatment-of-VENCLEXTA-R-venetoclax-and-Acalabrutinib-for-Previously-Untreated-Patients-with-Chronic-Lymphocytic-Leukemia-CLL

AbbVie Submits for U.S. FDA Approval of Combination ... "This FDA submission marks a milestone for CLL treatment with the potential approval for the first oral combination regimen of VENCLEXTA and ...

5. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/ACE-CL-311

Study of Acalabrutinib (ACP-196) in combination with ... The purpose of this study is to evaluate the efficacy and safety of acalabrutinib in combination with venetoclax and acalabrutinib in combination with ...

6. ashpublications.org ashpublications.org/blood/article/146/11/1276/536611/Acalabrutinib-obinutuzumab-improves-survival-vs

Acalabrutinib-obinutuzumab improves survival vs ... First-line acalabrutinib-obinutuzumab resulted in significantly higher PFS and OS than chemoimmunotherapy regardless of high-risk features.