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

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well acalabrutinib and venetoclax with or without early obinutuzumab work for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma that is high risk, has come back (recurrent), or does not respond to treatment (refractory). Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax may stop the growth cancer cells by blocking BCL-2 protein needed for cell growth. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving acalabrutinib and venetoclax together with early obinutuzumab may improve clinical outcomes and control the disease.

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.

What data supports the effectiveness of the drug combination Acalabrutinib, Venetoclax, and Obinutuzumab for treating Chronic Lymphocytic Leukemia?

Research shows that the combination of Venetoclax and Obinutuzumab is effective for treating Chronic Lymphocytic Leukemia, leading to longer progression-free survival and higher response rates compared to other treatments. Additionally, Acalabrutinib and Venetoclax have been effective as individual therapies, suggesting that their combination could provide deep and lasting remissions. ^{1 2 3 4 5}

Is the combination of Acalabrutinib, Venetoclax, and Obinutuzumab safe for treating chronic lymphocytic leukemia?

Venetoclax combined with Obinutuzumab has been shown to have an acceptable safety profile for treating chronic lymphocytic leukemia, though it can cause significant neutropenia (a drop in white blood cells), which is manageable with supportive care and dose adjustments. ^{2 3 5 6 7}

What makes the drug combination of Acalabrutinib, Venetoclax, and Obinutuzumab unique for treating Chronic Lymphocytic Leukemia?

This drug combination is unique because it targets cancer cells in multiple ways: Acalabrutinib blocks a protein that helps cancer cells grow, Venetoclax helps kill cancer cells by making them self-destruct, and Obinutuzumab is an antibody that helps the immune system attack cancer cells. This multi-pronged approach may offer a more effective treatment option compared to using these drugs individually. ^{8 9 10 11 12}

Research Team

William G Wierda, MD, PhD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. [2021]

2. England 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. [2020]

3. England 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. [2022]

4. France pubmed.ncbi.nlm.nih.gov

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

5. New Zealand pubmed.ncbi.nlm.nih.gov

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

6. United States pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. [2022]

8. Switzerland 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). [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Phase I/II trial of continuous infusion vinorelbine for advanced breast cancer. [2018]

10. England 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. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Taxanes Plus Trastuzumab Compared To Oral Vinorelbine Plus Trastuzumab in HER2-Overexpressing Metastatic Breast Cancer. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Optimizing clinical care of patients with metastatic breast cancer: a new oral vinorelbine plus trastuzumab combination. [2020]