Venetoclax + Obinutuzumab +/- Acalabrutinib for Chronic Lymphocytic Leukemia

Recruiting at 2 trial locations

Overseen By Jacob D. Soumerai, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: BTK inhibitors, BCL2 inhibitors

Disqualifiers: Richter's transformation, Active malignancy, HIV, 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: 2-3 years

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of drugs—venetoclax, obinutuzumab, and sometimes acalabrutinib (a Bruton's tyrosine kinase inhibitor)—can effectively treat chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The study aims to identify the best drug mix to manage these cancers. Participants with CLL or SLL who have previously received treatment and require further therapy may be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot take strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9, and CYP2C19 within 7 days before starting the study drugs. Also, avoid grapefruit, Seville oranges, and star fruit within 3 days before starting. If you're on dual antiplatelet therapy or warfarin, you cannot participate.

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

Research has shown that patients generally tolerate the combination of venetoclax and obinutuzumab well. In past studies, side effects were manageable and not severe. Common side effects include low blood cell counts and tiredness, but these can often be managed with extra care.

Studies have found acalabrutinib to be safe and effective for treating chronic lymphocytic leukemia (CLL). Large studies in Europe showed that patients tolerate acalabrutinib well. Compared to traditional treatments that combine chemotherapy and immune-targeting drugs, acalabrutinib has fewer and less severe side effects. The most common side effects are headache, diarrhea, and muscle pain, but these are usually mild.

Overall, previous studies have shown the treatments in this trial to be safe. Participants have generally tolerated the treatments well, with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Venetoclax, Obinutuzumab, and Acalabrutinib for treating chronic lymphocytic leukemia (CLL) because it offers a unique multi-targeted approach. Unlike traditional chemotherapy or single-agent therapies, this combination targets different pathways in cancer cells, potentially leading to better outcomes. Venetoclax specifically targets and inhibits BCL-2, a protein that helps cancer cells survive, while Obinutuzumab is an antibody that targets CD20 on B-cells, marking them for destruction. Acalabrutinib adds another layer by inhibiting Bruton’s tyrosine kinase, which is essential for CLL cell survival and proliferation. This comprehensive targeting could result in deeper remissions and a reduction in detectable minimal residual disease (MRD), which is promising for longer-lasting control of the disease.

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

Research has shown that combining the drugs venetoclax and obinutuzumab holds promise for treating chronic lymphocytic leukemia (CLL). This treatment effectively reduces cancer cells, leading to significant patient improvements. In this trial, some participants will receive venetoclax and obinutuzumab alone, while others may also receive acalabrutinib. Acalabrutinib, another drug under study, has demonstrated a high success rate in CLL patients. Specifically, one study found that 83% of patients taking acalabrutinib experienced no cancer growth or spread. These drugs work together to target and reduce leukemia cells, offering hope for individuals with CLL or small lymphocytic lymphoma (SLL). ^{1 2 6 7 8}

Who Is on the Research Team?

Jacob D. Soumerai, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults over 18 with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who need treatment and have previously received systemic therapy. They must be in good enough health, not pregnant, agree to contraception, and not have certain heart conditions or other serious illnesses that could interfere with the study.

Inclusion Criteria

I am over 18 years old.

I have been diagnosed with CLL or SLL.

For females of childbearing potential, a negative serum pregnancy test within 7 days of study treatment

Exclusion Criteria

My CLL has transformed into an aggressive form of lymphoma.

I have not had a brain hemorrhage or stroke in the last 6 months.

I do not have any current infections or recent major infections that required IV antibiotics or hospitalization.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive obinutuzumab and venetoclax, with acalabrutinib added for those with detectable MRD or progression

2-3 years

Monthly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Regular follow-up visits

Extension

Participants with progression on VO may continue acalabrutinib indefinitely

Indefinite

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The trial is testing a combination of drugs: obinutuzumab, venetoclax, and possibly acalabrutinib. It aims to find out if these drugs can effectively treat CLL/SLL when given together compared to current standard treatments.

How Is the Trial Designed?

Group I: Venetoclax-Obinutuzumab +/- Acalabrutinib Experimental Treatment 3 Interventions

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)

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?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

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

Published Research Related to This Trial

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, an oral BCL-2 inhibitor, combined with obinutuzumab, has demonstrated superior efficacy compared to traditional chemoimmunotherapy in both treatment-naive and relapsed/refractory chronic lymphocytic leukemia (CLL) patients.

Obinutuzumab, a novel anti-CD20 monoclonal antibody, has been safely used with other targeted therapies like venetoclax, showing better outcomes than the older drug rituximab when paired with chlorambucil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update of venetoclax and obinutuzumab in chronic lymphocytic leukemia. Salvaris, R., Opat, S.[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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40736551/

Real-world efficacy and safety outcomes of acalabrutinib in ... NAOS, a real-world study, complements these trials with real-world (rw) acalabrutinib data generated from clinical practice.

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5151/503709/Real-World-Effectiveness-and-Safety-Outcomes-of

Real-World Effectiveness and Safety Outcomes of ... Real-world effectiveness and safety outcomes of Acalabrutinib treatment by line of therapy in patients with chronic lymphocytic leukemia and/or small ...

3. calquence.com calquence.com/why-calquence/how-effective-calquence-cll.html

How Effective Is CALQUENCE® (acalabrutinib)? | CLL 83% (128 of 155) of people on CALQUENCE had no cancer growth or spread compared to 56% (87 of 155) of people taking an alternative combination treatment.§.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1509981

Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic ... At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39463596/

Assessment of the Efficacy and Safety of Acalabrutinib in ... Acalabrutinib is an active drug in treating CLL that induces significant clinical benefits concerning response rates and PFS.

6. hematologyadvisor.com hematologyadvisor.com/news/chronic-leukemia-cll-safety-profile-acalabrutinib-superior-chemoimmunotherapy/

Safety Profile of Acalabrutinib Superior to ... Results of the study showed a significantly lower risk of mortality in the acalabrutinib treatment group compared with the chemoimmunotherapy ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04008706

NCT04008706 | Acalabrutinib Safety Study in Untreated ... To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia.

8. nejm.org nejm.org/doi/full/10.1056/NEJMoa2409804

Fixed-Duration Acalabrutinib Combinations in Untreated ... Acalabrutinib–venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients ...