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

Trial Summary

What is the purpose of this trial?

This research study is studying a combination of drugs as a possible treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The names of the study drugs involved in this study are: * obinutuzumab * venetoclax * acalabrutinib

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.

What data supports the idea that Venetoclax + Obinutuzumab +/- Acalabrutinib for Chronic Lymphocytic Leukemia is an effective drug?

The available research shows that the combination of Venetoclax and Obinutuzumab is effective for treating Chronic Lymphocytic Leukemia. In a study comparing this combination to another treatment (Chlorambucil plus Obinutuzumab), patients who received Venetoclax and Obinutuzumab had longer periods without the disease getting worse. They also had higher rates of the disease being undetectable and better overall responses. Another study found that adding Acalabrutinib to Venetoclax and Obinutuzumab could lead to even deeper and longer-lasting remissions. These findings suggest that Venetoclax and Obinutuzumab, with or without Acalabrutinib, are effective options for treating this type of leukemia. ^{1 2 3 4 5}

What safety data is available for the treatment of Venetoclax, Obinutuzumab, and Acalabrutinib in CLL?

The combination of Venetoclax and Obinutuzumab has been studied in the CLL14 trial, showing an acceptable tolerability profile with notable adverse events like grade 3 or 4 neutropenia, which can be managed with supportive therapy and dose modifications. The incidence of grade 3-4 neutropenia was reported between 52.8%-57.7%. Acalabrutinib, when added to Venetoclax and Obinutuzumab, is being evaluated for its potential to induce deep and durable remissions in CLL patients, but specific safety data for this triplet combination is not detailed in the provided studies. ^{1 2 3 4 6}

Is the drug combination of Acalabrutinib, Obinutuzumab, and Venetoclax promising for treating Chronic Lymphocytic Leukemia?

Yes, the drug combination of Acalabrutinib, Obinutuzumab, and Venetoclax is promising for treating Chronic Lymphocytic Leukemia. Venetoclax and Obinutuzumab have shown to be effective in improving progression-free survival and response rates compared to traditional chemotherapy. This combination offers a chemotherapy-free option, which is beneficial for patients who cannot tolerate intensive treatments. ^{1 2 4 6 7}

Research Team

Jacob D. Soumerai, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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 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 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 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]

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]

References

1. 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]

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

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

3. 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]

4. 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]

5. France pubmed.ncbi.nlm.nih.gov

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

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

An update of venetoclax and obinutuzumab in chronic lymphocytic leukemia. [2021]