Venetoclax + Obinutuzumab for Chronic Lymphocytic Leukemia

Not currently recruiting at 15 trial locations

Overseen By Jae Park, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Warfarin, CYP3A inhibitors, others

Disqualifiers: Prior CLL therapy, Active infection, 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: 9-21 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining venetoclax and obinutuzumab for individuals with chronic lymphocytic leukemia (CLL) who have not received prior treatment. Researchers seek to determine if these medications can effectively target and treat CLL cancer cells. Individuals with a confirmed CLL diagnosis who require treatment but have not yet begun any cancer therapy may be suitable candidates for this study. Participants will receive these medications over several cycles to assess their impact on leukemia. As a Phase 2 trial, this study focuses on measuring the treatment's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to significant research.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot use warfarin or certain other drugs that interact with the study medications. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that the combination of venetoclax and obinutuzumab is likely to be safe for humans?

Research has shown that the combination of venetoclax and obinutuzumab has been studied for safety in treating chronic lymphocytic leukemia (CLL). In studies with patients who had not received prior treatment, this combination helped patients live longer without disease progression compared to treatments like chlorambucil. Patients generally tolerated venetoclax and obinutuzumab well, with manageable side effects. The FDA has approved this treatment for similar conditions, indicating a known safety record. Overall, evidence suggests that this combination is relatively safe. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for CLL?

Researchers are excited about venetoclax and obinutuzumab for chronic lymphocytic leukemia (CLL) because these drugs work together in a unique way. Venetoclax targets and disrupts a protein called BCL-2, which helps cancer cells survive, leading to their death. Obinutuzumab, on the other hand, is an antibody that targets CD20 on the surface of cancer cells, marking them for destruction by the immune system. Unlike traditional chemotherapy, which can have widespread effects on the body, this combination specifically targets cancer cells, potentially offering a more effective and less toxic treatment option for CLL patients.

What evidence suggests that the combination of venetoclax and obinutuzumab is effective for treating chronic lymphocytic leukemia?

Research has shown that the combination of venetoclax and obinutuzumab, which participants in this trial will receive, effectively treats chronic lymphocytic leukemia (CLL). A major study found that this combination led to 6-year progression-free survival (PFS) rates of 53%, meaning that over half of the patients experienced no disease worsening after six years. The time to next treatment (TTNT) rate was also high at 65%, indicating that many patients did not require another treatment for an extended period. This treatment often proves more effective than older chemoimmunotherapy methods. These results suggest that venetoclax and obinutuzumab can provide lasting, long-term remission for people newly diagnosed with CLL. ^{6 7 8 9 10}

Who Is on the Research Team?

Meghan Thompson, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with untreated chronic lymphocytic leukemia who are generally in good health and have normal organ function. They must be able to perform daily activities with ease or only limited assistance (ECOG Performance Status of 0 or 1). Participants need to agree to use effective contraception and not donate sperm or eggs. People with a history of other cancers, significant infections, liver disease, positive tests for hepatitis B/C or HIV, recent major surgery, inability to swallow tablets, known drug allergies, or those requiring warfarin are excluded.

Inclusion Criteria

AST or ALT ≤ 2.5 x ULN

My hemoglobin level is at least 8 g/dL without needing a blood transfusion.

My blood counts are within normal ranges, not affected by my condition.

Exclusion Criteria

I had or have hidden hepatitis B but no active virus, and I agree to monthly DNA tests.

I have had treatment for CLL, but may have taken steroids for less than a week to manage symptoms.

I had surgery for early-stage, low-grade prostate cancer and currently show no signs of the disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a minimum of 9 cycles of therapy with venetoclax and obinutuzumab, with each cycle lasting 28 days. Additional 12 cycles of venetoclax monotherapy for MRD positive patients at Cycle 9.

9-21 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Venetoclax

Trial Overview The trial is testing the effectiveness of combining two drugs: Venetoclax and Obinutuzumab in treating CLL. The study includes adults who haven't been treated before for their cancer. It aims to gather more data on how well these drugs work together when given as an initial treatment.

How Is the Trial Designed?

Group I: Venetoclax and Obinutuzumab Experimental Treatment 2 Interventions

All patients will receive a minimum of 9 cycles (cycle = 28 days) of therapy with venetoclax and obinutuzumab during the treatment period. For patients who remain MRD positive at Cycle 9 of therapy, an additional 12 cycles of venetoclax monotherapy will be given.

Obinutuzumab is already approved in United States, European Union for the following indications:

Approved in United States as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Approved in European Union as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

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 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]

The study analyzed pharmacokinetics and exposure-response parameters of a 400 mg once-daily venetoclax regimen combined with obinutuzumab in 274 patients, confirming its suitability for first-line treatment of chronic lymphocytic leukemia (CLL).

No significant correlations were found between venetoclax exposure and progression-free survival or severe treatment-emergent adverse events, indicating that the treatment is both effective and safe at the studied dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. Samineni, D., Gibiansky, L., Wang, B., et al.[2022]

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]

The combination of venetoclax and obinutuzumab was found to be safe and well-tolerated in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia, with no dose-limiting toxicities observed during the study.

The treatment resulted in a high overall response rate of 95% in relapsed/refractory patients and 100% in previously untreated patients, with significant rates of undetectable minimal residual disease, indicating effective disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Flinn, IW., Gribben, JG., Dyer, MJS., et al.[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]

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

Citations

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VENCLEXTA efficacy results: 6-year overall survival 1 Learn about VENCLEXTA® 6-year overall survival and treatment efficacy results. See full safety and Prescribing Information for more details.

2. ashpublications.org ashpublications.org/blood/article/144/18/1924/516941/Venetoclax-obinutuzumab-for-previously-untreated

6-year results of the randomized phase 3 CLL14 study | Blood One-year fixed-duration Ven-Obi results in durable treatment-free remissions, with a 6-year PFS rate of 53% and TTNT rate of 65%, in CLL.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic ... Venetoclax–obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11899398/

Real-World Effectiveness of Frontline Treatments Among ... We describe the effectiveness of front-line CLL treatments in adult patients with CLL in real-world settings.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497124018755

6-year results of the randomized phase 3 CLL14 study One-year fixed-duration Ven-Obi results in durable treatment-free remissions, with a 6-year PFS rate of 53% and TTNT rate of 65%, in CLL.

6. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT01685892?term=ABT-199+CLL&rank=7

A Study of Venetoclax in Combination With Obinutuzumab ... This multi-center, open-label, dose-finding study will evaluate the safety and pharmacokinetics as well as the preliminary efficacy of venetoclax (GDC-0199; ...

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa1815281

Venetoclax and Obinutuzumab in Patients with CLL and ... Among patients with untreated CLL and coexisting conditions, venetoclax–obinutuzumab was associated with longer progression-free survival than chlorambucil– ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5026291/

The potential of venetoclax (ABT-199) in chronic lymphocytic ... This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data ...

9. ashpublications.org ashpublications.org/blood/article/129/19/2702/36147/Venetoclax-and-obinutuzumab-in-chronic-lymphocytic

Venetoclax and obinutuzumab in chronic lymphocytic leukemia Here, we report the safety and efficacy results of the run-in phase of the CLL14 trial. ... Our data suggest that venetoclax and obinutuzumab ...

10. venclextahcp.com venclextahcp.com/cll/dosing-and-administration/ven-g-dosing.html

VEN+G Dosing Schedule for CLL/SLL - venclexta VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Important Safety ...