Triple Drug Therapy for Follicular Lymphoma

Recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Joseph Tuscano

Must not be taking: Strong CYP3A inhibitors

Disqualifiers: CNS lymphoma, HIV, Hepatitis, 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: 24 months

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well obinutuzumab, ibrutinib, and venetoclax work in treating patients with previously untreated stage II-IV follicular lymphoma. Immunotherapy with obinutuzumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Ibrutinib and venetoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving obinutuzumab, ibrutinib, and venetoclax together may work better in treating follicular lymphoma compared to each drug alone.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on a strong CYP3A4 inhibitor, you may need to stop it before starting the trial.

What data supports the effectiveness of the drug combination of Ibrutinib, Obinutuzumab, and Venetoclax for treating follicular lymphoma?

Research shows that the combination of Ibrutinib, Obinutuzumab, and Venetoclax is effective in treating mantle cell lymphoma, with high response rates and good tolerance. Additionally, Venetoclax combined with Obinutuzumab has shown significant benefits in chronic lymphocytic leukemia, suggesting potential effectiveness in similar blood cancers like follicular lymphoma. ^{1 2 3 4 5}

Is the triple drug therapy for follicular lymphoma generally safe for humans?

The combination of ibrutinib and venetoclax has shown an acceptable safety profile in studies for other conditions like chronic lymphocytic leukemia and mantle cell lymphoma. Notable side effects such as neutropenia (low white blood cell count) can be managed with supportive care and dose adjustments. No new safety concerns were observed in these studies. ^{1 4 5 6 7}

How is the triple drug therapy for follicular lymphoma unique?

The triple drug therapy for follicular lymphoma combines ibrutinib, obinutuzumab, and venetoclax, which are known for their effectiveness in other types of blood cancers like chronic lymphocytic leukemia (CLL). This combination is unique because it targets cancer cells in multiple ways, potentially offering a chemotherapy-free option with a distinct safety profile compared to traditional treatments. ^{1 3 4 5 8}

Research Team

Joseph M. Tuscano

Principal Investigator

University of California, Davis

Eligibility Criteria

This trial is for adults with previously untreated stage II-IV follicular lymphoma. Participants must have measurable disease, not be pregnant or breastfeeding, and agree to use reliable contraception. They should not have severe illnesses that could interfere with the study, known HIV or hepatitis infections, significant heart conditions, or a history of certain other malignancies.

Inclusion Criteria

I need treatment for my condition.

Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [B-hCG]) pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study

Able and willing to provide written informed consent and to comply with the study protocol

Exclusion Criteria

My condition is Grade 3b follicular lymphoma.

I had major surgery less than 2 weeks ago.

I have a known bleeding disorder like von Willebrand's or hemophilia.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive obinutuzumab, venetoclax, and ibrutinib. Obinutuzumab is administered intravenously on specific days across 24 cycles, while venetoclax and ibrutinib are taken orally daily.

24 months

Multiple visits per cycle for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

2 years

Periodic visits

Treatment Details

Interventions

• Ibrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The trial tests a combination of three drugs: Obinutuzumab (an immunotherapy), Ibrutinib and Venetoclax (both target enzymes needed for cancer cell growth). It aims to see if using these drugs together is more effective than when they're used separately in treating follicular lymphoma.

Participant Groups

Group I: Treatment (obinutuzumab, venetoclax, ibrutinib) Experimental Treatment 3 Interventions

Patients receive obinutuzumab IV over 60 minutes on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. Patients also receive venetoclax PO QD on days 1-28 (days 4-28 of cycle 1) and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

Joseph Tuscano

Lead Sponsor

Trials

8

Recruited

180+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Pharmacyclics LLC.

Industry Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

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 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, ibrutinib, and obinutuzumab is well tolerated in patients with relapsed and untreated mantle cell lymphoma (MCL), with no dose-limiting toxicities reported and a maximum tolerated dose of 400 mg per day established for venetoclax.

High response rates were observed, with a complete response rate of 67% in relapsed patients and 86.6% in untreated patients, along with significant minimal residual disease clearance in 71.5% of relapsed and 100% of untreated patients after three cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Le Gouill, S., Morschhauser, F., Chiron, D., et al.[2021]

In a phase 3 trial with 523 patients, the combination of ibrutinib and venetoclax significantly improved progression-free survival compared to the traditional FCR treatment, with only 12 patients experiencing disease progression or death in the ibrutinib-venetoclax group versus 75 in the FCR group.

The study also found that 65.9% of patients on ibrutinib-venetoclax achieved undetectable measurable residual disease (MRD) in bone marrow after 5 years, indicating effective disease control, although there was a higher incidence of serious cardiac adverse events in this group compared to FCR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir, T., Cairns, DA., Bloor, A., et al.[2023]

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

In a retrospective study of 22 patients with chronic lymphocytic leukaemia (CLL) who progressed on ibrutinib, the combination of ibrutinib and venetoclax resulted in a median overall survival of 47.1 months, indicating potential efficacy in this challenging patient group.

For 11 patients with double-refractory CLL, the same combination therapy led to a median overall survival of 27.0 months, suggesting that this treatment may provide a valuable option for patients who have limited alternatives after failing standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia. Hampel, PJ., Rabe, KG., Call, TG., et al.[2022]

In a safety run-in cohort of 21 patients with relapsed/refractory mantle cell lymphoma, the combination of ibrutinib and venetoclax showed an impressive overall response rate of 81%, with 62% achieving a complete response after a median follow-up of 31 months.

The study indicated that concurrent administration of ibrutinib and venetoclax is safe, with only three dose-limiting toxicities observed and no new safety concerns, allowing the trial to proceed without an ibrutinib lead-in.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. Wang, M., Ramchandren, R., Chen, R., et al.[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]

Ibrutinib, idelalisib, and venetoclax are effective B cell signaling agents for treating non-Hodgkin's lymphomas, but they come with distinct toxicity profiles that differ from traditional chemotherapy.

Ibrutinib can increase the risk of atrial fibrillation and bleeding, while idelalisib requires close monitoring of liver function and infection risks, and venetoclax necessitates careful monitoring to prevent tumor lysis syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring and Management of Toxicities of Novel B Cell Signaling Agents. Rhodes, J., Mato, A., Sharman, JP.[2021]

References

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

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

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

Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. [2021]

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

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. [2023]

4. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax for treatment of patients with ibrutinib-resistant or double-refractory chronic lymphocytic leukaemia. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. [2021]

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

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

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

Monitoring and Management of Toxicities of Novel B Cell Signaling Agents. [2021]