VIPOR Regimen for CNS-involved B-Cell Lymphoma

Overseen By NCI Medical Oncology Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: BTK inhibitors, Bcl-2 inhibitors

Disqualifiers: HIV, Congestive heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 22

Duration: 18 weeks

14 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial uses a combination of drugs called VIPOR-Nivo to treat adults with specific aggressive brain lymphomas that are hard to treat. The drugs work together to kill cancer cells and boost the immune system.

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 take strong CYP3A inhibitors/inducers or warfarin. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the VIPOR regimen drugs for CNS-involved B-cell lymphoma?

The combination of ibrutinib and venetoclax has shown promising results in treating other types of B-cell lymphomas, such as mantle cell lymphoma, with high response rates and complete responses in some patients. This suggests potential effectiveness for similar conditions. ^{1 2 3 4 5}

What safety data exists for the VIPOR Regimen components in humans?

Ibrutinib can cause bleeding and atrial fibrillation (irregular heartbeat), while venetoclax may lead to tumor lysis syndrome (a condition where cancer cells break down rapidly, potentially harming the kidneys). These side effects can be severe and may require dose adjustments or special monitoring. ^{1 3 6 7 8}

What makes the VIPOR regimen unique for treating CNS-involved B-cell lymphoma?

The VIPOR regimen is unique because it combines multiple drugs, including ibrutinib, lenalidomide, obinutuzumab, prednisone, and venetoclax, which target different pathways involved in B-cell lymphoma. This combination aims to enhance treatment effectiveness by using a multi-faceted approach, potentially offering benefits over traditional single-agent therapies. ^{1 2 9 10 11}

Research Team

Mark J Roschewski, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults aged 18+ with B-cell lymphoma in the CNS that's unresponsive to treatment, relapsed after treatment, or ineligible for standard therapy due to age or kidney function. Must have measurable disease and adequate organ/marrow function. Participants must not be pregnant, agree to use birth control, and can't have certain other cancers needing active treatment.

Inclusion Criteria

Participants must have evaluable disease by clinical exam and/or imaging.

I have a second cancer that doesn't need ongoing treatment.

My organs and bone marrow are working well.

Exclusion Criteria

I have had irregular heartbeats from the lower chambers of my heart.

I cannot swallow pills or have major stomach problems.

I haven't had chemotherapy, radiation, or antibody treatment in the last 7 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles

18 weeks

Visits every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

Periodic follow-up visits

Treatment Details

Interventions

• Ibrutinib
• Lenalidomide
• Obinutuzumab
• Prednisone
• Venetoclax

Trial Overview The VIPOR-Nivo trial is testing a combination of drugs (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Revlimid) on patients with primary diffuse large B-cell lymphoma of the CNS or aggressive B-cell lymphomas with secondary CNS involvement. The study involves up to six 21-day cycles of medication taken orally and by infusion.

Participant Groups

Group I: 1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) Experimental Treatment 15 Interventions

VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Ibrutinib, idelalisib, and venetoclax are novel oral therapies for chronic lymphocytic leukemia that provide unique clinical benefits compared to traditional treatments, but they also come with specific safety concerns and logistical challenges.

Each of these agents has distinct adverse effects: ibrutinib can cause bleeding and atrial fibrillation, idelalisib may lead to hepatotoxicity, and venetoclax carries a risk of tumor lysis syndrome, necessitating careful monitoring and potential dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax. Waldron, M., Winter, A., Hill, BT.[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]

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]

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 retrospective analysis of 4 patients with relapsed/refractory mantle-cell lymphoma (MCL), the combination of ibrutinib and venetoclax resulted in a 50% complete response rate, demonstrating its potential efficacy as a treatment option.

All patients who responded to the treatment were able to undergo allogeneic stem cell transplantation, with two patients remaining in complete remission, indicating that this combination therapy may be a viable bridge to transplant for MCL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in association with venetoclax for the treatment of mantle-cell lymphoma: a multicenter case series. Fabbri, A., Cencini, E., Congiu, AG., et al.[2021]

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]

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 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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax. [2021]

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

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

3. 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]

4. England pubmed.ncbi.nlm.nih.gov

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

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

Ibrutinib in association with venetoclax for the treatment of mantle-cell lymphoma: a multicenter case series. [2021]

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

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia. [2020]

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

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

8. Hungary pubmed.ncbi.nlm.nih.gov

Interdisciplinary approach to the current management of chronic lymphocytic leukemia [2021]

9. England pubmed.ncbi.nlm.nih.gov

Venetoclax with high-dose methotrexate and rituximab seem effective and well-tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report. [2020]

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

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

11. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]