Venetoclax + Chemotherapy for Richter's Syndrome

Recruiting at3 trial locations

Overseen by Matthew S. Davids

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Waitlist Available

Sponsor: Dana-Farber Cancer Institute

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This research study is evaluating the combination of a study drug, venetoclax, and a standard chemotherapy regimen, R-EPOCH or R-CHOP, as a possible treatment for Richter's Syndrome. The drugs involved in this study are: * Venetoclax * R-EPOCH: * Rituximab * Etoposide * Prednisone * Vincristine Sulfate (Oncovin) * Cyclophosphamide * Doxorubicin Hydrochloride (Hydroxydaunomycin) * R-CHOP: * Rituximab * Cyclophosphamide Vincristine * Doxorubicin Hydrochloride (Hydroxydaunomycin) * Sulfate (Oncovin) * Prednisone

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

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have received any anti-cancer therapy within 14 days before starting the trial, and certain medications like strong inhibitors or inducers of CYP3A are not allowed. If you're on ibrutinib or acalabrutinib, you can continue until the day before starting venetoclax. It's best to discuss your specific medications with the trial team.

What data supports the idea that Venetoclax + Chemotherapy for Richter's Syndrome is an effective treatment?

The available research shows that combining Venetoclax with chemotherapy for Richter's Syndrome led to a complete response in 50% of patients, meaning their cancer was no longer detectable. Additionally, 62% of patients had a positive response overall. This combination treatment also resulted in deeper and more lasting responses compared to past treatments. However, it did come with some side effects, like low blood cell counts and fever. This suggests that Venetoclax with chemotherapy is a promising option for treating Richter's Syndrome. ^{1 2 3 4 5}

What safety data is available for Venetoclax + Chemotherapy in treating Richter's Syndrome?

The combination of Venetoclax with dose-adjusted EPOCH-R (VR-EPOCH) has been studied in a phase 2 trial for Richter's Syndrome. The trial involved 26 patients, with 50% achieving complete response and an overall response rate of 62%. Hematologic toxicities were significant, including grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38% of patients. No tumor lysis syndrome was observed with the daily venetoclax ramp-up. The study suggests that VR-EPOCH is active in RS, with deeper and more durable responses than historical regimens, but also highlights the toxicities associated with this intensive treatment. ^{1 2 3 6 7}

Is the drug Venetoclax combined with chemotherapy a promising treatment for Richter's Syndrome?

Yes, Venetoclax combined with chemotherapy shows promise for treating Richter's Syndrome. In a study, 50% of patients achieved a complete response, and the overall response rate was 62%. This suggests that the drug can help improve outcomes for patients with this condition. ^{1 2 3 7 8}

Research Team

Matthew S. Davids

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma that has transformed into diffuse large B cell lymphoma (Richter's Syndrome) can join. They must have certain blood counts, liver and kidney function within set limits, and agree to use contraception. Excluded are those with bleeding disorders, recent cancer treatments, HIV/HBV/HCV infections, significant heart disease, CNS involvement, severe allergies to trial drugs or who are pregnant.

Inclusion Criteria

My blood test results meet the required levels, unless my bone marrow is significantly affected.

Ability to understand and sign a written informed consent document

Agree to use adequate contraception prior to study entry and for the duration of study participation

Exclusion Criteria

I have been treated with R-CHOP, R-EPOCH, or R-hyper-CVAD.

I do not have bleeding disorders, recent major surgery, heart disease, severe infections, or am not pregnant/breastfeeding.

I am not on any other clinical trials, have no brain involvement, normal heart rhythm, not on blood thinners like warfarin, and can take infection prevention treatments.

Treatment Details

Interventions

• DA-EPOCH-R (Chemotherapy)
• R-CHOP (Chemotherapy)
• Venetoclax (BCL-2 Inhibitor)

Trial Overview The trial is testing the effectiveness of Venetoclax combined with standard chemotherapy regimens R-EPOCH or R-CHOP in treating Richter's Syndrome. Participants will receive Venetoclax alongside a mix of other drugs including Rituximab and various chemotherapeutic agents like Etoposide and Cyclophosphamide.

Participant Groups

Group I: VR-EPOCH Experimental Treatment 2 Interventions

* Standard chemotherapy regimen, DA-EPOCH-R, with a novel oral Bcl-2 inhibitor, venetoclax will be administered to patients * Chemotherapy cycles will be administered approximately every 3 weeks * Initial venetoclax dose ramp-up will be done in a condensed fashion over approximately 5 days, followed by continuous daily dosing

Group II: VR-CHOP Experimental Treatment 2 Interventions

* Standard chemotherapy regimen, R-CHOP, with a novel oral Bcl-2 inhibitor, venetoclax will be administered to patients * Chemotherapy cycles will be administered approximately every 3 weeks * Initial venetoclax dose ramp-up will be done in a condensed fashion over approximately 5 days, followed by continuous daily dosing

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Dr. Benjamin L. Ebert

Dana-Farber Cancer Institute

Chief Executive Officer

MD from Harvard Medical School, PhD from Oxford University

Dr. Craig A. Bunnell

Dana-Farber Cancer Institute

Chief Medical Officer since 2012

MD from Harvard Medical School, MPH from Harvard School of Public Health, MBA from MIT Sloan School of Management

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 1 study involving 30 patients with aggressive B-cell lymphomas, the combination of venetoclax and dose-adjusted EPOCH-R demonstrated a high overall response rate of 96.7%, with 93.3% achieving a complete response, indicating strong efficacy in this high-risk population.

The maximum tolerated dose of venetoclax was determined to be 800 mg for 10 days, with a recommended phase 2 dose of 600 mg for 5 days, showing an acceptable safety profile despite common adverse events like cytopenias and febrile neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study. Rutherford, SC., Abramson, JS., Bartlett, NL., et al.[2021]

In a phase 2 trial involving 26 patients with Richter syndrome, the combination of venetoclax and VR-EPOCH resulted in a 50% complete response rate, with 11 patients achieving undetectable minimal residual disease, indicating significant efficacy in treating this chemoresistant condition.

Despite notable hematologic toxicities, including high rates of neutropenia and thrombocytopenia, the treatment did not lead to tumor lysis syndrome, suggesting a manageable safety profile for venetoclax when used in this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome. Davids, MS., Rogers, KA., Tyekucheva, S., et al.[2023]

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 study of 323 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), a daily dose of 400 mg of venetoclax resulted in a median progression-free survival (PFS) of 1.8 years.

The addition of 6 cycles of rituximab to venetoclax treatment significantly increased the median PFS to 3.9 years, demonstrating a synergistic effect that enhances treatment efficacy beyond increasing the venetoclax dose alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. Freise, KJ., Jones, AK., Menon, RM., et al.[2018]

The MURANO trial demonstrated that the combination of venetoclax and rituximab (VenR) significantly improves progression-free survival (PFS) and overall survival (OS) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) compared to bendamustine and rituximab (BR), with a median PFS of 53.6 months for VenR versus 17.0 months for BR.

Patients treated with VenR who achieved undetectable minimal residual disease (uMRD) at the end of treatment had a 3-year overall survival rate of 95.3%, indicating that achieving uMRD is associated with better long-term outcomes, and no new safety concerns were identified during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Seymour, JF., Kipps, TJ., Eichhorst, BF., et al.[2023]

In a pooled analysis of 150 patients with HIV-associated aggressive B-cell non-Hodgkin lymphoma, those treated with R-EPOCH showed significantly better event-free survival (EFS) and overall survival (OS) compared to those receiving R-CHOP, particularly in patients with a CD4 count ≥100/μL.

Patients with CD4 counts <50/μL experienced a much higher rate of treatment-related deaths (37% vs 6%), indicating that lower immune function increases the risk of lethal toxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Barta, SK., Lee, JY., Kaplan, LD., et al.[2022]

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]

Venetoclax, a BCL2 inhibitor, has shown significant clinical benefits for patients with relapsed/refractory chronic lymphocytic leukaemia (CLL), but it carries a risk of tumour lysis syndrome (TLS) due to rapid tumour debulking.

The use of predose monitoring and a gradual dose escalation schedule for venetoclax has been effective in mitigating the risk of TLS while providing sustained clinical benefits to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical management of tumour lysis syndrome in venetoclax-treated patients with chronic lymphocytic leukaemia. Gribben, JG.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study. [2021]

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

Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome. [2023]

3. France pubmed.ncbi.nlm.nih.gov

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

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

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. [2018]

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

Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. [2023]

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

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. [2022]

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

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

8. England pubmed.ncbi.nlm.nih.gov

Practical management of tumour lysis syndrome in venetoclax-treated patients with chronic lymphocytic leukaemia. [2023]