Venetoclax + Chemotherapy for Richter's Syndrome

Not currently recruiting at 3 trial locations

Overseen By Celeste Carey

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Immunosuppressants, CYP3A inducers

Disqualifiers: Hodgkin variant, 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

Compensation: Varies

Number of Visits: 3

Duration: 6-8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs to treat Richter's Syndrome, where chronic lymphocytic leukemia transforms into a more aggressive form called diffuse large B-cell lymphoma. The study combines venetoclax, a new oral drug, with standard chemotherapy regimens, R-EPOCH (also known as DA-EPOCH-R) or R-CHOP, to evaluate the effectiveness of this combination. Individuals with a confirmed diagnosis of chronic lymphocytic leukemia that has transformed into this aggressive type of lymphoma might be suitable for this trial. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of participants, offering them a chance to potentially benefit from a promising new therapy.

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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong inhibitors or inducers of CYP3A, and you must stop any anti-cancer therapy 14 days before starting the trial, except for ibrutinib or acalabrutinib, which can be continued until the day before starting venetoclax.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study tested the combination of venetoclax with the chemotherapy treatment R-EPOCH in patients with Richter's Syndrome. The results showed that many patients tolerated this combination well. Half of the patients experienced a complete response, meaning their cancer was no longer detectable after treatment.

Another study examined venetoclax with R-CHOP, a different chemotherapy treatment, involving 206 patients. This research focused on safety and effectiveness, finding that the combination was generally safe for most participants.

Both venetoclax and the chemotherapy drugs used have been studied before and are known to be relatively safe for other conditions. However, chemotherapy can cause common side effects like nausea, tiredness, and hair loss. Discussing these potential effects with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard chemotherapy treatments for Richter's Syndrome, like R-CHOP and DA-EPOCH-R, the investigational treatments VR-EPOCH and VR-CHOP incorporate a novel drug called venetoclax. Venetoclax is a Bcl-2 inhibitor, which means it specifically targets and disrupts a protein that helps cancer cells survive. This targeted approach could lead to more effective and potentially less toxic treatments. Researchers are excited because combining venetoclax with traditional chemotherapy could enhance the treatment's power, offering hope for improved outcomes in a condition that is notoriously tough to treat.

What evidence suggests that this trial's treatments could be effective for Richter's Syndrome?

This trial will evaluate the addition of venetoclax to traditional chemotherapy treatments for Richter's Syndrome. Participants will receive either the VR-EPOCH regimen, which combines venetoclax with DA-EPOCH-R, or the VR-CHOP regimen, which combines venetoclax with R-CHOP. Studies have shown that adding venetoclax to DA-EPOCH-R led to half of the patients experiencing a complete response, with an average survival time of about 19.6 months. Similarly, venetoclax combined with R-CHOP has produced positive results, improving patient response to treatment for this aggressive disease. These findings suggest that adding venetoclax to standard chemotherapy may enhance treatment effectiveness for Richter's Syndrome, offering hope for better management of this challenging condition. ^{2 4 5 6 7}

Who Is on the Research Team?

Matthew S. Davids

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax in combination with either R-EPOCH or R-CHOP chemotherapy regimen

6-8 weeks

Chemotherapy cycles every 3 weeks, initial venetoclax dose ramp-up over 5 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• DA-EPOCH-R
• R-CHOP
• Venetoclax

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.

How Is the Trial Designed?

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

DA-EPOCH-R is already approved in United States for the following indications:

Approved in United States as DA-EPOCH-R for:

• Non-Hodgkin lymphoma
• Diffuse large B-cell lymphoma

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

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 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 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 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]

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]

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]

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]

Citations

1. oncologynewscentral.com oncologynewscentral.com/article/adding-venetoclax-to-r-epoch-improves-response-in-patients-with-richters-syndrome

Venetoclax (Venclexta) Improves Response in Patients ... Results from a phase 2 trial point to a more effective treatment for patients with Richter's syndrome, an aggressive form of chronic ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11720094/

Updates in the Management of Richter Transformation - PMC A single-arm phase II trial of venetoclax (ramp up to 400 mg, dosed days 22–27 in cycle 1 and days 1–10 in subsequent cycles) plus DA-EPOCH-R ( ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03054896

NCT03054896 | A Phase II Study of Venetoclax in ... A small number of patients with Richter's Syndrome have been treated with venetoclax as a single drug, and some of these patients had improvement of their ...

4. onclive.com onclive.com/view/novel-strategies-in-managing-patients-with-high-risk-chronic-lymphocytic-leukemia

Novel Strategies in Managing Patients With High-Risk ... Unfortunately, clinical trial data to guide us aren't significant. We did have a poster presentation looking at the use of venetoclax in various ...

5. researchgate.net researchgate.net/publication/344357319_A_phase_II_study_of_venetoclax_plus_R-CHOP_as_first-line_treatment_for_patients_with_diffuse_large_B-cell_lymphoma

A phase II study of venetoclax plus R-CHOP as first-line ... In a pivotal phase 2 trial known as CAVALLI, the therapeutic efficacy and safety of combining venetoclax with R-CHOP chemotherapy were assessed in 206 patients ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8814674/

Venetoclax plus dose-adjusted R-EPOCH for Richter ... Richter syndrome responds poorly to chemotherapy and has a median survival of 3 to 6 months. Davids et al report results of a phase 2 trial of venetoclax ...

7. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2017-00489

Venetoclax, Rituximab, and Combination Chemotherapy in ... This phase II trial studies how well venetoclax, rituximab, and combination chemotherapy works in treating patients with Richter syndrome.