Venetoclax + Chemotherapy for B-Cell Lymphoma

Recruiting at 732 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Strong CYP3A4 inhibitors, inducers

Disqualifiers: Pregnancy, CNS involvement, active 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: 18

Duration: 18 weeks

363 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II/III trial tests whether it is possible to decrease the chance of high-grade B-cell lymphomas returning or getting worse by adding a new drug, venetoclax to the usual combination of drugs used for treatment. Venetoclax may stop the growth of cancer cells by blocking a protein called Bcl-2. Drugs used in usual chemotherapy, such as rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax together with usual chemotherapy may work better than usual chemotherapy alone in treating patients with high-grade B-cell lymphomas, and may increase the chance of cancer going into remission and not returning.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong CYP3A4 inhibitors or inducers at least 14 days before starting venetoclax. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Venetoclax combined with chemotherapy for B-cell lymphoma?

Research shows that combining Venetoclax with chemotherapy drugs like R-CHOP in patients with non-Hodgkin lymphoma, including diffuse large B-cell lymphoma, resulted in high overall response rates of 87.5% and complete response rates of around 79%. This suggests that Venetoclax can enhance the effectiveness of standard chemotherapy in treating aggressive B-cell lymphomas. ^{1 2 3 4 5}

Is the combination of Venetoclax and chemotherapy safe for humans?

Research shows that Venetoclax, when combined with chemotherapy drugs like those in the EPOCH-R regimen, has been studied for safety in aggressive B-cell lymphoma. These studies help ensure that the treatment is generally safe for humans, although individual reactions can vary. ^{1 4 6 7 8}

What makes the drug Venetoclax combined with chemotherapy unique for treating B-cell lymphoma?

Venetoclax is unique because it specifically targets and inhibits the B-cell lymphoma-2 (BCL-2) protein, which helps cancer cells survive, making it effective in overcoming resistance to chemotherapy in aggressive B-cell lymphomas. ^{1 3 4 8 9}

Research Team

Jeremy S Abramson

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

This trial is for patients with high-grade B-cell lymphomas, including those with certain genetic markers like MYC and BCL2 translocations. It's not open to individuals who have had previous treatments for this cancer, except possibly one round of specific chemotherapy or corticosteroids. Pregnant or nursing women can't participate due to unknown risks to fetuses and newborns.

Inclusion Criteria

My lymphoma is classified as triple hit due to specific gene changes.

I have DLBCL/HGBCL and have only had limited initial treatment or steroids for symptom relief.

I am not pregnant or breastfeeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive R-CHOP or DA-EPOCH-R chemotherapy regimen with or without venetoclax for 6 cycles

18 weeks

6 cycles, each 21 days apart

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Every 12 weeks for 2 years, then every 24 weeks for up to 5 years, then every 6 months for up to 10 years

Treatment Details

Interventions

• Cyclophosphamide
• Doxorubicin Hydrochloride
• Etoposide
• Prednisone
• Rituximab
• Venetoclax
• Vincristine Sulfate

Trial Overview The trial is testing the addition of Venetoclax, a drug that blocks a protein called Bcl-2 which may help stop cancer growth, to standard chemotherapy drugs (rituximab, cyclophosphamide, doxorubicin, vincristine sulfate, prednisone etoposide) in treating high-grade B-cell lymphomas.

Participant Groups

Group I: Arm 2 (R-CHOP, DA-EPOCH-R, venetoclax) Experimental Treatment 11 Interventions

DEL: Patients with DEL receive R-CHOP chemotherapy regimen as in Arm 1. Patients also receive venetoclax PO QD on days 4-8 of cycle 1 and days 1-5 for cycles 2-6. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study. DHL: Patients with DHL receive DA-EPOCH-R chemotherapy regimen as in Arm 1. Patients also receive venetoclax PO QD on days 4-8 of cycle 1 and days 1-5 for cycles 2-6. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study.

Group II: Arm 1 (R-CHOP, DA-EPOCH-R) Active Control 10 Interventions

DEL: Patients with DEL receive R-CHOP chemotherapy regimen consisting of rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study. DHL: Patients with DHL receive DA-EPOCH-R chemotherapy regimen consisting of rituximab IV on day 1, doxorubicin hydrochloride IV on days 1-4, etoposide IV on days 1-4, vincristine sulfate IV on days 1-4, prednisone PO BID on days 1-5, and cyclophosphamide IV on day 5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET scan, CT scan and blood sample collection and may undergo bone marrow biopsy and lumbar puncture throughout the study

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

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]

The combination of venetoclax with bendamustine-rituximab (BR) was found to be safe and tolerable in a study of 60 patients with relapsed/refractory non-Hodgkin's lymphoma, with the recommended phase II dose established at 800 mg daily.

The overall response rate to the treatment was 65%, with a median duration of response of 38.3 months, indicating preliminary efficacy for this combination therapy in managing B-cell NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. de Vos, S., Swinnen, LJ., Wang, D., et al.[2021]

Coadministration of azithromycin with venetoclax resulted in a modest reduction in venetoclax levels (25% lower maximum concentration and 35% lower area under the curve), but did not require any dose adjustments, indicating that azithromycin is a safe option for patients taking venetoclax.

The study involved 12 healthy female subjects and found that venetoclax was well tolerated with no serious adverse events, suggesting that azithromycin can be used as an alternative antibiotic without significantly impacting venetoclax pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. Agarwal, SK., Tong, B., Bueno, OF., et al.[2019]

In a study involving 272 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), higher concentrations of venetoclax led to a quicker reduction in lymphocyte counts and tumor size, resulting in a high objective response rate (ORR) of 84.8% at a daily dose of 400 mg.

Importantly, increasing the dose of venetoclax did not correlate with a higher risk of serious adverse events like neutropenia or infections, suggesting that the 400 mg daily regimen is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Freise, KJ., Jones, AK., Eckert, D., et al.[2018]

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]

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

Population Pharmacokinetics and Exposure-Response Analyses for Venetoclax in Combination with R-CHOP in Relapsed/Refractory and Previously Untreated Patients with Diffuse Large B Cell Lymphoma. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Bayesian Population Model of the Pharmacokinetics of Venetoclax in Combination with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results from the Phase III MURANO Study. [2020]

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

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. [2021]

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

Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial. [2021]

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

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. [2019]

7. Cyprus pubmed.ncbi.nlm.nih.gov

Combination of Venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia: A case series from a single center. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. [2018]

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

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