Venetoclax + Chemotherapy for B-Cell Lymphoma

Not currently recruiting at 754 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding a new drug, venetoclax, to standard chemotherapy can more effectively treat high-grade B-cell lymphomas. Venetoclax may inhibit cancer growth by blocking a specific protein, potentially reducing the chance of recurrence. The trial compares standard chemotherapy alone to treatments combined with venetoclax. It seeks participants diagnosed with certain types of B-cell lymphoma, such as diffuse large B-cell lymphoma, who have received minimal prior treatment. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that venetoclax, when combined with standard chemotherapy, is generally well-tolerated. Studies have found that venetoclax alone is safe, even for patients with challenging conditions like relapsed or refractory non-Hodgkin lymphoma. Common side effects include headache, nausea, and fatigue, which are typical of cancer treatments.

However, some serious side effects have been reported, such as neutropenia (a decrease in white blood cells that help fight infection) and tumor lysis syndrome (TLS, a condition where cancer cells break down quickly and release substances into the blood). Monitoring these is important, but they are known risks of using venetoclax.

The trial's later phase indicates that earlier studies have demonstrated sufficient safety to continue testing. Additionally, venetoclax has already received approval for other types of cancers, providing some reassurance about its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about adding venetoclax to the treatment regimen for B-cell lymphoma because it targets cancer cells differently than standard chemotherapy. Unlike traditional treatments like R-CHOP and DA-EPOCH-R, which attack cancer cells and some healthy cells, venetoclax specifically blocks a protein called BCL-2. This protein helps cancer cells survive, so by blocking it, venetoclax can make cancer cells die off more effectively. This more targeted approach could potentially improve outcomes for patients with B-cell lymphoma, making treatment more efficient and possibly leading to better survival rates.

What evidence suggests that this trial's treatments could be effective for B-cell lymphoma?

Research shows that adding venetoclax to chemotherapy might help treat high-grade B-cell lymphomas. In this trial, some participants will receive a combination of venetoclax with chemotherapy. Earlier studies showed promising results for venetoclax, with about 71% of patients experiencing their cancer shrinking or disappearing. Venetoclax blocks a protein called Bcl-2, which helps cancer cells survive. By inhibiting this protein, venetoclax may enhance chemotherapy's ability to kill cancer cells. This combination aims to improve treatment outcomes and reduce the risk of cancer recurrence. ^{1 6 7 8 9}

Who Is on the Research Team?

Jeremy S Abramson

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4654800/

ABT-199 (venetoclax) and BCL-2 inhibitors in clinical ...

Preliminary data from a phase I trial of ABT-199 showed an overall response rate (ORR) of 84 % in 56 patients with relapsed/refractory CLL [81] (Table 1). At a ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10320213/

A multicenter analysis of the outcomes with venetoclax in ...

In high-risk patients with relapsed MCL, most of whom received prior BTKi, venetoclax resulted in ORR of 40% and median PFS of 3.7 months.

3.

ashpublications.org

ashpublications.org/blood/article/134/Supplement_1/756/427131/Three-Year-Update-of-the-Phase-II-ABT-199

Three Year Update of the Phase II ABT-199 (Venetoclax) and ...

Additionally, overall response rate (ORR) by PET of 71%, with attainment of minimal residual disease (MRD) negativity was reported. At the time ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02055820

NCT02055820 | A Study Evaluating the Safety, Efficacy ...

Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade ...

5.

jhoonline.biomedcentral.com

jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01295-3

Clinical experiences with venetoclax and other pro-apoptotic ...

Diffuse large B cell lymphoma and other aggressive B cell lymphomas. Venetoclax monotherapy has limited efficacy in R/R DLBCL, achieving an ORR ...

6.

ashpublications.org

ashpublications.org/blood/article/126/23/254/112989/A-Phase-1-Study-of-Venetoclax-ABT-199-GDC-0199

A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199 ...

Conclusions: Venetoclax monotherapy demonstrated a tolerable safety profile in pts with R/R NHL. Several pts with DLBCL had an initial response ...

7.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/28691866/

Safety and pharmacodynamics of venetoclax (ABT-199) in ...

The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by ...

8.

cdn.clinicaltrials.gov

cdn.clinicaltrials.gov/large-docs/20/NCT02055820/Prot_002.pdf

A Phase IB/II, Open-Label Study Evaluating the Safety and

Consistent with expected pharmacological activity, venetoclax caused moderate to marked decreases in lymphocytes including both T and B cell subsets, and.

9.

jaadcasereports.org

jaadcasereports.org/article/S2352-5126(20)30885-7/fulltext

B-cell lymphoma 2 inhibitor venetoclax treatment of a ...

The most serious reported side effects of venetoclax therapy include neutropenia and TLS (eg, acute renal failure, cardiac arrhythmia, seizures, ...