Venetoclax + BEAM Conditioning for Lymphoma

Recruiting at 1 trial location

Overseen By Allison Winter, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Case Comprehensive Cancer Center

Must not be taking: Antiretrovirals, CYP3A4 modulators

Disqualifiers: Pregnancy, HIV, Metastatic cancer, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

25 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial, especially if they interact with Venetoclax. If you are on medications that affect the CYP3A4 enzyme or P-gp, a 7-day break from these drugs is required before starting Venetoclax. It's important to discuss your current medications with the trial team to see if any changes are needed.

What data supports the effectiveness of the drug Venetoclax for lymphoma?

Venetoclax has shown high effectiveness in treating blood cancers like acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), which suggests it may also be beneficial for lymphoma. ^{1 2 3 4 5}

Is Venetoclax safe for use in humans?

Venetoclax has been shown to have an acceptable safety profile in patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma, with common side effects including nausea, diarrhea, and low blood cell counts. Serious side effects are rare, and the drug is generally well-tolerated. ^{6 7 8 9 10}

How does the Venetoclax + BEAM Conditioning treatment for lymphoma differ from other treatments?

Venetoclax + BEAM Conditioning is unique because it combines Venetoclax, a drug that targets and inhibits a protein called BCL-2 to promote cancer cell death, with the BEAM regimen, a high-dose chemotherapy used before stem cell transplantation. This combination aims to enhance the effectiveness of the conditioning regimen by specifically targeting cancer cells, potentially improving outcomes for patients with lymphoma. ^{11 12 13 14 15}

What is the purpose of this trial?

The purpose of this study is to determine the correct dose and safety of adding a new cancer drug, Venetoclax, to a standard combination of chemotherapy drugs used prior to Autologous stem cell transplant (ASCT) in participants with Non-Hodgkin Lymphoma (NHL). In this study, Venetoclax will be added to BEAM (BCNU or carmustine, etoposide, cytarabine or ara-c, and melphalan). All NHL participants are admitted for conditioning chemotherapy which is given prior to the infusion of stem cells. Venetoclax is a new anti-cancer drug that works by targeting a protein (known as the Bcl-2 protein). By inhibiting or "blocking" this protein, a downstream cascade occurs which results in cancer cells to die. Adding Venetoclax to the standard BEAM conditioning chemotherapy with autologous stem cell transplant is believed to increase the chance of remission. Venetoclax is Food and Drug Administration (FDA) approved for participants with chronic lymphocytic leukemia (CLL). However, Venetoclax is investigational for this study because it is not yet approved for use in participants with NHL or in combination with BEAM chemotherapy.

Research Team

Allison Winter, MD

Principal Investigator

Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Eligibility Criteria

This trial is for people with Non-Hodgkin Lymphoma who've had at least one prior treatment. They must have certain blood cell counts, normal organ function, and not be pregnant or breastfeeding. People with severe allergies to Venetoclax or similar drugs, unresolved treatment toxicities, uncontrolled illnesses, HIV on antiretrovirals, recent major surgery, or using certain medications can't join.

Inclusion Criteria

I do not have active Hepatitis B according to my test results.

I am in remission or my disease is stable, and I am recommended for autologous transplantation.

I have Non-Hodgkin Lymphoma and have undergone at least one treatment like CHOP or R-CHOP.

Exclusion Criteria

Patients who have not recovered from adverse events due to agents administered more than 2 weeks earlier, Prior treatment toxicities have not resolved to ≤ Grade 2 according to NCI CTCAE Version 5.0 (except clinically unrelated toxicities such as alopecia or peripheral neuropathy), Patients receiving any other investigational agents, History of allergic reactions attributed to compounds of similar chemical or biologic composition to Venetoclax or other agents used in this study, Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, Patients who are pregnant or breastfeeding will be excluded from this study because carmustine, etoposide, cytarabine, and melphalan are chemotherapeutic agents with the potential for teratogenic or abortifacient effects, HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Venetoclax, Malabsorption syndrome or other condition that precludes enteral route of Venetoclax administration, Patients with metastatic solid tumor malignancies, Major surgery, other than diagnostic surgery, within 2 weeks, Medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent), Patients with chronic use of moderate or strong CYP3A4 modulators (inhibitor or inducer) or use of a P-gp inhibitor, or a P-gp substrate with a narrow therapeutic index are prohibited, Concomitant medications that could potentially lead to adverse reactions and should be considered cautionary

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Treatment

Participants receive Venetoclax in combination with BEAM chemotherapy prior to Autologous Stem Cell Transplant (ASCT)

1 cycle (approximately 1 week)

Inpatient stay for conditioning and ASCT

Autologous Stem Cell Transplant (ASCT)

Infusion of previously collected autologous stem cells following V+BEAM therapy

Immediate post-conditioning

Inpatient stay for ASCT

Follow-up

Participants are monitored for safety, engraftment, and survival outcomes

24 months

Follow-up visits at 3, 6, 12, 18, and 24 months post-discharge

Treatment Details

Interventions

• Venetoclax

Trial Overview The study tests adding Venetoclax to BEAM chemotherapy before a stem cell transplant in NHL patients. The goal is to find the right dose and check safety. Venetoclax targets a protein that helps cancer cells survive; it's approved for leukemia but investigational here.

Participant Groups

Group I: Venetoclax+BEAM x 1 cycle prior to ASCT Experimental Treatment 1 Intervention

Venetoclax dose escalation cohorts + BEAM (Carmustine, Etoposide, Cytarabine, Melphalan) begin with dose level 1 (800mg on Day -7 and Day -6). The dosing cohorts are escalated in a 3 + 3 design but with increasing duration instead of increasing dosage. Carmustine 300 mg/m2 by IV over 2 hours on Day -7. Etoposide 100 mg/m2 by IV over 6 hours daily for 4 consecutive days, Day-6 through Day-3. Cytarabine 200 mg/m2 by IV over 2 hours every 12 hours for 3 consecutive days, Day-6 through Day-4. Melphalan 140 mg/m2 by IV over 30 minutes or IV push once on Day -2. Following V+BEAM therapy, participants will receive Autologous Stem Cell Transplant (ASCT): infusion of previously collected autologous stem cells and supportive care per institutional guidelines

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Findings from Research

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 is an effective and well-tolerated treatment for advanced hematological malignancies, particularly in patients with chronic lymphocytic leukemia, showing a satisfactory overall event rate of 73%.

The most common adverse events associated with venetoclax include nausea, diarrhea, and thrombocytopenia, but these are generally mild and manageable, with few cases of severe complications like tumor lysis syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Bcl-2 Inhibitor Venetoclax in Hematological Malignancy: A Systematic Review and Meta-Analysis of Clinical Trials. Li, Q., Cheng, L., Shen, K., et al.[2020]

In a retrospective study of 34 adult patients with various types of non-Hodgkin lymphoma treated off-label with venetoclax, the overall response rate was 26%, indicating modest efficacy in heavily pretreated patients.

Adverse events occurred in 76% of patients, with higher incidence than reported in clinical trials, highlighting the need for further investigation into the safety and dosing strategies of venetoclax in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. Hughes, ME., Landsburg, DJ., Rubin, DJ., et al.[2020]

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

In a study of 23 patients with aggressive B-cell non-Hodgkin lymphoma, the combination of rituximab with CODOX-M/IVAC showed promising efficacy, with 83% of low-risk and 71% of high-risk patients achieving complete remission after treatment.

The safety profile was acceptable, with no treatment-related deaths and manageable toxicity, including only two cases of grade 3 neutropenia, suggesting that this treatment combination is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in combination with CODOX-M/IVAC: a retrospective analysis of 23 cases of non-HIV related B-cell non-Hodgkin lymphoma with proliferation index >95%. Mohamedbhai, SG., Sibson, K., Marafioti, T., et al.[2015]

References

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Venetoclax Induces Cardiotoxicity through Modulation of Oxidative-Stress-Mediated Cardiac Inflammation and Apoptosis via NF-κB and BCL-2 Pathway. [2022]

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

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Efficacy and Safety of Bcl-2 Inhibitor Venetoclax in Hematological Malignancy: A Systematic Review and Meta-Analysis of Clinical Trials. [2020]

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

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. [2020]

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

Venetoclax: First Global Approval. [2018]

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Venetoclax: A First-in-Class Oral BCL-2 Inhibitor for the Management of Lymphoid Malignancies. [2018]

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Lymph cancer chemotherapy: delivery of doxorubicin-gemcitabine prodrug and vincristine by nanostructured lipid carriers. [2022]

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Iodine-131 rituximab radioimmunotherapy with BEAM conditioning and autologous stem cell transplant salvage therapy for relapsed/refractory aggressive non-Hodgkin lymphoma. [2020]

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

Radioimmunotherapy and Autologous Stem-Cell Transplantation in the Treatment of B-Cell Non-Hodgkin Lymphoma. [2016]

15. England pubmed.ncbi.nlm.nih.gov

Rituximab in combination with CODOX-M/IVAC: a retrospective analysis of 23 cases of non-HIV related B-cell non-Hodgkin lymphoma with proliferation index >95%. [2015]