Venetoclax in Combination With BEAM Conditioning Regimen for ASCT in Non-Hodgkin Lymphoma

NCT03713580 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: CASE2418
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Non-hodgkin Lymphoma

Keywords

Autologous stem cell transplant (ASCT); Venetoclax

Outcome Measures

Primary Outcomes (1)

• Safety of intervention as defined by hematopoietic non-engraftment (failure of either ANC engraftment or platelet engraftment).

  Safety of intervention will be measured by the effect on hematologic engraftment (engraftment Dose Limiting Toxicity DLT). This includes failure of absolute neutrophil count (ANC) engraftment OR platelet engraftment. • Failure of ANC engraftment which is defined as failure to engraft by day 15. OR • Failure of platelet engraftment which is defined as failure to engraft by day 30.

  Up to 30 days after Autologous Stem Cell Transplant (ASCT)

Secondary Outcomes (4)

• Time to neutrophil engraftment

  24 months after hospital discharge

• Time to platelet engraftment

  24 months after hospital discharge

• Progression-free survival (PFS)

  24 months after hospital discharge

• Overall Survival (OS)

  24 months after hospital discharge

Study Arms (1)

Venetoclax+BEAM x 1 cycle prior to ASCT

EXPERIMENTAL

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

Drug: Venetoclax

Interventions

Venetoclax DRUG

Adding Venetoclax, a BCL-2 inhibitor, to standard high dose therapy prior to autologous stem cell transplant (ASCT). Venetoclax is a novel, orally bioavailable, small-molecule B-cell lymphoma-2 (Bcl-2) family inhibitor.

Venetoclax+BEAM x 1 cycle prior to ASCT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed Non-Hodgkin Lymphoma (NHL) including T-cell lymphomas, after at least one prior systemic treatment regimen such as CHOP, R-CHOP, CHOEP, R-EPOCH, R-HyperCVAD, BR, VR-CAP alternating with rituximab and cytarabine, etc.
• Patients in complete or partial remission, or in the case of patients with stable or refractory disease are undergoing autologous transplantation because it has been recommended by their treating physician as representing their best treatment option.
• ECOG Performance status ≤ 2 at time of consent \[See Appendix I\].
• Patients must have normal organ and marrow function as defined below:
• Hemoglobin ≥ 8.0 g/dl
• Absolute neutrophil count ≥ 1,000/mcL
• Platelet count ≥ 75,000/mcL
• Total bilirubin ≤ 1.5X the upper limit of normal (ULN) unless a known history of impaired bilirubin conjugation such as Gilbert's.
• AST (SGOT) ≤ 2.5 X institutional ULN
• ALT (SGPT) ≤ 2.5 X institutional ULN
• Patients must have a calculated serum creatinine clearance \> 50 mL/min using Cockcroft-Gault calculation or based on 24-hour urine collection performed within 7 days prior to treatment.
• Cardiac ejection fraction \>45% or clearance by PI or Cardiology
• DLCO of \>45% predicted or clearance by PI or Pulmonology
• HBsAg negative, HBcAb negative, HBsAb negative patients are eligible.
• HBsAg negative, HBcAb negative, HBsAb positive patients are eligible.

You may not qualify if:

• 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. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with carmustine, etoposide, cytarabine, and melphalan, breastfeeding should be discontinued if the mother is treated with these agents. These potential risks may also apply to other agents used in this study.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Venetoclax. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. HIV testing prior to enrollment is not required for screening but strongly encouraged for patients with no documented prior HIV assessment.
• Malabsorption syndrome or other condition that precludes enteral route of Venetoclax administration
• Patients with metastatic solid tumor malignancies. Patients who have early stage solid tumors and have completed curative treatment are eligible at the discretion of the primary investigator. Patients with unresected but localized stage prostate cancer or other carcinomas in situ that are undergoing observation are also allowed. Patients with transformed lymphoma and/or underlying indolent lymphoproliferative disorder are allowed at the discretion of the investigator.
• 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). Brief (\<15 days) treatment with glucocorticoids (prednisone 100 mg by mouth daily, or equivalent) is acceptable.
• 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. A washout period of 7 days is required prior to Venetoclax dosing if a prohibited medication is discontinued. Lists including medications or substances known or with the potential to interact with the specific CYP3A4 isoenzymes and P-gp are provided in Appendix II.
• Concomitant medications that fall into the categories below could potentially lead to adverse reactions and should be considered cautionary (except where noted). Medications and cautionary medications that fall into the categories within this section can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table. If a potential study patient is taking any of the medications in the categories described below, the investigator will assess and document the use of medications known or suspected to fall in the following medication categories:
• Moderate/Weak CYP3A inducers such as efavirenz and oxcarbazepine.
• CYP2C8 substrates such as thiazolidinediones (glitazones) and select statins (because of expected inhibition of the metabolism of CYP2C8 substrates by Venetoclax).

Sponsors & Collaborators

• Case Comprehensive Cancer Center: lead

Study Sites (2)

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44195, United States

Location

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

venetoclax

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Allison Winter, MD

  Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2018
• First Posted: October 19, 2018
• Study Start: March 12, 2019
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: July 1, 2025

Record last verified: 2025-06

Locations

US (2)