Venetoclax in Combination With BEAM Conditioning Regimen for ASCT in Non-Hodgkin Lymphoma
|ClinicalTrials.gov Identifier: NCT03713580|
Recruitment Status : Suspended (waiting for new cohort to open)
First Posted : October 19, 2018
Last Update Posted : June 26, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Non-hodgkin Lymphoma||Drug: Venetoclax||Phase 1|
The primary objective of this study is to establish the safety of V-BEAM conditioning regimen prior to autologous stem cell transplant in order to identify the recommended phase II dose (RPD2). This study will also seek to compare time to neutrophil engraftment and time to platelet engraftment of participants who receive V-BEAM and ASCT, compared to historical controls and among cohorts. And finally, it will determine the Progression Free Survival (PFS) and Overall Survival (OS) of V+BEAM followed by ASCT relative to historical controls of BEAM alone followed by ASCT.
This will be a single-institution, open label, phase I study designed to evaluate the safety of this combination. The target population will be participants with NHL who are eligible for ASCT. Dose escalation will proceed using a standard 3 + 3 design with 5 dose levels, a minimum of 6 participants and a maximum of 30 participants will be required to identify the RP2D. If a participant does not take all scheduled doses of Venetoclax according to his/her cohort, the participant will be replaced because he/she has not taken enough drug to confirm safety at that dose level.
Once the conditioning regimen has been delivered and autologous stem cells have been infused there is no further disease-directed treatment as part of this protocol. In accordance with routine practice the bone marrow transplant program at the Cleveland Clinic, participants receive supportive care and follow-up until disease relapse or death. In the absence of treatment delays during the conditioning regimen due to adverse events, participants will remain on study for 24 months or until one of the following criteria applies:
- Disease progression
- Intercurrent illness that prevents further administration of treatment
- The investigator considers it, for safety reasons, to be in the best interest of the participant.
- General or specific changes in the participant's condition rendering the participant unacceptable for further treatment in the judgment of the investigator.
- Participants decision to withdraw from treatment (partial consent) or from the study (full consent)
- Pregnancy during the course of the study for a child-bearing participant
- Death, or
- Sponsor reserves the right to temporarily suspend or prematurely discontinue this study.
Participants will be followed for toxicity for 24 months after hospital discharge or until a protocol approved outcome. The first 3 months will be at the treating center and continued recommended follow-up should be at a minimum of 6 months, 12 months, 18 months and 24 months after hospital discharge or as clinically appropriate according to local practices.
The clinical course of each event will be followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not the cause.
Serious adverse events that are still ongoing at the end of the study period will necessitate follow-up to determine the final outcome. Any serious adverse event that occurs after the study period and is considered to be possibly related to the study treatment or study participation will be recorded and reported immediately.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Trial of Venetoclax in Combination With BEAM Conditioning Regimen for Autologous Stem Cell Transplantation in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma|
|Actual Study Start Date :||December 11, 2018|
|Estimated Primary Completion Date :||December 31, 2020|
|Estimated Study Completion Date :||December 31, 2020|
Experimental: Venetoclax+BEAM x 1 cycle prior to ASCT
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
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.
- Safety of intervention as defined by hematopoietic non-engraftment (failure of either ANC engraftment or platelet engraftment). [ Time Frame: Up to 30 days after Autologous Stem Cell Transplant (ASCT) ]
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.
• Failure of platelet engraftment which is defined as failure to engraft by day 30.
- Time to neutrophil engraftment [ Time Frame: 24 months after hospital discharge ]Compare time to neutrophil engraftment of patients who receive V-BEAM followed by ASCT, compared to historical controls and among cohorts.
- Time to platelet engraftment [ Time Frame: 24 months after hospital discharge ]Compare time to platelet engraftment of patients who receive V-BEAM followed by ASCT, compared to historical controls and among cohort.
- Progression-free survival (PFS) [ Time Frame: 24 months after hospital discharge ]
Determine the Progression Free Survival (PFS) of V+BEAM followed by ASCT relative to historical controls of BEAM alone followed by ASCT.
PFS is defined as the time from entry onto study until lymphoma progression or death from any cause. PFS reflects tumor growth and, therefore, occurs prior to the endpoint of overall survival.
- Overall Survival (OS) [ Time Frame: 24 months after hospital discharge ]Determine the Overall Survival (OS) of V+BEAM followed by ASCT relative to historical controls of BEAM alone followed by ASCT.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03713580
|United States, Ohio|
|Cleveland Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center|
|Cleveland, Ohio, United States, 44106|
|Cleveland Clinic, Case Comprehensive Cancer Center|
|Cleveland, Ohio, United States, 44195|
|Principal Investigator:||Brian Hill, MD,PhD||The Cleveland Clinic|