Venetoclax, Carmustine, Etoposide, Cytarabine, and Melphalan Before Stem Cell Transplant in Treating Participants With Relapsed or Refractory Non-Hodgkin Lymphoma
Primary Purpose
Hematopoietic Cell Transplantation Recipient, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma
Status
Unknown status
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Carmustine
Cytarabine
Etoposide
Hematopoietic Cell Transplantation
Melphalan
Venetoclax
Sponsored by
About this trial
This is an interventional treatment trial for Hematopoietic Cell Transplantation Recipient
Eligibility Criteria
Inclusion Criteria:
- Subjects must have histologically confirmed diagnosis of non-Hodgkin?s lymphoma that has relapsed, or is refractory, after upfront induction therapy. Excluded histologies are T-cell lymphomas, post-transplant lymphoproliferative disorder, Burkitt lymphoma, lymphoblastic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma. All other histologies are eligible that include but not limited to: diffuse-large B-cell lymphoma, follicular lymphoma (grades I, II, and III), marginal zone lymphoma, transformed indolent lymphoma, grey zone lymphoma, and undifferentiated B-cell lymphoma. Patients with non-Hodgkin's lymphoma (NHL) who are at high risk of relapse can be enrolled in sustained partial response (PR) after induction chemotherapy (PR1)
- Expected survival of more than six months
- Karnofsky performance status >= 80%
- Within 1 week prior to initiation of treatment: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3 x upper limits of normal (ULN) unless due to disease
- Within 1 week prior to initiation of treatment: Total bilirubin < 2 x ULN unless due to disease
- Within 1 week prior to initiation of treatment: Calculated glomerular filtration rate (GFR) 30 ml/min
- Within 1 week prior to initiation of treatment: Absolute neutrophil count (ANC) > 500 cells/mm^3
- Within 1 week prior to initiation of treatment: Platelet count > 50 mm^3
- Left ventricular ejection fraction >= 40%
- Diffusion capacity of carbon monoxide (DLCO) >= 50% predicted
- Ability to collect 2 x 10^6/kg CD34+ cells for transplantation
- Patient must be otherwise eligible for autologous stem cell transplantation (ASCT) per local institutional guidelines
- No serious disease, or condition, that, in the opinion of the investigator, would compromise the patient?s ability to participate in the study
- Subjects must have the ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Subjects who sustained a complete metabolic response (CMR) by positron emission tomography (PET)-computed tomography (CT) (Deauville score of =< 3) after salvage chemotherapy unless lymphoma relapsed less than 12 months from the first day of last cycle of induction chemotherapy OR patient required more than 2 lines of salvage chemotherapy to sustain a CMR
- Subjects receiving any other investigational agents
- Prior treatment with venetoclax
- Patients with central nervous system (CNS) involved by lymphoma can be included if CNS disease is deemed controlled prior to enrollment as determined by the investigator. Patients with uncontrolled CNS disease will be excluded
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax or other agents used in this study
- Subjects 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 human immunodeficiency virus (HIV) positive and receiving combination antiretroviral therapy will be excluded; because of the potential for pharmacokinetic interactions with venetoclax
- Female patients who are pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Male or female patients, who are sexually active and of the child bearing age, must be willing to practice accepted birth control measures
Sites / Locations
- Ohio State University Comprehensive Cancer Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (venetoclax, BEAM)
Arm Description
Participants receive venetoclax PO QD on days -10 to -1, carmustine IV on day -6, etoposide IV BID on days -5 to -2, cytarabine IV BID on days -5 to -2, and melphalan IV on day -1. Participants then undergo hematopoietic cell transplantation on day 0.
Outcomes
Primary Outcome Measures
Maximum tolerated dose of venetoclax defined to be the dose cohort below which 3 out of 6 patients experience dose limiting toxicities or the highest dose cohort of 1200 mg, if 2 dose limiting toxicities are not observed at any dose cohort
Overall response rate
Will be estimated as the proportions of patients who achieve a complete response or partial response divided by the number of evaluable patients. Each will be reported with their associated 95% confidence interval.
Secondary Outcome Measures
Incidence of progression
Estimated using Kaplan-Meier method.
Incidence of freedom from relapse
Estimated using Kaplan-Meier method.
Overall survival
Estimated using Kaplan-Meier method.
Full Information
NCT ID
NCT03583424
First Posted
June 28, 2018
Last Updated
September 29, 2021
Sponsor
Ohio State University Comprehensive Cancer Center
1. Study Identification
Unique Protocol Identification Number
NCT03583424
Brief Title
Venetoclax, Carmustine, Etoposide, Cytarabine, and Melphalan Before Stem Cell Transplant in Treating Participants With Relapsed or Refractory Non-Hodgkin Lymphoma
Official Title
A Phase I/II Trial of Venetoclax and BEAM Conditioning Followed by Autologous Stem Cell Transplantation for Patients With Primary Refractory Non-Hodgkin Lymphoma
Study Type
Interventional
2. Study Status
Record Verification Date
September 2021
Overall Recruitment Status
Unknown status
Study Start Date
September 10, 2018 (Actual)
Primary Completion Date
December 31, 2022 (Anticipated)
Study Completion Date
December 31, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ohio State University Comprehensive Cancer Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase I/II trial studies the side effects and best dose of venetoclax when given together with carmustine, etoposide, cytarabine, and melphalan before stem cell transplant in treating participants with non-Hodgkin lymphoma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as venetoclax, carmustine, etoposide, cytarabine, and melphalan, 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 chemotherapy before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient?s bone marrow for new blood-forming cells (stem cells) to grow.
Detailed Description
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) of venetoclax that can be safely combined with carmustine, etoposide, cytarabine, and melphalan (BEAM) prior to autologous stem cell transplant which will the recommended phase II dose (RP2D).
II. Determine the safety and efficacy of venetoclax as measured by overall response rate (ORR) at day 100, 12-month survival and freedom from relapse (FFR-12).
SECONDARY OBJECTIVES:
I. Long term effects (progression-free survival [PFS] and overall survival [OS]) of addition of venetoclax to BEAM.
II. Correlation of response and survival with expression of BCL-2, BCL-XL, and MCL-1 as measured by immunohistochemistry (IHC).
OUTLINE: This is a dose-escalation study of venetoclax.
Participants receive venetoclax orally (PO) once daily (QD) on days -10 to -1, carmustine intravenously (IV) on day -6, etoposide IV twice daily (BID) on days -5 to -2, cytarabine IV BID on days -5 to -2, and melphalan IV on day -1. Participants then undergo hematopoietic stem cell transplantation on day 0.
After completion of study treatment, participants are followed up for 2 years.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hematopoietic Cell Transplantation Recipient, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Non-Hodgkin Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory Follicular Lymphoma, Refractory Marginal Zone Lymphoma, Refractory Non-Hodgkin Lymphoma, Refractory Transformed Indolent Non-Hodgkin Lymphoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
19 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment (venetoclax, BEAM)
Arm Type
Experimental
Arm Description
Participants receive venetoclax PO QD on days -10 to -1, carmustine IV on day -6, etoposide IV BID on days -5 to -2, cytarabine IV BID on days -5 to -2, and melphalan IV on day -1. Participants then undergo hematopoietic cell transplantation on day 0.
Intervention Type
Drug
Intervention Name(s)
Carmustine
Other Intervention Name(s)
BCNU, Becenum, Becenun, BiCNU, Bis(chloroethyl) Nitrosourea, Bis-Chloronitrosourea, Carmubris, Carmustin, Carmustinum, FDA 0345, Gliadel, N,N'-Bis(2-chloroethyl)-N-nitrosourea, Nitrourean, Nitrumon, SK 27702, SRI 1720, WR-139021
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Hematopoietic Cell Transplantation
Other Intervention Name(s)
HCT, Hematopoietic Stem Cell Transplantation, HSCT, stem cell transplantation
Intervention Description
Undergo hematopoietic cell transplantation
Intervention Type
Drug
Intervention Name(s)
Melphalan
Other Intervention Name(s)
Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Maximum tolerated dose of venetoclax defined to be the dose cohort below which 3 out of 6 patients experience dose limiting toxicities or the highest dose cohort of 1200 mg, if 2 dose limiting toxicities are not observed at any dose cohort
Time Frame
Up to 2 years
Title
Overall response rate
Description
Will be estimated as the proportions of patients who achieve a complete response or partial response divided by the number of evaluable patients. Each will be reported with their associated 95% confidence interval.
Time Frame
At day 100
Secondary Outcome Measure Information:
Title
Incidence of progression
Description
Estimated using Kaplan-Meier method.
Time Frame
Up to 2 years
Title
Incidence of freedom from relapse
Description
Estimated using Kaplan-Meier method.
Time Frame
Up to 2 years
Title
Overall survival
Description
Estimated using Kaplan-Meier method.
Time Frame
Up to 2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Subjects must have histologically confirmed diagnosis of non-Hodgkin?s lymphoma that has relapsed, or is refractory, after upfront induction therapy. Excluded histologies are T-cell lymphomas, post-transplant lymphoproliferative disorder, Burkitt lymphoma, lymphoblastic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma. All other histologies are eligible that include but not limited to: diffuse-large B-cell lymphoma, follicular lymphoma (grades I, II, and III), marginal zone lymphoma, transformed indolent lymphoma, grey zone lymphoma, and undifferentiated B-cell lymphoma. Patients with non-Hodgkin's lymphoma (NHL) who are at high risk of relapse can be enrolled in sustained partial response (PR) after induction chemotherapy (PR1)
Expected survival of more than six months
Karnofsky performance status >= 80%
Within 1 week prior to initiation of treatment: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3 x upper limits of normal (ULN) unless due to disease
Within 1 week prior to initiation of treatment: Total bilirubin < 2 x ULN unless due to disease
Within 1 week prior to initiation of treatment: Calculated glomerular filtration rate (GFR) 30 ml/min
Within 1 week prior to initiation of treatment: Absolute neutrophil count (ANC) > 500 cells/mm^3
Within 1 week prior to initiation of treatment: Platelet count > 50 mm^3
Left ventricular ejection fraction >= 40%
Diffusion capacity of carbon monoxide (DLCO) >= 50% predicted
Ability to collect 2 x 10^6/kg CD34+ cells for transplantation
Patient must be otherwise eligible for autologous stem cell transplantation (ASCT) per local institutional guidelines
No serious disease, or condition, that, in the opinion of the investigator, would compromise the patient?s ability to participate in the study
Subjects must have the ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
Subjects who sustained a complete metabolic response (CMR) by positron emission tomography (PET)-computed tomography (CT) (Deauville score of =< 3) after salvage chemotherapy unless lymphoma relapsed less than 12 months from the first day of last cycle of induction chemotherapy OR patient required more than 2 lines of salvage chemotherapy to sustain a CMR
Subjects receiving any other investigational agents
Prior treatment with venetoclax
Patients with central nervous system (CNS) involved by lymphoma can be included if CNS disease is deemed controlled prior to enrollment as determined by the investigator. Patients with uncontrolled CNS disease will be excluded
History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax or other agents used in this study
Subjects 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 human immunodeficiency virus (HIV) positive and receiving combination antiretroviral therapy will be excluded; because of the potential for pharmacokinetic interactions with venetoclax
Female patients who are pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Male or female patients, who are sexually active and of the child bearing age, must be willing to practice accepted birth control measures
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kami Maddocks, MD
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Links:
URL
http://cancer.osu.edu
Description
The Jamesline
Learn more about this trial
Venetoclax, Carmustine, Etoposide, Cytarabine, and Melphalan Before Stem Cell Transplant in Treating Participants With Relapsed or Refractory Non-Hodgkin Lymphoma
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