Clinical Trials /

Venetoclax, Carmustine, Etoposide, Cytarabine, and Melphalan Before Stem Cell Transplant in Treating Participants With Relapsed or Refractory Non-Hodgkin Lymphoma

NCT03583424

Description:

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.

Related Conditions:
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: OSU-17225
  • SECONDARY ID: NCI-2018-01039
  • SECONDARY ID: OSU-17225
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT03583424

Conditions

  • 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

Interventions

DrugSynonymsArms
CarmustineBCNU, 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-139021Treatment (venetoclax, BEAM)
Cytarabine.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-28453Treatment (venetoclax, BEAM)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Treatment (venetoclax, BEAM)
MelphalanAlanine 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-19813Treatment (venetoclax, BEAM)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaTreatment (venetoclax, BEAM)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, BEAM)ExperimentalParticipants 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.
  • Carmustine
  • Cytarabine
  • Etoposide
  • Melphalan
  • Venetoclax

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure: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
Safety Issue:
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.

Secondary Outcome Measures

Measure:Incidence of progression
Time Frame:Up to 2 years
Safety Issue:
Description:Estimated using Kaplan-Meier method.
Measure:Incidence of freedom from relapse
Time Frame:Up to 2 years
Safety Issue:
Description:Estimated using Kaplan-Meier method.
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Estimated using Kaplan-Meier method.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ohio State University Comprehensive Cancer Center

Last Updated

August 26, 2019