Venetoclax, Carmustine, Etoposide, Cytarabine, and Melphalan before Stem Cell Transplant in Treating Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Status: Active

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 patients 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.

Eligibility Criteria

Inclusion Criteria

  • Subjects must have histologically confirmed diagnosis of non-Hodgkin’s lymphoma that is refractory after upfront induction therapy, in partial remission or worse after salvage, or relapsed. Excluded histologies are post-transplant lymphoproliferative disorder, and chronic lymphocytic leukemia/small lymphocytic lymphoma. All other histologies are eligible. These include but are not limited to: diffuse-large B-cell lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma (PTCL), hairy cell leukemia (classic or variant), lymphoblastic lymphoma, prolymphocytic leukemia (T or B-cell), 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 regardless of response * High risk is defined as 1) requiring 3 or more lines of therapy, 2) transformed lymphoma, 3) relapse within 12 months of day (D)1 of last cycle of induction chemotherapy, 4) mantle cell lymphoma (MCL) or PTCL undergoing consolidation with ASCT in CR1/PR1
  • Expected survival of more than six months
  • Karnofsky performance status >= 80%
  • 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 or greater (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 (within 1 week prior to initiation of treatment)
  • 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) (5-point scale of =< 3) unless lymphoma relapsed within 12 months from the first day of last cycle of induction chemotherapy or patients have "high risk disease"
  • Subjects receiving any other investigational agents
  • 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
  • Patients receiving strong inhibitors or inducers of CYP3A4. All such medications would have to be discontinued for 72 hours prior to start of 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

Locations & Contacts

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: Active
Contact: Basem M.Y. William
Phone: 614-688-7942
Email: Basem.William@osumc.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of venetoclax that can be safely combined with BEAM prior to autologous stem cell transplant.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of venetoclax combined with carmustine, etoposide, cytarabine, and melphalan (BEAM) prior to autologous stem cell transplant.

II. To obtain a preliminary estimate of the efficacy of venetoclax in combination with BEAM as measured by overall response rate (ORR) at day 100.

III. To estimate the progression free survival (PFS) and overall survival (OS) of venetoclax and BEAM followed by autologous stem cell transplant (ASCT).

OPTIONAL EXPLORATORY OBJECTIVES:

I. Determine any correlation of response and survival endpoints with the expression of BCL-2, BCL-XL, and MCL-1 as measured by immunohistochemistry (IHC).

OUTLINE: This is a dose-escalation study of venetoclax.

Patients 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. Patients then undergo hematopoietic stem cell transplantation on day 0.

After completion of study treatment, patients are followed up for 1 year.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Ohio State University Comprehensive Cancer Center

Principal Investigator
Basem M.Y. William

Trial IDs

Primary ID OSU-17225
Secondary IDs NCI-2018-01039, 2018C0087
Clinicaltrials.gov ID NCT03583424