Clinical Trials /

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

NCT03713580

Description:

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.

Related Conditions:
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax in Combination With BEAM Conditioning Regimen for ASCT in Non-Hodgkin Lymphoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: CASE2418
  • NCT ID: NCT03713580

Conditions

  • Non-hodgkin Lymphoma

Interventions

DrugSynonymsArms
VenetoclaxVenetoclax+BEAM x 1 cycle prior to ASCT

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Venetoclax+BEAM x 1 cycle prior to ASCTExperimentalVenetoclax 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
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  Specific guidelines will be followed regarding inclusion of NHL based on Hepatitis B
             serological testing as follows:

               -  HBsAg negative, HBcAb negative, HBsAb negative patients are eligible.

               -  HBsAg negative, HBcAb negative, HBsAb positive patients are eligible.

               -  Patients who test positive for HBsAg are ineligible.

               -  Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status)
                  should have a HBV DNA testing performed and protocol eligibility determined as
                  follows:

                    -  If HBV DNA is positive, the patient is ineligible.

                    -  If HBV DNA is negative, the patient may be included but must undergo HBV DNA
                       PCR testing monthly x 3 months beginning from the start of treatment

          -  Female patients who are not surgically sterile or postmenopausal (for at least 1year)
             must practice at least one of the following methods of birth control throughout the
             duration of study participation and for at least 30 days after study treatment:

               -  Total abstinence from sexual intercourse

               -  A vasectomized partner

               -  Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that
                  started at least 3months prior to study drug administration

               -  Double-barrier method (condom+diaphragm or cervical cup with spermicidal
                  contraceptive sponge, jellies, or cream)

          -  Patients must have the ability to understand and the willingness to sign a written
             informed consent document.

        Exclusion Criteria: The presence of any of the following will exclude a patient from study
        enrollment:

          -  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).

               -  CYP2C9 substrates such as tolbutamide (because of expected inhibition of the
                  metabolism of CYP2C9 substrates by Venetoclax). It is recommended to exclude
                  CYP2C9 substrates with a narrow therapeutic index such as phenytoin.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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 Issue:
Description: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.

Secondary Outcome Measures

Measure:Time to neutrophil engraftment
Time Frame:24 months after hospital discharge
Safety Issue:
Description:Compare time to neutrophil engraftment of patients who receive V-BEAM followed by ASCT, compared to historical controls and among cohorts.
Measure:Time to platelet engraftment
Time Frame:24 months after hospital discharge
Safety Issue:
Description:Compare time to platelet engraftment of patients who receive V-BEAM followed by ASCT, compared to historical controls and among cohort.
Measure:Progression-free survival (PFS)
Time Frame:24 months after hospital discharge
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:24 months after hospital discharge
Safety Issue:
Description:Determine the Overall Survival (OS) of V+BEAM followed by ASCT relative to historical controls of BEAM alone followed by ASCT.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • Autologous stem cell transplant (ASCT)
  • Venetoclax

Last Updated

October 5, 2020