Clinical Trials /

Study of Venetoclax in Combination With Chemotherapy in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Leukemia of Ambiguous Lineage

NCT03194932

Description:

The purpose of this study is to test the safety and determine the best dose of venetoclax and cytarabine when given with or without idarubicin in treating pediatric patients with acute myeloid leukemia (AML) that did not respond to treatment (refractory) or has come back after treatment (relapsed). PRIMARY OBJECTIVE: Determine a tolerable combination of venetoclax plus chemotherapy in pediatric patients with relapsed or refractory AML or acute leukemia of ambiguous lineage. The primary endpoints are the recommended phase 2 doses (RP2D) of venetoclax plus cytarabine and venetoclax plus cytarabine and idarubicin. SECONDARY OBJECTIVE: Estimate the overall response rate to the combination of venetoclax and chemotherapy in pediatric patients with relapsed or refractor AML or acute leukemia of ambiguous lineage. The secondary endpoints are the rates of complete remission (CR) and complete remission with incomplete count recovery (CRi) for patients treated at the RP2D.

Related Conditions:
  • Acute Leukemia of Ambiguous Lineage
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Venetoclax in Combination With Chemotherapy in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Leukemia of Ambiguous Lineage
  • Official Title: A Phase I and Expansion Cohort Study of Venetoclax in Combination With Chemotherapy in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: VENAML
  • SECONDARY ID: NCI-2017-01129
  • NCT ID: NCT03194932

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
VenetoclaxVenclextra®, ABT-199Treatment
CytarabineCytosine arabinoside, Ara-C, Cytosar®Treatment
IdarubicinIdamycin PFSTreatment
Intrathecal Triple TherapyITMHA, methotrexate/hydrocortisone/cytarabineTreatment

Purpose

The purpose of this study is to test the safety and determine the best dose of venetoclax and cytarabine when given with or without idarubicin in treating pediatric patients with acute myeloid leukemia (AML) that did not respond to treatment (refractory) or has come back after treatment (relapsed). PRIMARY OBJECTIVE: Determine a tolerable combination of venetoclax plus chemotherapy in pediatric patients with relapsed or refractory AML or acute leukemia of ambiguous lineage. The primary endpoints are the recommended phase 2 doses (RP2D) of venetoclax plus cytarabine and venetoclax plus cytarabine and idarubicin. SECONDARY OBJECTIVE: Estimate the overall response rate to the combination of venetoclax and chemotherapy in pediatric patients with relapsed or refractor AML or acute leukemia of ambiguous lineage. The secondary endpoints are the rates of complete remission (CR) and complete remission with incomplete count recovery (CRi) for patients treated at the RP2D.

Detailed Description

      This study will be done in two parts:

        -  Part 1 - Dose Escalation: The goal of Part 1 of the study is to find the highest
           tolerable combination and recommended phase 2 doses (RP2D) of venetoclax plus cytarabine
           and venetoclax plus cytarabine and idarubicin that can be given to patients with
           leukemia.

        -  Part 2 - Dose Expansion: After determination of doses in Part 1, patients will be
           enrolled on Part 2 to look at the effects of venetoclax plus cytarabine and venetoclax
           plus cytarabine and idarubicin.

      Depending on when participants enroll on the study, Part 1 participants will receive one of
      the following courses of therapy:

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours on days 8-17; OR

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours on days 8-11; OR

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours on days 8-11; idarubicin once
           on day 8; OR

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours on days 8-17; idarubicin once
           on day 8.

      Part 2 participants will receive one of the following courses of therapy:

        -  Venetoclax daily on days 1-28; cytarabine - to be determined from Part 1 of the study;
           OR

        -  Venetoclax daily on days 1-28; cytarabine - to be determined from Part 1 of the study;
           idarubicin once on day 8.

      The cytarabine dosage will be that found in Part 1 to be the highest safest dose.

      Those participants receiving idarubicin will also receive dexrazoxane.

      Note: Part 1 has been completed. Part 2 participants receive the following determined from
      Part 1 of the study:

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours days 8-11 OR

        -  Venetoclax daily on days 1-28; cytarabine every 12 hours days 8-11; idarubicin once on
           day 8.

      All participants on both Part 1 and Part 2 receive one intrathecal (IT) chemotherapy before
      starting the first cycle. Patients with CNS disease will receive weekly IT therapy until the
      cerebrospinal fluid becomes free of leukemia (minimum of 4 doses). Bone marrow aspiration and
      biopsy to assess response will be performed between days 28 and 42 of cycle 1. Patients who
      achieve complete remission/complete remission with incomplete count recovery/partial
      remission (CR/CRi/PR) and who do not experience unacceptable toxicity during cycle 1 may
      receive up to four cycles of chemotherapy.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalIn Part 1, venetoclax with cytarabine will initially be given at dose level 1 and escalated based on tolerability. Idarubicin will be given only at dose level 4. Note: Part 1 has been completed. Two expansion cohorts will be enrolled: Cohort A will be a group of 12 participants receiving the recommended phase 2 doses (RP2D) of venetoclax plus cytarabine. Cohort B will be a group of 12 participants receiving the RP2D of venetoclax plus cytarabine and idarubicin. Intrathecal Triple Therapy (ITMHA) will be given prior to cycle 1. Patients without evidence of central nervous system (CNS) leukemia will receive no further IT therapy during cycle 1. Patients with CNS disease will receive weekly ITMHA beginning on day 8 until the cerebrospinal fluid becomes free of leukemia.
  • Venetoclax
  • Cytarabine
  • Idarubicin
  • Intrathecal Triple Therapy

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have a diagnosis of AML or acute leukemia of ambiguous lineage
             (acute undifferentiated leukemia or mixed phenotype a cute leukemia) and meet the
             criteria below:

               -  Refractory leukemia, defined as persistent leukemia after at least two courses of
                  induction chemotherapy, OR

               -  Early relapsed leukemia, defined as the re-appearance of leukemia after the
                  achievement of remission and within one year of diagnosis, OR

               -  Relapsed leukemia that is refractory to at least one course of salvage therapy
                  (i.e., therapy given after the relapse has occurred), OR

               -  Second or greater relapse

               -  Patients with late relapses, defined as the re-appearance of leukemia after the
                  achievement of remission and greater than one year from diagnosis, may be
                  enrolled in the dose expansion portion of the study only.

               -  Patients in all categories above must have ≥ 5% blasts in the bone marrow as
                  assessed by morphology or > 1 blasts in the bone marrow as assessed by flow
                  cytometry. However, if an adequate bone marrow sample cannot be obtained,
                  patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5%
                  blasts in the peripheral blood. In addition, patients in all categories must not
                  be eligible to undergo curative therapy, such as immediate SCT, because of
                  disease burden, time needed to identify a stem cell donor, or other reasons.

          -  Adequate organ function defined as the following:

               -  Direct bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

               -  AST (SGOT) and ALT (SGPT) ≤ 4 x ULN

               -  Normal creatinine for age or a calculated creatinine clearance ≥ 60 mL/min/1.73
                  m2

               -  Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%

          -  St. Jude patients must be between 2 years and ≤ 21 years of age, on therapy (active
             patient), or within 3 years of completion of therapy. Patients treated at
             collaborating sites must be ≤ 24 years old.

          -  Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥
             50% for patients who are > 16 years old.

          -  Patients must have fully recovered from the acute effects of all prior therapy and
             cannot have evidence of graft-versus-host disease (GVHD)

        Exclusion Criteria:

          -  Must not be pregnant or breastfeeding. Male or female of reproductive potential must
             agree to use effective contraception for the duration of study participation.

          -  Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic
             leukemia, or bone marrow failure syndromes are not eligible.

          -  Uncontrolled infection. Infections controlled on concurrent anti-microbial agents are
             acceptable, and anti-microbial prophylaxis per institutional guidelines are
             acceptable.

          -  Impairment of GI function or GI disease that may significantly alter the absorption of
             venetoclax.
      
Maximum Eligible Age:20 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated combination (MTC)
Time Frame:28 days after start of therapy
Safety Issue:
Description:The MTC will be the highest intensity level at which six participants have been treated, with at most one participant experiencing an intensity-limiting toxicity.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

Last Updated

June 17, 2019