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

February 10, 2023 updated by: St. Jude Children's Research Hospital

A Phase I and Expansion Cohort Study of Venetoclax in Combination With Chemotherapy in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Cohort C (Amendment 5.0): Treatment of participants enrolled in cohort C will include: Venetoclax daily on days 1-21; cytarabine every 12 hours days 8-11; azacytidine days 1-7. Participants will receive one intrathecal (IT) chemotherapy before starting the first cycle. Participants with CNS disease will receive weekly ITMHA until the cerebrospinal fluid becomes free of leukemia.

The rolling-6 design will be used to determine the safety of cohort C. After cohort C is deemed to be safe, additional patients will be enrolled, if necessary, so that at least 6 patients are treated in cohort C to confirm tolerability. After tolerability is confirmed, 6 additional patients will be treated to explore activity.

Study Type

Interventional

Enrollment (Actual)

62

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • California
      • Palo Alto, California, United States, 94304
        • Lucille Packard Children's Hospital Stanford University
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • UNC Lineberger Comprehensive Cancer Center
    • Tennessee
      • Memphis, Tennessee, United States, 38105
        • St. Jude Children's Research Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 20 years (ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Participants must have a diagnosis of AML or acute leukemia of ambiguous lineage (acute undifferentiated leukemia or mixed phenotype acute leukemia) and have refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy; or relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission.

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Treatment

In 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.

Cohort C: Participants will receive venetoclax PO on days 1-21, azacitidine IV on days 1-7, and cytarabine Q12H on days 8-11.
Drug: Venetoclax
Venetoclax will be given as oral tablets, which are intended to be swallowed intact and may not to be crushed or otherwise altered for administration, or as an oral suspension for patients who cannot swallow tablets.
Other Names:
  • ABT-199
  • Venclextra®
Drug: Cytarabine
Given intravenously (IV) or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosine arabinoside
  • Cytosar®
Drug: Idarubicin
Given IV.
Other Names:
  • Idamycin PFS
Drug: Intrathecal Triple Therapy
Given IT.
Other Names:
  • ITMHA
  • methotrexate/hydrocortisone/cytarabine
Drug: Azacitidine
Given IV.
Other Names:
  • VIDAZA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum tolerated combination (MTC)
Time Frame: 28 days after start of therapy
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.
28 days after start of therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete Remission (CR)
Time Frame: Up to 6 weeks
Will be assessed for the patients enrolled at the MTC (RP2D). Will be presented as a point estimate with a 95% exact binomial confidence interval.
Up to 6 weeks
Complete remission with incomplete count recovery (CRi)
Time Frame: Up to 6 weeks
Will be assessed for the patients enrolled at the MTC (RP2D). Will be presented as a point estimate with a 95% exact binomial confidence interval.
Up to 6 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Jude Children's Research Hospital

Collaborators

Gateway for Cancer Research

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 11, 2017

Primary Completion (ACTUAL)

October 27, 2020

Study Completion (ACTUAL)

June 22, 2022

Study Registration Dates

First Submitted

June 19, 2017

First Submitted That Met QC Criteria

June 19, 2017

First Posted (ACTUAL)

June 21, 2017

Study Record Updates

Last Update Posted (ESTIMATE)

February 14, 2023

Last Update Submitted That Met QC Criteria

February 10, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • VENAML
  • NCI-2017-01129 (REGISTRY: NCI Clinical Trial Registration Program)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Acute Myeloid Leukemia

Clinical Trials on Venetoclax

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Switzerland

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe