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

NCT03194932 | Completed Phase 1 FDA Drug

• 2 other identifiers: VENAMLNCI-2017-01129
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated combination (MTC)

  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 Outcomes (2)

• Complete Remission (CR)

  Up to 6 weeks

• Complete remission with incomplete count recovery (CRi)

  Up to 6 weeks

Study Arms (1)

Treatment

EXPERIMENTAL

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; Drug: Cytarabine; Drug: Idarubicin; Drug: Intrathecal Triple Therapy; Drug: Azacitidine

Interventions

Venetoclax DRUG

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.

Also known as: Venclextra®, ABT-199

Treatment

Cytarabine DRUG

Given intravenously (IV) or intrathecally (IT).

Also known as: Cytosine arabinoside, Ara-C, Cytosar®

Treatment

Idarubicin DRUG

Given IV.

Also known as: Idamycin PFS

Treatment

Intrathecal Triple Therapy DRUG

Given IT.

Also known as: ITMHA, methotrexate/hydrocortisone/cytarabine

Treatment

Azacitidine DRUG

Given IV.

Also known as: VIDAZA®

Treatment

Eligibility Criteria

• Age: 2 Years - 20 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Gateway for Cancer Research: collaborator

Study Sites (3)

Lucille Packard Children's Hospital Stanford University

Palo Alto, California, 94304, United States

Location

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Publications (2)

• Badawi M, Gopalakrishnan S, Engelhardt B, Palenski T, Karol SE, Rubnitz JE, Menon R, Salem AH. Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships. Clin Ther. 2024 Oct;46(10):759-767. doi: 10.1016/j.clinthera.2024.09.008. Epub 2024 Oct 5.

  PMID: 39368878 DERIVED

• Karol SE, Alexander TB, Budhraja A, Pounds SB, Canavera K, Wang L, Wolf J, Klco JM, Mead PE, Das Gupta S, Kim SY, Salem AH, Palenski T, Lacayo NJ, Pui CH, Opferman JT, Rubnitz JE. Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Lancet Oncol. 2020 Apr;21(4):551-560. doi: 10.1016/S1470-2045(20)30060-7. Epub 2020 Mar 11.

  PMID: 32171069 DERIVED

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

venetoclax; Cytarabine; Idarubicin; Methotrexate; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Aza Compounds; Ribonucleosides

Study Officials

• Jeffrey E. Rubnitz, MD, PhD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants receive venetoclax plus cytarabine alone or combination chemotherapy of cytarabine plus idarubicin.

Study Record Dates

• First Submitted: June 19, 2017
• First Posted: June 21, 2017
• Study Start: July 11, 2017
• Primary Completion: October 27, 2020
• Study Completion: June 22, 2022
• Last Updated: February 14, 2023

Record last verified: 2023-02

Locations

US (3)