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Acute Myeloid LeukemiaPhase 1NCT03194932

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

A Phase 1 study testing Venetoclax, Cytarabine and Idarubicin in people with Acute Myeloid Leukemia, run by St. Jude Children's Research Hospital at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 2 to 20 years
Conditions the study is for
Acute Myeloid Leukemia
What is being tested?
Venetoclax, Cytarabine and Idarubicin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
62 participants
Where
3 sitesUnited States
Study dates
11 Jul 2017to 22 Jun 2022
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 to 20 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
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  • 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)

Who cannot join

  • 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.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • UNC Lineberger Comprehensive Cancer Center

    Chapel Hill, North Carolina, 27599

  • St. Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • Lucille Packard Children's Hospital Stanford University

    Palo Alto, California, 94304

Other trials in United States

About this study

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

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.

Read the 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.

Being tested
Venetoclax, Cytarabine, Idarubicin, Intrathecal Triple Therapy, Azacitidine
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VenetoclaxDrug

    Also called Venclextra®, ABT-199

    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.

  • CytarabineDrug

    Also called Cytosine arabinoside, Ara-C, Cytosar®

    Given intravenously (IV) or intrathecally (IT).

  • IdarubicinDrug

    Also called Idamycin PFS

    Given IV.

  • Intrathecal Triple TherapyDrug

    Also called ITMHA, methotrexate/hydrocortisone/cytarabine

    Given IT.

  • AzacitidineDrug

    Also called VIDAZA®

    Given IV.

Study groups in NCT03194932
Study groupRoleWhat they receive
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. Cohort C: Participants will receive venetoclax PO on days 1-21, azacitidine IV on days 1-7, and cytarabine Q12H on days 8-11.
Receives: Drug: Venetoclax; Drug: Cytarabine; Drug: Idarubicin; Drug: Intrathecal Triple Therapy; Drug: Azacitidine

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 28 days after start of therapy

Secondary outcomes (2)

  1. Complete Remission (CR)

    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.

    Measured: Up to 6 weeks

  2. Complete remission with incomplete count recovery (CRi)

    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.

    Measured: Up to 6 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jun 2017
  2. Study start11 Jul 2017
  3. Primary completion27 Oct 2020
  4. Study completion22 Jun 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
Participants receive venetoclax plus cytarabine alone or combination chemotherapy of cytarabine plus idarubicin.
Masking
None (open label)
Enrolment
62 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03194932
Sponsor's protocol ID
VENAML
Other IDs
NCI-2017-01129
Status last verified
Feb 2023
First submitted
19 Jun 2017
Last updated
14 Feb 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Daniels KP, Pounds SB, Wu H, Wang L, Alexander TB, Budhraja A, Wolf J, Westover T, Mead PE, Mehr CM, Gupta SD, Lacayo NJ, Inaba H, Rees M, Pui CH, Opferman JT, Klco JM, Rubnitz JE, Karol SE. Venetoclax in combination with cytarabine with or without idarubicin or azacitidine in children, adolescents, and young adults with relapsed or refractory acute myeloid leukaemia (VENAML): a multicentre, phase 1 expansion study. Lancet Haematol. 2026 Aug;13(8):e545-e554. doi: 10.1016/S2352-3026(26)00136-5. Epub 2026 Jul 8.

    PubMed 42419338

  • 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.

    PubMed 39368878

  • 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.

    PubMed 32171069

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Venetoclax, Cytarabine and Idarubicin in people with Acute Myeloid Leukemia, run by St. Jude Children's Research Hospital at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated combination (MTC) (time frame: 28 days after start of therapy). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03194932, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Feb 2023.

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