Summary

A study to evaluate if the randomized addition of venetoclax to a chemotherapy backbone
(fludarabine/cytarabine/gemtuzumab ozogamicin [GO]) improves survival of
children/adolescents/young adults with acute myeloid leukemia (AML) in 1st relapse who are
unable to receive additional anthracyclines, or in 2nd relapse.

Objectives

Relapse of AML is driven by chemotherapy resistant stem cells. One mechanism of
chemotherapeutic resistance in AML is the overexpression of the protein B-cell lymphoma 2
(BCL-2), an anti-apoptotic protein which sequesters intracellular activators of apoptosis.
Venetoclax is a selective, potent, orally bioavailable, small molecule inhibitor of B-cell
lymphoma (BCL)-2 that restores programmed cell death in cancer cells.

This is a trial for children, adolescents and young adults with 2nd relapsed AML or 1st
relapsed AML unable to receive additional anthracycline.

This is randomized trial of venetoclax in combination with intensive chemotherapy
(fludarabine/cytarabine/gemtuzumab ozogamicin) for the first two cycles that would inform and
evaluate if this agent is an effective option for this population to improve its poor
prognosis. Participants can receive up to two cycles of induction chemotherapy before
hematopoietic stem cell transplantation (HSCT). Participants benefiting from treatment and
who are not able to proceed to HSCT have the possibility to continue to receive azacitidine
in monotherapy (Arm A, control arm) or in combination with venetoclax (Arm B, experimental
arm).

Eligibility

1. Participants must have enrolled on APAL2020SC, NCT Number: NCT04726241 prior to enrollment on ITCC-101/APAL2020D. (This is only applicable for participants in USA/Canada/Australia/New Zealand sites/LLS territory).
2. Participants must be = 29 days of age and = 21 years of age at enrollment.
3. Participants must have one of the following:
4. Children, adolescents, and young adults with acute myeloid leukemia without FLT3/internal tandem duplication (ITD) mutation in:
5. Second relapse, who are sufficiently fit to undergo another round of intensive chemotherapy
6. First relapse who per investigator discretion cannot tolerate additional anthracycline containing chemotherapy.
7. Participants must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (= 50% Lansky or Karnofsky score)
8. Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to start of protocol treatment:
9. Cytotoxic chemotherapy: Must not have received cytotoxic chemotherapy within 14 days prior to start of protocol treatment, except for corticosteroids, low dose cytarabine or hydroxyurea that can be given up to 24 hours prior to start of protocol treatment.
10. Intrathecal cytotoxic therapy: No wash-out time is required for participants having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone.
11. Antibodies: = 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate before start of protocol treatment. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before start of protocol treatment. Any toxicity related to prior antibody therapy must be recovered to Grade = 1.
12. Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): = 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors) before start of protocol treatment.
13. Hematopoietic growth factors: = 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or =7 days for short-acting growth factor before start of protocol treatment.
14. Radiation therapy (RT) (before start of protocol treatment):
15. = 14 days have elapsed for local palliative RT (small port);
16. = 84 days must have elapsed if prior craniospinal RT or if = 50% radiation of pelvis;
17. = 42 days must have elapsed if other substantial bone marrow (BM) radiation.
18. Stem Cell Infusions (before start of protocol treatment):
19. = 84 days since allogeneic (non-autologous) bone marrow or stem cell transplant (with or without total body irradiation [TBI]) or boost infusion (any stem cell product; not including donor lymphocyte infusion [DLI])
20. No evidence of active graft versus host disease (GVHD).
21. Participants who are receiving cyclosporine, tacrolimus or other agents to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial. Participants must be off medications to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant for at least 14 days prior to enrollment.
22. Cellular Therapy: = 42 days after the completion of donor lymphocyte infusion (DLI) or any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.) before start of protocol treatment.
23. Participants with prior exposure to venetoclax are eligible in this trial
24. Adequate organ function:
25. Adequate Renal Function defined as:
26. Creatinine clearance or radioisotope glomerular filtration rate (GFR) = 60ml/min/1.73 m^2, or
27. Normal serum creatinine based on age/sex
28. Adequate Liver Function defined as:
29. Direct bilirubin < 1.5 x upper limit of normal (ULN), and
30. Alkaline phosphatase = 2.5 x ULN, and
31. Serum glutamic pyruvic transaminase (SGPT) alanine aminotransferase (ALT) = 2.5 x ULN. If liver abnormality is due to radiographically identifiable leukemia infiltrate, the participant will remain eligible.
32. Cardiac performance: Minimum cardiac function defined as:
33. No history of congestive heart failure in need of medical treatment
34. No pre-treatment diminished left ventricular function on echocardiography (shortening fraction [SF] < 25% or ejection fraction [EF] < 40%)
35. No signs of congestive heart failure at presentation of relapse.
36. Participant, parent or guardian must sign and date informed consent and pediatric assent (when required), prior to the initiation of screening or study specific procedures, according to local law and legislation.