Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)

Study Overview
=================
Brief 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.

Detailed Description
-----------------
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).

Official Title
-----------------
A Randomized Phase 3 Trial of Fludarabine/Cytarabine/Gemtuzumab Ozogamicin With or Without Venetoclax in Children With Relapsed AML

Conditions
-----------------
Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: Fludarabine
* Drug: Cytarabine
* Drug: Gemtuzumab Ozogamicin
* Drug: Azacitidine
* Drug: Venetoclax


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria 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). Participants must be ≥ 29 days of age and ≤ 21 years of age at enrollment. Participants must have one of the following: Children, adolescents, and young adults with acute myeloid leukemia without FLT3/internal tandem duplication (ITD) mutation in: Second relapse, who are sufficiently fit to undergo another round of intensive chemotherapy First relapse who per investigator discretion cannot tolerate additional anthracycline containing chemotherapy. Participants must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (≥ 50% Lansky or Karnofsky score) 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: 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. Intrathecal cytotoxic therapy: No wash-out time is required for participants having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone. 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. 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. 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. Radiation therapy (RT) (before start of protocol treatment): ≥ 14 days have elapsed for local palliative RT (small port); ≥ 84 days must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis; ≥ 42 days must have elapsed if other substantial bone marrow (BM) radiation. Stem Cell Infusions (before start of protocol treatment): ≥ 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]) No evidence of active graft versus host disease (GVHD). 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. 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. Participants with prior exposure to venetoclax are eligible in this trial Adequate organ function: Adequate Renal Function defined as: Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60ml/min/1.73 m^2, or Normal serum creatinine based on age/sex Adequate Liver Function defined as: Direct bilirubin < 1.5 x upper limit of normal (ULN), and Alkaline phosphatase ≤ 2.5 x ULN, and 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. Cardiac performance: Minimum cardiac function defined as: No history of congestive heart failure in need of medical treatment No pre-treatment diminished left ventricular function on echocardiography (shortening fraction [SF] < 25% or ejection fraction [EF] < 40%) No signs of congestive heart failure at presentation of relapse. 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. Exclusion Criteria Participants who in the opinion of the investigator may not be able to comply with the study requirements of the study, are not eligible. Participants with Down syndrome. Participants with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic leukemia (JMML). Participants with isolated CNS3 disease or symptomatic CNS3 disease. Participants with malabsorption syndrome or any other condition that precludes enteral administration of venetoclax. Participants who are currently receiving another investigational drug (GO is not considered investigational in this study). Participants with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known congenital bone marrow failure syndrome. Participants with known prior allergy to any of the medications used in protocol therapy. Participants with documented active, uncontrolled infection at the time of study entry. No known human immunodeficiency virus (HIV) infection. Post menarchal female participants with positive pregnancy test. Concomitant Medications Participants who have received strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort within 7 days of the start of study treatment. Participants who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days of the start of study treatment. Participants who have hypersensitivity to the active substance or to any of the excipients listed in summary of product characteristics (SPC). Pregnancy or Breast-Feeding: Participants who are pregnant or breast-feeding. Participants of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method per clinical trials facilitation group (CTFG) guidelines for the duration of study therapy and for 6 months after the completion of all study therapy. Male participants must use a condom during intercourse and agree not to father a child or donate sperm during therapy and for the duration of study therapy and for 4 months after the completion of all study therapy. Additional criteria to receive a gemtuzumab ozogamicin infusion: Gemtuzumab ozogamicin should not be given: to participants with history of veno-occlusive disease (VOD)/Sinusoidal obstruction syndrome (SOS) grade 4 to participants with history of VOD/SOS grade 3 to participants with CD33 negative leukemic blasts (determined at local lab) Note that these participants are eligible for the study but will not be treated with gemtuzumab ozogamicin.

Ages Eligible for Study
-----------------
Minimum Age: 29 Days
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Control Arm without Venetoclax<br>During cycle 1 (each cycle is 42 days), participants will receive 30 mg/m^2 of fludarabine followed by 2 g/m^2 of cytarabine on Days 1-5. Gemtuzumab 3 mg/m^2 will be given on Day 6 (only for participants with CD33 expression on leukemia blasts). During cycle 2 participants will receive 30 mg/m^2 of fludarabine followed by 2 g/m^2 of cytarabine on Days 1-5. After cycle 2 participants are assessed for hematopoietic stem cell transplantation (HSCT) or azacitidine maintenance therapy. | Drug: Fludarabine<br>* Intravenous (IV) infusion<br>Drug: Cytarabine<br>* Intravenous (IV) infusion<br>Drug: Gemtuzumab Ozogamicin<br>* Intravenous (IV) infusion<br>Drug: Azacitidine<br>* Intravenous (IV) infusion or subcutaneous injection<br>|
| Experimental: Arm B: Experimental Arm with Venetoclax<br>During cycle 1 (each cycle is 42 days), participants will receive 300 mg adult dose equivalent of venetoclax once on Day 1 followed by 600 mg adult dose equivalent of venetoclax on Days 2-21. Participants will also receive 30 mg/m^2 of fludarabine followed by 2 g/m^2 of cytarabine on Days 8-12. Gemtuzumab 3 mg/m^2 will be given on Day 13 (only for participants with CD33 expression on leukemia blasts). During cycle 2, participants will receive 600 mg adult dose equivalent of venetoclax on Days 1-21. Participants will receive 30 mg/m^2 of fludarabine followed by 2 g/m^2 of cytarabine on Days 1-5. After cycle 2 participants are assessed for HSCT or azacitidine maintenance therapy in combination with venetoclax. | Drug: Fludarabine<br>* Intravenous (IV) infusion<br>Drug: Cytarabine<br>* Intravenous (IV) infusion<br>Drug: Gemtuzumab Ozogamicin<br>* Intravenous (IV) infusion<br>Drug: Azacitidine<br>* Intravenous (IV) infusion or subcutaneous injection<br>Drug: Venetoclax<br>* Orally via tablet or powder suspension<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morphology Event Free Survival (EFS) |  | Up to 5 years | 
| Flow-based Event Free Survival (EFS) |  | Up to 5 years | 
| Morphological Overall Response Rate (ORR) |  | Up to Day 84 | 
| Flow-based Overall Response Rate (ORR) |  | Up to Day 84 | 
| Duration of Response (DOR) |  | Up to 5 years | 
| Cumulative Incidence of Relapse (CIR) |  | Up to 5 years | 
| Number of Participants with Non-relapse Mortality (NRM) |  | Up to 5 years | 
| Hematopoietic Stem Cell Transplantation (HSCT) Rate |  | Up to 5 years | 
| Number of Participants with Adverse Events (AEs) |  | Up to 5 years | 
| Maximum Observed Plasma Concentration (Cmax) of Venetoclax |  | Pre-dose, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 8 and Day 13 (cycle is 42 days); once on follow-up visits of Cycle 2 between Day 5 and Day 21 | 
| Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax |  | Pre-dose, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 8 and Day 13 (cycle is 42 days); once on follow-up visits of Cycle 2 between Day 5 and Day 21 | 
| Area Under the Plasma Concentration-time Curve Over a 24-hour Dose Interval (AUC0-24) |  | Pre-dose, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 8 and Day 13 (cycle is 42 days); once on follow-up visits of Cycle 2 between Day 5 and Day 21 | 
| Participants That Are Minimal Residual Disease (MRD) Negative with Complete Remission (CR), Partial Complete Remission (CRp), or Complete Remission with Incomplete Hematologic Recovery (CRi) |  | Up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Venetoclax, Gemtuzumab Ozogamicin, Fludarabine, Cytarabine, Relapsed refractory, Azacitidine