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.
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 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 (42-day-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). If participants who have perceived clinical benefit cannot be transplanted after the 2 cycles, maintenance treatment may be given at the discretion of the investigator. In Arm B (experimental arm), participants can continue venetoclax if they have perceived clinical benefit, and maintenance therapy will combine venetoclax with azacitidine for a maximum of 24 cycles. In Arm A (control arm), participants will receive azacitidine in monotherapy. Maintenance is continued until clinical progression or unacceptable toxicity with a maximum of 24 cycles.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
130
Intravenous (IV) infusion
Intravenous (IV) infusion
Intravenous (IV) infusion
Overall Survival (OS)
Time frame: Up to 5 years
Morphology Event Free Survival (EFS)
Time frame: Up to 5 years
Flow-based Event Free Survival (EFS)
Time frame: Up to 5 years
Flow-based Overall Response Rate (ORR)
Time frame: Up to Day 84
Morphological Overall Response Rate (ORR)
Time frame: Up to Day 84
Duration of Response (DOR)
Time frame: Up to 5 years
Cumulative Incidence of Relapse (CIR)
Time frame: Up to 5 years
Disease-related Mortality
Time frame: Up to 5 years
Non-disease-related Mortality
Time frame: Up to 5 years
Hematopoietic Stem Cell Transplantation (HSCT) Rate
Time frame: Up to 5 years
Number of Participants with Adverse Events (AEs)
Time frame: Up to 5 years
Maximum Observed Plasma Concentration (Cmax) of Venetoclax
Time frame: 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
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Intravenous (IV) infusion or subcutaneous injection
Orally via tablet or powder suspension
Phoenix Children's Hospital
Phoenix, Arizona, United States
RECRUITINGArkansas Children's Hospital
Little Rock, Arkansas, United States
RECRUITINGMemorialCare Miller Children's and Women's Hospital Long Beach
Long Beach, California, United States
RECRUITINGChildren's Hospital of Orange County Main Campus - Orange
Orange, California, United States
RECRUITINGBenioff Children's Hospital - Mission Bay
San Francisco, California, United States
RECRUITINGChildren's Hospital Colorado
Aurora, Colorado, United States
RECRUITINGYale University
New Haven, Connecticut, United States
RECRUITINGNemours Alfred I. Dupont Hospital for Children
Wilmington, Delaware, United States
RECRUITINGChildren's National - Main Hospital
Washington D.C., District of Columbia, United States
RECRUITINGGolisano Children's Hospital of Southwest Florida
Fort Myers, Florida, United States
RECRUITING...and 80 more locations
Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
Time frame: 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)
Time frame: 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
Number of Participants That Are Pediatric Minimal Residual Disease (Ped-MRD) Negative with Complete Remission (CR), Partial Complete Remission (CRp), or Complete Remission with Incomplete Hematologic Recovery (CRi)
Time frame: Up to 5 years
Number of Participants with International Working Group Complete Response (IWG-CR)
Time frame: Up to 5 years