Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Registration Number
- NCT05183035
- Lead Sponsor
- LLS PedAL Initiative, LLC
- 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 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 98
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A: Control Arm without Venetoclax Fludarabine During Cycle 1 (42-day-cycles), 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 HSCT or azacitidine maintenance therapy. Arm A: Control Arm without Venetoclax Cytarabine During Cycle 1 (42-day-cycles), 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 HSCT or azacitidine maintenance therapy. Arm A: Control Arm without Venetoclax Gemtuzumab Ozogamicin During Cycle 1 (42-day-cycles), 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 HSCT or azacitidine maintenance therapy. Arm A: Control Arm without Venetoclax Azacitidine During Cycle 1 (42-day-cycles), 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 HSCT or azacitidine maintenance therapy. Arm B: Experimental Arm with Venetoclax Azacitidine During Cycle 1 (42-day-cycles), 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. Arm B: Experimental Arm with Venetoclax Venetoclax During Cycle 1 (42-day-cycles), 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. Arm B: Experimental Arm with Venetoclax Fludarabine During Cycle 1 (42-day-cycles), 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. Arm B: Experimental Arm with Venetoclax Cytarabine During Cycle 1 (42-day-cycles), 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. Arm B: Experimental Arm with Venetoclax Gemtuzumab Ozogamicin During Cycle 1 (42-day-cycles), 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.
- Primary Outcome Measures
Name Time Method Overall Survival (OS) Up to 5 years
- Secondary Outcome Measures
Name Time Method Morphology Event Free Survival (EFS) Up to 5 years Flow-based Event Free Survival (EFS) Up to 5 years Disease-related Mortality 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 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) Up to 5 years Number of Participants with International Working Group Complete Response (IWG-CR) Up to 5 years Morphological 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 Non-disease-related Mortality 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 Flow-based Overall Response Rate (ORR) Up to Day 84 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
Related Research Topics
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Trial Locations
- Locations (82)
Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
MemorialCare Miller Children's and Women's Hospital Long Beach
🇺🇸Long Beach, California, United States
Children's Hospital of Orange County Main Campus - Orange
🇺🇸Orange, California, United States
Benioff Children's Hospital - Mission Bay
🇺🇸San Francisco, California, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Nemours Alfred I. Dupont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸Fort Myers, Florida, United States
Nemours Children's Specialty Care Jacksonville
🇺🇸Jacksonville, Florida, United States
Scroll for more (72 remaining)Phoenix Children's Hospital🇺🇸Phoenix, Arizona, United States