The purpose of the study is to determine the recommended phase 2 dose (RP2D) of ponatinib (tablet and age-appropriate formulation [AAF]) in combination with chemotherapy in Phase 1 and the efficacy of ponatinib in combination with chemotherapy as measured by the rate of complete remission (CR) at the end of the reinduction block at the RP2D.
Name: Ponatinib
Name: Ponatinib AAF
Name: Chemotherapy Agents
Description: The RP2D is the maximum tolerated dose (MTD) or less.
Measure: Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy Time: Up to Week 4Description: CR rate is defined as percentage of participants with CR. CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000/μl (or >100 × 10^9 platelets /L).
Measure: Phase 2: Complete Remission (CR) Rate at the end of Reinduction Block Time: Up to Week 4Description: CR rate is defined as percentage of participants with CR. CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000/μl (or >100 × 10^9 platelets /L).
Measure: Phase 1: CR Rate at the end of Reinduction Block Time: Up to Week 4Description: CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μl (or >100 × 10^9 platelets /L).
Measure: Phase 2: Percentage of Participants with Continued CR or who Achieved CR at the End of Consolidation Block Time: Up to Week 8Description: MRD negative rate is the percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirate at <0.01% threshold.
Measure: Phase 2: Percentage of Participants with Negative Minimal Residual Disease (MRD) Time: Up to Weeks 4 and 8Description: EFS is defined as time from date of enrollment until death due to any cause; refractory to treatment (no disease response by end of the consolidation block) or relapse from CR. CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μl (or >100 × 10^9 platelets /L).
Measure: Phase 2: Event-free Survival (EFS) Time: Up to approximately 36 monthsDescription: PFS is defined as time from date of enrolment until death due to any cause; disease progression (clinical deterioration associated with disease process, including evidence of increasing blasts in the bone marrow and/or evidence of new organ involvement) or relapse from CR. CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μl (or >100 × 10^9 platelets /L).
Measure: Phase 2: Progression-free Survival (PFS) Time: Up to approximately 36 monthsDescription: OS is defined as time from first dose of ponatinib until death due to any cause.
Measure: Phase 2: Overall Survival (OS) Time: Up to approximately 36 monthsDescription: DOR is defined as the interval between the first assessment at which the criteria for CR are met until the time at which relapse from CR occurs. CR is defined as no circulating blasts and <5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC >1000 cells/μl (or >1.0 × 10^9 cells/L); Platelets >100,000 platelets/μl (or >100 × 10^9 platelets /L).
Measure: Phase 2: Duration of Response (DOR) Time: Up to approximately 36 monthsSequential Assignment
There is one SNP
A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evaluate the Safety and Efficacy of Ponatinib With Chemotherapy in Pediatric Patients With Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Who Have Relapsed or Are Resistant or Intolerant to a Prior Tyrosine Kinase Inhibitor-Containing Therapy, or Who Have the T315I Mutation. --- T315I ---
Ponatinib With Chemotherapy in Pediatric Participants With Relapsed, Resistant, or Intolerant Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) or Have the T315I Mutation The purpose of the study is to determine the recommended phase 2 dose (RP2D) of ponatinib (tablet and age-appropriate formulation [AAF]) in combination with chemotherapy in Phase 1 and the efficacy of ponatinib in combination with chemotherapy as measured by the rate of complete remission (CR) at the end of the reinduction block at the RP2D. --- T315I ---
Inclusion Criteria: 1. Have a diagnosis of acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia (MPAL) with definite evidence of breakpoint cluster region- Abelson 1 (BCR-ABL1) fusion (Ph) or Ph-like ALL (USA-only) with targetable kinase-activating lesions and either (i) or (ii) as follows: (i) For non-US sites: participants who have relapsed or are resistant or intolerant to at least one prior therapy that contained a BCR-ABL-targeted tyrosine kinase inhibitor (TKI); or for US sites: participants who have relapsed or are resistant or intolerant to at least one prior therapy that contained a second-generation BCR-ABL1-targeted TKI (ie, dasatinib, nilotinib, and bosutinib); or (ii) have a T315I mutation. --- T315I ---
2. Participants with BCR-ABL1 T315I mutation, irrespective of relapse, resistance/intolerance, or transplant status and irrespective of any prior TKI use. 3. Participants with Ph-like ALL (US only) with TKI-targetable lesions involving any of the following kinase genes: ABL1, ABL2, cerebrospinal fluid (CSF1R), and platelet-derived growth factor receptor, beta polypeptide (PDGFRB). --- T315I ---
Ponatinib is being tested to treat pediatric population who have Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who have relapsed or are resistant or intolerant to a prior tyrosine kinase inhibitor (TKI)-containing therapy, or who have the T315I mutation. --- T315I ---