A Phase 1/2, Multicenter, Open-Label, Single Arm, Dose Escalation and Expansion Study of Gilteritinib (ASP2215) Combined With Chemotherapy in Children, Adolescents and Young Adults With FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

Phase 1: Maximum Tolerated Dose (MTD) of Gilteritinib

时间窗: C1D1 up to day 28

MTD reflects the highest dose that did not cause a Dose Limiting Toxicity (DLT).DLT:any Grade ≥3 non-hematologic/extramedullary toxicity with the following exceptions that occurred during the DLT observations like alopecia, anorexia, or fatigue, grade 3 vomiting or diarrhea that resolved(with or without supportive care) to ≤ grade 2 within 48 hours, grade 3 nausea that resolved(with or without supportive care) to ≤ grade 2 within 7 days, grade 3 elevation in total bilirubin (TBL) that is asymptomatic and that returned to ≤ grade 2 elevation within 7 days, grade 3 elevation in hepatic transaminases\[alanine aminotransferase (ALT/SGPT) aspartate aminotransferase (AST/SGOT) and gammaglutamyl transferase (GGT)\] or Alkaline Phosphatase (ALP) level that returns to ≤ grade 2 elevation within 14 days, grade 3 fever with neutropenia, with/without infection, grade 3 infection/grade 4 infections expected as direct complication of cytopenia due to active underlying leukemia, grade 3 mucositis.

Phase 1: Recommended Phase 2 Dose (RP2D) of Gilteritinib

时间窗: C1D1 up to day 28

The RP2D was a safe dose of gilteritinib that demonstrated sufficient activity.

Phase 2: Complete Remission (CR) Rate

时间窗: From date of randomization to end of induction (induction= 1-2 cycles, each cycle = 28 days)

CR rate was defined as the number of participants with best response of CR divided by the number of participants in the analysis population. CR was defined as a morphologically leukemia-free state post-baseline and had absolute neutrophil count (ANC) \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts. and were red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. Derived and investigator-assessed responses are reported.

Phase 2: Composite CR (CRc) Rate

时间窗: From date of randomization to end of induction (induction= 1-2 cycles, each cycle = 28 days)

CRc was defined as participants who achieved either CR, complete remission with incomplete platelet recovery (CRp) or complete remission with incomplete hematologic recovery (CRi) at the visit. CR was defined as a morphologically leukemia-free state post-baseline and had ANC \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts. and were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. CRp was defined as met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi was defined as met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. Derived and investigator-assessed responses are reported.

Duration of CR

时间窗: From the date of first CR until the date of documented relapse for participants who achieved CR (Maximum duration: 28 months)

Duration of CR was defined as the time from the date of first CR until the date of documented relapse for participants who achieved CR. CR was defined as a morphologically leukemia-free state post-baseline and had ANC \>= 1 x 10\^9/L, platelet count \>= 100 x 10\^9/L and normal marrow differential with \< 5% blasts, and were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia and no evidence of Auer rods. The blast counts in peripheral blood must be \<= 2%. Relapse was defined as a reappearance of leukemic blasts in the peripheral blood or \>= 5% blasts in the bone marrow aspirate (BMA) not attributable to any other cause or reappearance or new appearance of extramedullary leukemia. Duration of CR was estimated using the Kaplan-Meier method.

Phase 1: Number of Participants With Dose Limiting Toxicity (DLT) of Gilteritinib

时间窗: C1D1 up to day 28

DLT: any Grade \>=3 non-hematologic/extramedullary toxicity with the following exceptions that occurred during the DLT observation: Alopecia, anorexia, or fatigue. Grade 3 vomiting or diarrhea that resolved(with or without supportive care) to \<= grade 2 within 48 hours. Grade 3 nausea that resolved(with or without supportive care) to \<= grade 2 within 7 days. Grade 3 elevation in TBL that was asymptomatic and that returned to \<= grade 2 elevation within 7 days. Grade 3 elevation in hepatic transaminases (ALT/SGPT, AST/SGOT) and GGT) or ALP level that returns to \<= grade 2 elevation within 14 days. Grade 3 fever with neutropenia, with or without infection. Grade 3 infection or grade 4 infections expected as direct complication of cytopenia due to active underlying leukemia. Grade 3 mucositis.