A Study of ASP2215 Versus Salvage Chemotherapy In Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase 3 (FLT3) Mutation

EFS: time from the date of randomization until the date of documented relapse, treatment failure, death, reported off treatment relapse or new AML therapy start whichever occued first, including the long-term follow-up data. KM estimate was used for analysis.

Relapse was defined as documentation of any of following events:

• Bone marrow (BM) blasts ≥ 5% (not attributable to regenerating BM)
• Reappearance or new appearance of extramedullary leukemia
• Reappearance of significant numbers of peripheral blasts

Treatment failure: Treatment failure was defined as participant who ends treatment without having a previous response of CR, CR with incomplete platelet recovery (CRp) and CR with incomplete hematological recover (CRi).

Percentage of participants with CR were reported. CR: morphologically leukemia-free state, with absolute neutrophil count (ANC) > 1x10^9 per liter (1x10^9/L), platelet count ≥ 100x10^9/L and normal marrow differential with <5% blasts. They were red blood cell (RBC) and platelet transfusion independent and no evidence of extramedullary leukemia or Auer rods was necessary.

Duration of CR: time from the date of achieving first CR until date of first documented relapse for participants who achieved CR. KM estimate was used for analysis.

CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with < 5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

Relapse was defined as documentation of any of following events:

• BM blasts ≥ 5% (not attributable to regenerating BM)
• Reappearance or new appearance of extramedullary leukemia
• Reappearance of significant numbers of peripheral blasts

Duration of CRc: time from date of achieving first CRc until date of first documented relapse for participants who achieved CRc. KM estimate was used for analysis.

CRc: rate of all complete \& incomplete remissions [CR + CRp + CRi]. CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with <5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

CRp: met all CR criteria except incomplete platelet recovery (< 100x10^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia < 1x10^9/L with or without complete platelet recovery.

Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts.

Duration of CR/CRh: time from date of achieving first CR/CRh until date of first documented relapse for participants who achieved CR/CRh. KM estimate was used for analysis.

CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with <5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

CRh was defined as a condition at the post baseline visit, having bone marrow blasts < 5%, partial hematologic recovery ANC ≥ 0.5x10^9/L and platelets ≥ 50x10^9/L, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood was ≤ 2%.

Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts.

DOR: time from date of first CRc (CR+CRp+CRi)/PR until date of first documented relapse for participants who achieved CRc or PR. KM estimate used for analysis.

CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with <5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

CRp: met all CR criteria except incomplete platelet recovery (< 100x10^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia < 1x10^9/L with or without complete platelet recovery.

PR: condition with regeneration of normal hematopoietic cells in BM, no detectable blasts, ≥ 50% decrease of blasts in BM aspirate \& total BM blasts of 5-25%.

Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts and increase in the percentage of blasts in the BM aspirate to > 25%.

Percentage of participants with CR/CRh was reported. CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with <5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

CRh was defined as a condition at the post baseline visit, having bone marrow blasts < 5%, partial hematologic recovery ANC ≥ 0.5x10^9/L and platelets ≥ 50x10^9/L, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%.

Defined as percentage of participants with CR, CRp, CRi, PR, no response (NR) \& not estimable (NE). CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L \& normal marrow differential with < 5% blasts. They were RBC \& platelet transfusion independent \& no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (<100x10^9/L). CRi: met all CR criteria, except incomplete hematological recovery with residual neutropenia < 1x10^9/L with/without complete platelet recovery. PR: condition with regeneration of normal hematopoietic cells in BM, no detectable blasts, ≥ 50% decrease of blasts in BM aspirate \& total BM blasts of 5-25%. <=5% BM blasts if Auer rods are present, no evidence of extramedullary leukemia. Not Estimable (NE): No BM assessed/no myeloblast value, no blast value from peripheral blood or ≤2%, \& no extramedullary leukemia. No Response (NR): Response not categorized as CR, CRp, CRi, PR or NE.

LFS: time from the date of first CRc (CR+CRp+CRi) until the date of documented relapse or death for participants who achieved CRc.

CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with < 5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

CRp: met all CR criteria except incomplete platelet recovery (< 100x10^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia < 1x10^9/L with or without complete platelet recovery.

Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts.

Percentage of participants with CRc (CR+CRp+CRi) was reported. CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with <5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

CRp: met all CR criteria except incomplete platelet recovery (< 100x10^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia < 1x10^9/L with or without complete platelet recovery.

Time to CRc (TTCRc) was defined as the time from the date of randomization until the date of first CRc.

CRc: Rate of all complete and incomplete remissions (CR + CRp +Cri) CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with <5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

CRp: met all CR criteria except incomplete platelet recovery (< 100x10^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia < 1x10^9/L with or without complete platelet recovery.

Time to CR (TTCR) was defined as the time from the date of randomization until the date of first CR.

CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with < 5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

Time to Response (TTR) was defined as the time from the date of randomization until the date of either first response (CRc or PR).

CRc: Rate of all complete and incomplete remissions (CR + CRp +Cri) CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with <5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

CRp: met all CR criteria except incomplete platelet recovery (< 100x10^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia < 1x10^9/L with or without complete platelet recovery.

PR: condition with regeneration of normal hematopoietic cells in BM, no detectable blasts, ≥ 50% decrease of blasts in BM aspirate \& total BM blasts of 5-25%.

Time to CR/CRh (TTCRCRh) was defined as the time from the date of randomization until the date of first CR/CRh.

CR: morphologically leukemia-free state, with ANC> 1x10^9/L, platelet count ≥ 100x10^9/L and normal marrow differential with <5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.

CRh was defined as a condition at the post baseline visit, having bone marrow blasts < 5%, partial hematologic recovery ANC ≥ 0.5x10^9/L and platelets ≥ 50x10^9/L, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood was ≤ 2%.

Transfusion conversion rate: Percentage of transfusion dependent participants at baseline period but became transfusion independent at post-baseline period divided by total participants who were transfusion dependent at baseline period.

Transfusion maintenance rate: Percentage of transfusion independent participants at baseline period and still maintained transfusion independent at post-baseline period divided by total participants who were transfusion independent at baseline period.

Baseline transfusion status: Participants were classified as transfusion independent if there were no RBC or platelet transfusions within 28 days prior to first dose to 28 days after first dose; otherwise classified as transfusion dependent.

Post baseline transfusion status: Participants on treatment ≥ 84 days were classified as transfusion independent, if consecutive 56 days without any RBC or platelet transfusion; otherwise classified as transfusion dependent

Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period.

The BFI is a screening tool designed to assess the severity and impact of fatigue on daily functioning of participants with cancer during the 24 hours. There are 9 items on the scale. The first three questions ask participants to rate their fatigues on a scale from 0 (no fatigue) - 10 (as bad as you can imagine), with higher scores indicating worse outcome. The remaining six questions ask participants to rate how much fatigue has interfered with their daily activities on a scale from 0 (Does not interfere) to 10 (Completely interferes). A global fatigue score can be obtained by averaging all the items on the BFI, ranging between 0 to 10; a higher BFI fatigue score indicates worse outcome. The global BFI scores were calculated only if at least 5 of the 9 items are answered.

An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE was defined as an adverse event observed after starting administration of the study drug.

The ECOG Scale was used to assess performance status. Number of participants with each grade was reported.

Grade Description:

0: Fully active, able to carry on all pre-disease performance without restriction.

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.
2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.
3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5. Dead.

AUC24 was derived from the PK samples collected.

Cmax was derived from the PK samples collected.

Ctrough was derived from the PK samples collected.

tmax was derived from the PK samples collected.

Concentrations below the lower limit of quantification (0.5 ng/mL) were set to zero.