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

Phase 3Active Not RecruitingNCT03182244

Astellas Pharma Inc276 enrolled

Overview

The purpose of this study was to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated AML who were refractory to or had relapse after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy. In addition, this study evaluated safety as well as determined the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

Participants considered an adult according to local regulations at the time of signing informed consent were randomized in a 1:1 ratio and received ASP2215 or salvage chemotherapy. Participants entered the screening period up to 14 days prior to the start of treatment. Prior to randomization, the investigator preselected a salvage chemotherapy regimen for each participant; options included low-dose cytarabine (LoDAC), mitoxantrone, etoposide and intermediate-dose cytarabine (MEC) or fludarabine, high-dose cytarabine and granulocyte colony-stimulating factor (FLAG). The randomization was stratified by response to first-line therapy and preselected salvage chemotherapy. Participants were administered treatment over continuous 28-day cycles. Among the participants, approximately 20 Chinese participants who were randomized into the ASP2215 arm were allocated to the pharmacokinetic (PK) cohort. Participants in the PK cohort were requested to be hospitalized from the date of randomization (Day 1) to at least the completion of all the assessments planned on Day 2. All participants in the PK cohort underwent blood sampling for PK measurement of ASP2215. Participants in PK cohort were administered the study drug in the same manner and underwent the same efficacy and safety assessments as other participants except for blood sampling for additional PK measurements.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participant has a diagnosis of primary AML or AML secondary to myelodysplastic syndrome (MDS) according to World Health Organization (WHO) classification as determined by pathology review at the treating institution. * Participant is refractory to or relapsed after first-line AML therapy (with or without HSCT) * Refractory to first-line AML therapy is defined as: a. Participant did not achieve CR/CRi/CRp under initial therapy. A participant eligible for standard therapy must receive at least 1 cycle of an anthracycline containing induction block in standard dose for the selected induction regimen. A participant not eligible for standard therapy must have received at least 1 complete block of induction therapy seen as the optimum choice of therapy to induce remission for this participant. * Untreated first hematologic relapse is defined as: 1. Participant must have achieved a CR/CRi/CRp with first-line treatment and has hematologic relapse. * Participant is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. A participant with rapidly proliferative disease and unable to wait for the central lab results can be enrolled based on a local test performed after completion of the last interventional treatment. Participants can be enrolled from a local test result if the participants have any of the following FLT3 mutations: FLT3-internal tandem duplication (ITD), FLT3-tyrosine kinase domain (TKD)/D835 or FLT3-TKD/I836. * Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. * Participant is eligible for preselected salvage chemotherapy. * Participant must meet the following criteria as indicated on the clinical laboratory tests: * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) * Serum total bilirubin (TBL) ≤ 1.5 x ULN * Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of \> 50 mL/min as calculated by the Modification of Diet in Renal Disease equation. * Participant is suitable for oral administration of study drug. * Participant agrees not to participate in another interventional study while on treatment. Inclusion Criteria for COE: Participant is eligible for the COE if they continue to meet all inclusion criteria from the main protocol in addition to the following when the participant is evaluated for eligibility to participate in the COE portion of the study: * Participant has received study treatment of either LoDAC, MEC or FLAG and has no response or progressive disease. * Participant have not received other antileukemic therapy after EOT (hydroxyurea is allowed for the control of peripheral leukemic blasts in participants with leukocytosis). * Participant agrees not to participate in another interventional study while on treatment. Exclusion Criteria: * Participant was diagnosed as acute promyelocytic leukemia. * Participant has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). * Participant has AML secondary to prior chemotherapy for other neoplasms (except for MDS). * Participant is in second or later hematologic relapse or has received salvage therapy for refractory disease. * Participant has clinically active central nervous system leukemia.. * Participant has been diagnosed with another malignancy, unless disease-free for at least 5 years. Participants with treated nonmelanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. Participants with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy. * Participant has received prior treatment with ASP2215 or other FLT3 inhibitors (with the exception of sorafenib and midostaurin used in first-line therapy regimen as part of induction, consolidation and/or maintenance). * Participant has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation. * Participant has had major surgery within 4 weeks prior to the first study dose. * Participant has radiation therapy within 4 weeks prior to the first study dose. * Participant has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or participant with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram (ECHO) performed within 1 month prior to study entry results in a left ventricular ejection fraction (LVEF) that is ≥ 45%. * Participant with mean of triplicate Fridericia-corrected QT interval (QTcF) \> 450 ms at Screening based on central reading. * Participant with Long QT Syndrome at Screening. * Participant with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal \[LLN\]). * Participant requires treatment with concomitant drugs that are strong inducers of CYP3A. * Participant requires treatment with concomitant drugs that are strong inhibitors or inducers of P-gp with the exception of drugs that are considered absolutely essential for the care of the participant. * Participant requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the participant. * Participant has an active uncontrolled infection. * Participant is known to have human immunodeficiency virus infection. * Participant has active hepatitis B or C or other active hepatic disorder. * Participant has any condition which makes the participant unsuitable for study participation. * Participant has active clinically significant (graft-versus-host disease) GVHD or is on treatment with systemic corticosteroids for GVHD. * Participant has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836. Exclusion Criteria for COE: Participant will be excluded from participation in the COE if they meet any of the exclusion criteria listed in the main protocol or when the participant is evaluated for eligibility to participate in the COE portion of the study.

Outcomes

Primary Outcomes

Overall Survival (OS)

OS was defined as the time from the date of randomization to the date of death due to any cause. Participants who were still alive or lost to follow up were censored at the time they were last known to be alive. Kaplan-Meier (KM) estimates was used for analysis.

Time frame: From the date of randomization up to the date of death (up to approximatley 74 months)

Secondary Outcomes

Event-Free Survival (EFS)

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).

Time frame: From the date of randomization up to the date of documented relapse, treatment failure or death from any cause, off-treatment relapse and start of new AML therapy (up to approximately 74 months)

Complete Remission (CR) Rate

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.

Time frame: From the date of randomization up to approximately 74 months

Duration of CR

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

Time frame: From date of achieving CR until date of confirmed relapse (maximum duration was 53.4 months )

Duration of Composite Complete Remission (CRc)

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.

Time frame: From date of achieving CRc until date of confirmed relapse (maximum duration was 60 months)

Duration of CR/Complete Remission With Partial Hematologic Recovery (CRh)

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.

Time frame: From date of achieving CR/CRh until date of confirmed relapse (maximum duration was 58.1 months)

Duration Of Response (DOR)

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%.

Time frame: From date of achieving CRc/PR until date of confirmed relapse (maximum duration was 52.1 months)

CR/CRh Rate

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%.

Time frame: From the date of randomization up to approximately 74 months

Best Response Rate

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.

Time frame: From the date of randomization up to approximately 74 months

Leukemia-Fee Survival (LFS)

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.

Time frame: From first day of achieving first CRc to the first day of confirmed relapse/death (maximum duration was 60.0 months)

Composite Complete Remission (CRc)

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 frame: From the date of randomization up to approximately 74 months

Time to CRc

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 frame: From randomization until date of first CRc (up to approximately 74 months)

Time to CR

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 frame: From randomization until date of first CR (up to approximately 74 months)

Time to Response

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 frame: From randomization until date of first CRc or PR (up to approximately 74 months)

Time to CR/CRh

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%.

Time frame: From randomization until date of first CR/CRh (up to approximately 74 months)

Percentage of Participants With Transfusion Conversion and Transfusion Maintenance

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

Time frame: Baseline up to approximately 74 months

Percentage of Participants With Transplantation Rate

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

Time frame: Baseline up to approximately 74 months

Change From Baseline in Brief Fatigue Inventory (BFI)

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.

Time frame: Baseline, End of treatment (63 months)

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

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.

Time frame: From the date of first dose up to approximately 74 months

Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores

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.

Time frame: Baseline, end of treatment visit (63 months)

Pharmacokinetics (PK) of Gilteritinib in Chinese PK Cohort: Area Under the Concentration Curve at 24 Hours (AUC24)

AUC24 was derived from the PK samples collected.

Time frame: Cycle 1 Day 1(C1D1): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, Cycle 1 Day 15(C1D15): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose

PK of Gilteritinib in Chinese PK Cohort: Maximum Concentration (Cmax)

Cmax was derived from the PK samples collected.

Time frame: C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose

PK of Gilteritinib: Observed Trough Concentration (Ctrough)

Ctrough was derived from the PK samples collected.

Time frame: Predose on C1D15

PK of Gilteritinib in Chinese PK Cohort: Time to Maximum Concentration (Tmax)

tmax was derived from the PK samples collected.

Time frame: C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose

Ctrough Concentration of Gilteritinib

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

Time frame: Predose C1D8, C1D15, Day 1 of each cycle from C2 to C65, C67D1,C68D1,C69D1,C70D1

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

Overview

Conditions

Interventions

Eligibility

Locations (49)

Outcomes

Primary Outcomes

Secondary Outcomes