Clinical Trials/NCT02310321

NCT02310321

Completed

Phase 1

A Phase 1/2 Study of ASP2215 in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia

Astellas Pharma Inc55 sites in 2 countries97 target enrollmentFebruary 26, 2015

ConditionsAcute Myeloid Leukemia FLT3-mutated Acute Myeloid Leukemia

InterventionsGilteritinib Idarubicin Cytarabine

Overview

Phase: Phase 1
Intervention: Gilteritinib
Conditions: Acute Myeloid Leukemia
Sponsor: Astellas Pharma Inc
Enrollment: 97
Locations: 55
Primary Endpoint: Phase 1 Part: Maximum Tolerated Dose (MTD) of Gilteritinib
Status: Completed
Last Updated: 8 months ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of phase 1 part in this study was to determine the maximum tolerated dose (MTD) and/or recommended expansion dose (RED) of ASP2215 concomitant with cytarabine/idarubicin as induction chemotherapy based on the status of the onset of dose-limiting toxicity (DLT) in newly diagnosed Acute Myeloid Leukemia (AML) subjects. Phase 1 part also evaluated safety and tolerability and characterized the pharmacokinetic (PK) parameters of ASP2215 concomitant with induction and consolidation chemotherapy as well as evaluated the PK parameters of cytarabine concomitant with ASP2215.

The purpose of phase 2 part was to evaluate efficacy of ASP2215 in combination with induction therapy. Phase 2 cohort also evaluated safety and characterized the PK parameters of ASP2215 in combination with induction and consolidation therapy followed by maintenance therapy in newly diagnosed FLT3-mutated AML subjects.

Detailed Description

This study was composed of Phase 1 part (the dose-evaluation part and the expansion part) and Phase 2 part. In the dose-evaluation part of Phase 1 part, at least 3 subjects received ASP2215 at each dose (low, middle, and high) for determination of MTD and/or RED. Treatment of AML in Phase 1 part was composed of 3 periods of therapy: remission induction, consolidation, and maintenance. The decision of whether or not to proceed to the next dose was made based on the occurrence of DLT during Cycle 1 of the induction period. In the expansion part of Phase 1 part, a maximum of 3 subjects received ASP2215 at RED that had been recommended in the dose-evaluation part and the safety was assessed based on the onset of DLTs during Cycle 1 of the induction and consolidation periods. In Phase 2 part, Subjects received ASP2215 at the recommended dose established in Phase 1 part. The target population was limited to newly diagnosed FLT3-mutated AML.

Registry

clinicaltrials.gov

Start Date

February 26, 2015

End Date

July 9, 2024

Last Updated

8 months ago

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

Astellas Pharma Inc

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•\[Phase 1 part\]
•Subject is defined as having previously untreated de novo AML according to the World Health Organization (WHO) criteria (2008) within 28 days prior to study enrollment.
•Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤
•Subject must meet all of the following criteria in the laboratory test at screening:
•Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of ≤ 2.5 × institutional upper limit of normal (ULN)
•Total serum bilirubin level of ≤ 1.5 × institutional ULN
•Serum creatinine level of ≤ 1.5 × institutional ULN or an estimated glomerular filtration rate (eGFR) of \> 50 mL/min
•Subject is suitable for oral administration of ASP
•Female subject falls under the following:
•Of non-childbearing potential:

Exclusion Criteria

•\[Phase 1 part\]
•Subject was diagnosed with acute promyelocytic leukemia (APL).
•Subject has breakpoint cluster region-abelson (BCR-ABL)-positive leukemia (chronic myelogenous leukemia in blast crisis).
•Subject has active malignant tumors other than AML or myelodysplastic syndrome (MDS).
•Subject has received prior AML treatment except for the following:
•Urgent leukapheresis
•Hydroxyurea administration for emergency treatment of hyperleukocytosis (≤ 7 days)
•Administration of retinoic acid before the diagnosis to exclude APL (≤ 7 days)
•Supportive care using growth factors or cytokines
•Steroid administration to treat hypersensitivity or blood transfusion reactions

Arms & Interventions

Phase 1: Dose Evaluation (DEv)

Induction period: Participants received 120 milligrams (mg) gilteritinib (3 tablets of 40 mg) orally, once daily from day 4 to 17 combined with chemotherapy (idarubicin: 12 mg per square meters per day \[mg/m\^2/day\] on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via intravenous (IV) infusion; in cycles (C) 1 and 2 (1 cycle= 42 days). Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from day 1 to 14 combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined by site clinical practice and local package insert in both induction and consolidation periods.. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or untill discontinuation criterion is met (1 cycle= 28 days).

Intervention: Gilteritinib

Phase 1: Dose Evaluation (DEv)

Intervention: Idarubicin

Phase 1: Dose Evaluation (DEv)

Intervention: Cytarabine

Phase 1: Dose Expansion (DEx)

Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 4 to 17 in combination with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in the induction period in C1 and 2 (1 cycle= 42 days). Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 14 in combination with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined based on site clinical practice and the local package insert in both induction and consolidation periods. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days).

Intervention: Gilteritinib

Phase 1: Dose Expansion (DEx)

Intervention: Idarubicin

Phase 1: Dose Expansion (DEx)

Intervention: Cytarabine

Phase 2: FLT3-mutated AML

Induction period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 8 until blood recovery combined with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in C1 and 2. Each cycle was extended until blood recovery was observed. Consolidation period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 until blood recovery combined with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in C1 to 3. Each cycle was extended until blood recovery was observed. Duration of infusion was based on site clinical practice and the local package insert in both induction and consolidation periods. Maintenance period: Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once daily from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days).

Intervention: Gilteritinib

Phase 2: FLT3-mutated AML

Intervention: Idarubicin

Phase 2: FLT3-mutated AML

Intervention: Cytarabine

Outcomes

Primary Outcomes

Phase 1 Part: Maximum Tolerated Dose (MTD) of Gilteritinib

Time Frame: Day 1 up to the end of Induction period cycle 1 (up to 42 days)

The MTD was defined as the highest dose of gilteritinib at which the posterior mean of the DLT incidence during Cycle 1 of induction therapy was estimated to be closest to 33%.

Phase 1 Part: Recommended Expansion Dose (RED) of Gilteritinib

Time Frame: Day 1 up to the end of Induction period cycle 1 (up to 42 days)

RED was the recommended dose used in Phase 2 of the study that was decided by the sponsor's responsible person by comprehensively assessing the data obtained from the study.

Phase 1 Part: Number of Participants With Dose Limiting Toxicities (DLTs) of Gilteritinib

Time Frame: Day 1 up to the end of Consolidation Cycle 1 (approximately up to 4 months)

DLTs were defined as: Any Grade ≥ 3 non-hematologic or extramedullary toxicity with the following exceptions: * Anorexia or fatigue * Grade 3 nausea and/or vomiting if participant did not require tube feeding or total parenteral nutrition, or diarrhea if the events did not require or prolong hospitalization that could be managed to grade ≤ 2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset. * Grade 3 mucositis that resolved to Grade ≤ 2 within 7 days of onset, fever with neutropenia, with or without infection, infection * Grade 4 peripheral neutrophil count \< 500/cubic millimeters (mm\^3) * Platelet count \< 20,000/mm\^3 due to bone marrow hypoplasia * Grade ≥ 3 platelet count \< 50,000/mm\^3 accompanying bleeding * Grade 4 platelet count \< 25,000/mm\^3 requiring platelet transfusion DLT was assessed until cycle 1 of dose evaluation induction period and until cycle 1 of dose expansion consolidation period.

Phase 1 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Time Frame: From the date of first dose up to 30 days after the last dose ( maximum duration up to approximately 4.1 years)

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 included both serious and non-serious AEs. TEAE for Phase 1 was defined as an AE observed after the date of first dose until 30 days after the last dose.

Phase 2 Part: Complete Remission (CR) Rate: Induction Period

Time Frame: From the date of first dose up to the start of Consolidation (approximately up to 4 months)

Percentage of participants with CR was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm3 and platelet count of ≥ 100,000/mm3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%.

Secondary Outcomes

Phase 1 Part: Maximum Concentration (Cmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy(Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1)
Phase 1 Part: Time to Attain Cmax (Tmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy(Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1)
Phase 1 Part: Area Under Plasma Concentration-time Curve From Time 0 to 24 (AUC24) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy(Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1)
Phase 1 Part: Area Under The Concentration-Time Curve From The Time Zero to The Last Measurable Concentration (AUClast) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy(Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1)
Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy(Induction period: Pre-dose on Cycle 1 Day 8, 11, and 17 Consolidation period: Pre-dose on Cycle 1 Day 6 and 15)
Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period(Induction period: Predose on Cycle 1 Day 1, 3, and 8 Consolidation period: Predose on Cycle 1 Day 2 and 6)
Phase 2 Part: Plasma Trough Concentration of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy(Induction period : Predose on Cycle 1 Day 15 and 21 Consolidation period: Predose on Cycle 1 Day 8 and 15)
Phase 2 Part: Overall Survival (OS)(From the date of first dose up to the date of death (maximum duration: approximately 4.4 years))
Phase 2 Part: Event Free Survival (EFS)(From the date of first dose up to the date of documented relapse, treatment failure or death from any cause (maximum duration: approximately 4.4 years))
Phase 2 Part: Relapse Free Survival (RFS)(From the date of achievement of first CRc up to the date of documented relapse or death from any cause (maximum duration: approximately 3.9 years))
Phase 2 Part: CR Rate After Consolidation and Maintenance Period(CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years))
Phase 2 Part: CR Rate Without Minimal Residual Disease (MRD) After Each Treatment Therapy Period(IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years))
Phase 2 Part: CR With Partial Hematological Recovery (CRh) Rate After Each Treatment Therapy Period(IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years))
Phase 2 Part: Composite CR (CRc) Rate After Each Treatment Therapy Period(IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years))
Phase 2 Part: CR/CRh Rate After Each Treatment Therapy Period(IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years))
Phase 2 Part: Duration of CR(From the date of achieving CR up to the date of documented relapse (maximum duration: approximately 2.6 years))
Phase 2 Part: Duration of CR/CRh(From the date of achieving CR/CRh up to the date of documented relapse (maximum duration: approximately 2.6 years))
Phase 2 Part: Duration of CRh(From the date of achieving CRh up to the date of documented relapse (maximum duration: approximately 2.6 years))
Phase 2 Part: Duration of CRc(From the date of achieving CRc up to the date of documented relapse (maximum duration: approximately 2.7 years))
Phase 2 Part: Duration of Response (DoR)(From the date of achieving CR, CRp, CRi/PR up to the date of documented relapse (maximum duration: approximately 2.7 years))
Phase 2 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From the date of first dose up to 30 days after the last dose ( maximum duration up to approximately 4.4 years))