A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients With Relapsed or Refractory Acute Myeloid Leukemia
Overview
- Phase
- Phase 1
- Intervention
- Gilteritinib
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Astellas Pharma Global Development, Inc.
- Enrollment
- 265
- Locations
- 26
- Primary Endpoint
- Number of Participants With Dose Limiting Toxicities (DLTs)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The objective of this study was to assess the safety and tolerability, including the maximum tolerated dose, of gilteritinib in participants with relapsed or treatment-refractory acute myeloid leukemia (AML). This study also determined the pharmacokinetic (PK) parameters of gilteritinib.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subject is defined as morphologically documented primary or secondary AML by the World Health Organization (WHO) criteria (2008) and fulfills one of the following:
- •Refractory to at least 1 cycle of induction chemotherapy
- •Relapsed after achieving remission with a prior therapy
- •Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤
- •Subject's interval from prior treatment to time of study drug administration is at least 2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), or at least 5 half-lives for prior experimental agents or noncytotoxic agents.
- •Subject must meet the following criteria as indicated on the clinical laboratory tests\*:
- •Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<2.5 x institutional upper limit normal (ULN)
- •Total serum bilirubin \< 1.5x institutional ULN
- •Serum creatinine \< 1.5 x institutional ULN or an estimated glomerular filtration rate (eGFR) of \> 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation.
- •Subject agrees not to participate in another interventional study while on treatment.
Exclusion Criteria
- •Subject was diagnosed as acute promyelocytic leukemia (APL).
- •Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
- •Subject has active malignant tumors other than AML or Myelodysplastic syndrome (MDS).
- •Subject has persistent nonhematological toxicities of \>= Grade 2 (Common Terminology Criteria for Adverse Events v4), with symptoms and objective findings, from prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery).
- •Subject has had hematopoietic stem cell transplant (HSCT) and meets any of the following:
- •Is within 2 months of transplant from C1D1
- •Has clinically significant graft-versus-host disease requiring treatment
- •Has \>= Grade 2 persistent non-hematological toxicity related to the transplant. Donor lymphocytes infusion (DLI) is not permitted \<= 30 days prior to study registration or during the first cycle of treatment on the study in Cohort 1 and first two cycles of the treatment in Cohort 2
- •Subject has clinically active central nervous system leukemia
- •Subject has disseminated intravascular coagulation abnormality (DIC)
Arms & Interventions
Gilteritinib 20 mg in Escalation Phase
Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Intervention: Gilteritinib
Gilteritinib 20 mg in Escalation Phase
Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Intervention: Voriconazole
Gilteritinib 40 mg in Escalation Phase
Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Intervention: Gilteritinib
Gilteritinib 80 mg in Escalation Phase
Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Intervention: Gilteritinib
Gilteritinib 120 mg in Escalation Phase
Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Intervention: Gilteritinib
Gilteritinib 200 mg in Escalation Phase
Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Intervention: Gilteritinib
Gilteritinib 300 mg in Escalation Phase
Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Intervention: Gilteritinib
Gilteritinib 450 mg in Escalation Phase
Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Intervention: Gilteritinib
Gilteritinib 20 mg in Expansion Phase
Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.
Intervention: Gilteritinib
Gilteritinib 40 mg in Expansion Phase
Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.
Intervention: Gilteritinib
Gilteritinib 80 mg in Expansion Phase
Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.
Intervention: Gilteritinib
Gilteritinib 120 mg in Expansion Phase
Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.
Intervention: Gilteritinib
Gilteritinib 200 mg in Expansion Phase
Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Intervention: Gilteritinib
Gilteritinib 200 mg in Expansion Phase
Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Intervention: Cephalexin
Gilteritinib 300 mg in Expansion Phase
Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Intervention: Gilteritinib
Gilteritinib 300 mg in Expansion Phase
Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Intervention: Midazolam
Outcomes
Primary Outcomes
Number of Participants With Dose Limiting Toxicities (DLTs)
Time Frame: From first dose up to end of cycle 1 (30 days)
To determine the maximum tolerated dose, safety was assessed by DLTs, defined as any grade ≥ 3 non-hematologic or extramedullary toxicity that occurred within 30 days starting with the first dose taken on day -2, and included the first treatment cycle in the dose escalation phase and in the first treatment cycle (28 days) in the dose expansion phase, that was considered to be possibly or probably related to study drug. Exceptions to this were the following: (1) Alopecia, anorexia or fatigue, (2) Grade 3 nausea and/or vomiting if not required tube feeding or total parenteral nutrition, or diarrhea if not required or prolonged hospitalization that was managed to grade ≤ 2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset, (3) Grade 3 fever with neutropenia, with or without infection, (4) Grade 3 infection.
Number of Participants With Adverse Events (AEs)
Time Frame: From first dose of study drug up to 30 days after last dose of study drug (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug (for participants who underwent hematopoietic stem cell transplantation \[HSCT\]: defined as AEs observed after starting study drug until the last dose before on study HSCT plus 30 days, and AEs that began after resumption of gilteritinib and within 30 days after the last dose of gilteritinib). AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (1-Mild, 2-Moderate, 3-Severe, 4-LifeThreatening, 5-Death).
Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib
Time Frame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Plasma samples were used for pharmacokinetic assessments.
Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib
Time Frame: Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Plasma samples were used for pharmacokinetic assessments.
Accumulation Ratio After Multiple Doses of Gilteritinib
Time Frame: Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Plasma samples were used for pharmacokinetic assessments.
Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib
Time Frame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Plasma samples were used for pharmacokinetic assessments.
Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib
Time Frame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Plasma samples were used for pharmacokinetic assessments.
Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib
Time Frame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Plasma samples were used for pharmacokinetic assessments.
Secondary Outcomes
- Percentage of Participants With Complete Remission (CR) During the First 2 Cycles(During the first 2 cycles (56 days))
- Percentage of Participants With CR During Treatment(Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Percentage of Participants With CR With Incomplete Platelet Recovery (CRp)(Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Percentage of Participants With CR With Incomplete Hematological Recovery (CRi)(Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh)(Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Percentage of Participants With Composite CR (CRc)(Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Percentage of Participants With Partial Remission (PR)(Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Percentage of Participants With Best Response(Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh)(Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Duration of CR (DCR)(From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Duration of CRp (DCRp)(From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Duration of CRi (DCRi)(From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Duration of CRh (DCRh)(From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Duration of CRc (DCRc)(From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Duration of CR/CRh (DCRCRh)(From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Duration of Response(From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Time to CR (TTCR)(From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Time to CRp (TTCRp)(From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Time to CRi (TTCRi)(From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Time to First CR/CRh (TTFCRCRh)(From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Time to Best CR/CRh (TTBCRCRh)(From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Time to CRc (TTCRc)(From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Cmax of Midazolam Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam))
- Time to Response (TTR)(From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Time to Best Response (TTBR)(From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days))
- Overall Survival (OS)(From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days))
- Event Free Survival (EFS)(From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days))
- Leukemia Free Survival (LFS)(From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days))
- Percentage of Participants Who Achieved Transfusion Conversion(Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
- Percentage of Participants Who Achieved Transfusion Maintenance(Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
- AUC24 of Gilteritinib in Co-administration With Voriconazole(Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib))
- Cmax of Gilteritinib in Co-administration With Voriconazole(Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib))
- AUClast of Gilteritinib in Co-administration With Voriconazole(Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib))
- Tmax of Gilteritinib in Co-administration With Voriconazole(Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib))
- AUC24 of Midazolam Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam))
- AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam))
- Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam))
- AUClast of Midazolam Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam))
- AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam))
- Tmax of Midazolam Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam))
- Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam))
- Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin))
- Cmax of Cephalexin Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin))
- AUClast of Cephalexin Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin))
- Tmax of Cephalexin Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin))
- T1/2 of Cephalexin Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin))
- Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin))
- Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin))
- Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin))
- Fraction of Drug Excreted Into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin))
- Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib(Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin))