Clinical trial NCT02014558: Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics of ASP2215 in Patients With Relapsed or Refractory Acute Myeloid Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia
Gilteritinib
ASP2215
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2013-12-18
Enrollment: 265
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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 ≤ 2.
* 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)
* Subject has had major surgery within 4 weeks prior to the first study dose.
* Subject has had radiation therapy within 4 weeks prior to the first study dose
* Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%
* Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of Cytochrome P450-isozyme3A4 (CYP3A4) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care post-transplant or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the subject
* Subject required treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
* Subject has an active uncontrolled infection
* Subject is known to have human immunodeficiency virus infection
* Subject has active hepatitis B or C, or other active hepatic disorder

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: From first dose up to end of cycle 1 (30 days)
measure: Number of Participants With Adverse Events (AEs)
timeFrame: 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)
measure: Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib
timeFrame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
measure: Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib
timeFrame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
measure: Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib
timeFrame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
measure: Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib
timeFrame: Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
measure: Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib
timeFrame: Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
measure: Accumulation Ratio After Multiple Doses of Gilteritinib
timeFrame: Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Secondary outcomes:
measure: Percentage of Participants With Complete Remission (CR) During the First 2 Cycles
timeFrame: During the first 2 cycles (56 days)
measure: Percentage of Participants With CR During Treatment
timeFrame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Percentage of Participants With CR With Incomplete Platelet Recovery (CRp)
timeFrame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Percentage of Participants With CR With Incomplete Hematological Recovery (CRi)
timeFrame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh)
timeFrame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Percentage of Participants With Composite CR (CRc)
timeFrame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Percentage of Participants With Partial Remission (PR)
timeFrame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Percentage of Participants With Best Response
timeFrame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh)
timeFrame: Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Duration of CR (DCR)
timeFrame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Duration of CRp (DCRp)
timeFrame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Duration of CRi (DCRi)
timeFrame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Duration of CRh (DCRh)
timeFrame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Duration of CRc (DCRc)
timeFrame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Duration of CR/CRh (DCRCRh)
timeFrame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Duration of Response
timeFrame: From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
measure: Time to CR (TTCR)
timeFrame: 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)
measure: Time to CRp (TTCRp)
timeFrame: 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)
measure: Time to CRi (TTCRi)
timeFrame: 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)
measure: Time to First CR/CRh (TTFCRCRh)
timeFrame: 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)
measure: Time to Best CR/CRh (TTBCRCRh)
timeFrame: 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)
measure: Time to CRc (TTCRc)
timeFrame: 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)
measure: Time to Response (TTR)
timeFrame: 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)
measure: Time to Best Response (TTBR)
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: 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)
measure: Event Free Survival (EFS)
timeFrame: 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)
measure: Leukemia Free Survival (LFS)
timeFrame: 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)
measure: Percentage of Participants Who Achieved Transfusion Conversion
timeFrame: 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
measure: Percentage of Participants Who Achieved Transfusion Maintenance
timeFrame: 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
measure: AUC24 of Gilteritinib in Co-administration With Voriconazole
timeFrame: Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
measure: Cmax of Gilteritinib in Co-administration With Voriconazole
timeFrame: Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
measure: AUClast of Gilteritinib in Co-administration With Voriconazole
timeFrame: Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
measure: Tmax of Gilteritinib in Co-administration With Voriconazole
timeFrame: Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)
measure: AUC24 of Midazolam Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
measure: AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
measure: Cmax of Midazolam Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
measure: Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
measure: AUClast of Midazolam Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
measure: AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
measure: Tmax of Midazolam Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
measure: Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)
measure: Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
measure: Cmax of Cephalexin Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
measure: AUClast of Cephalexin Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
measure: Tmax of Cephalexin Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
measure: T1/2 of Cephalexin Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
measure: Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
measure: Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)
measure: Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)
measure: Fraction of Drug Excreted Into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)
measure: Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib
timeFrame: Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Site US10021
state: Alabama
city: Scottsdale
country: United States
facility: Site US10023
state: Arizona
city: Duarte
country: United States
facility: Site US10022
state: California
city: Los Angeles
country: United States
facility: Site US10008
state: California
city: San Francisco
country: United States
facility: Site US10005
state: California
city: Chicago
country: United States
facility: Site US10001
state: Illinois
city: Chicago
country: United States
facility: Site US10015
state: Illinois
city: Baltimore
country: United States
facility: Site US10012
state: Maryland
city: Baltimore
country: United States
facility: Site US10003
state: Maryland
city: Minneapolis
country: United States
facility: Site US10006
state: Minnesota
city: Rochester
country: United States
facility: Site US10011
state: Minnesota
city: Hackensack
country: United States
facility: Site US10020
state: New Jersey
city: Buffalo
country: United States
facility: Site US10010
state: New York
city: New York
country: United States
facility: Site US10009
state: New York
city: New York
country: United States
facility: Site US10013
state: New York
city: New York
country: United States
facility: Site US10019
state: New York
city: Cleveland
country: United States
facility: Site US10014
state: Ohio
city: Hershey
country: United States
facility: Site US10018
state: Pennsylvania
city: Philadelphia
country: United States
facility: Site US10004
state: Pennsylvania
city: Charleston
country: United States
facility: Site US10017
state: South Carolina
city: Nashville
country: United States
facility: Site US10007
state: Tennessee
city: Houston
country: United States
facility: Site US10002
state: Texas
city: Fairfax
country: United States
facility: Site US10026
state: Virginia
city: Berlin
country: Germany
facility: Site DE49002
city: Dresden
country: Germany
facility: Site DE49004
city: Bologna
country: Italy
facility: Site IT39001
Study officials:
affiliation: Astellas Pharma Global Development
name: Executive Medical Director
role: STUDY_DIRECTOR
References:
citation: James AJ, Smith CC, Litzow M, Perl AE, Altman JK, Shepard D, Kadokura T, Souda K, Patton M, Lu Z, Liu C, Moy S, Levis MJ, Bahceci E. Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor. Clin Pharmacokinet. 2020 Oct;59(10):1273-1290. doi: 10.1007/s40262-020-00888-w.
citation: Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Rollig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 Aug;18(8):1061-1075. doi: 10.1016/S1470-2045(17)30416-3. Epub 2017 Jun 20.
citation: Kasi PM, Litzow MR, Patnaik MM, Hashmi SK, Gangat N. Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3) inhibitor therapy with evolving actionable targets. Leuk Res Rep. 2016 Jan 12;5:7-10. doi: 10.1016/j.lrr.2016.01.002. eCollection 2016.