Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics of ASP2215 in Patients With Relapsed or Refractory Acute Myeloid Leukemia
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
1 other identifier
interventional
265
3 countries
26
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Oct 2013
Longer than P75 for phase_1
26 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
October 9, 2013
CompletedFirst Submitted
Initial submission to the registry
November 6, 2013
CompletedFirst Posted
Study publicly available on registry
December 18, 2013
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 4, 2017
CompletedStudy Completion
Last participant's last visit for all outcomes
March 7, 2018
CompletedResults Posted
Study results publicly available
February 20, 2019
CompletedDecember 3, 2024
October 1, 2024
3.8 years
November 6, 2013
December 19, 2018
November 7, 2024
Conditions
Keywords
Outcome Measures
Primary Outcomes (8)
Number of Participants With Dose Limiting Toxicities (DLTs)
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.
From first dose up to end of cycle 1 (30 days)
Number of Participants With Adverse Events (AEs)
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).
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)
Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Accumulation Ratio After Multiple Doses of Gilteritinib
Plasma samples were used for pharmacokinetic assessments.
Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose
Secondary Outcomes (51)
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)
- +46 more secondary outcomes
Study Arms (13)
Gilteritinib 20 mg in Escalation Phase
EXPERIMENTALParticipants 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.
Gilteritinib 40 mg in Escalation Phase
EXPERIMENTALParticipants 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.
Gilteritinib 80 mg in Escalation Phase
EXPERIMENTALParticipants 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.
Gilteritinib 120 mg in Escalation Phase
EXPERIMENTALParticipants 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.
Gilteritinib 200 mg in Escalation Phase
EXPERIMENTALParticipants 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.
Gilteritinib 300 mg in Escalation Phase
EXPERIMENTALParticipants 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.
Gilteritinib 450 mg in Escalation Phase
EXPERIMENTALParticipants 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.
Gilteritinib 20 mg in Expansion Phase
EXPERIMENTALParticipants 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.
Gilteritinib 40 mg in Expansion Phase
EXPERIMENTALParticipants 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.
Gilteritinib 80 mg in Expansion Phase
EXPERIMENTALParticipants 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.
Gilteritinib 120 mg in Expansion Phase
EXPERIMENTALParticipants 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.
Gilteritinib 200 mg in Expansion Phase
EXPERIMENTALParticipants 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.
Gilteritinib 300 mg in Expansion Phase
EXPERIMENTALParticipants 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.
Interventions
Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles.
Participants received 200 mg voriconazole tablets daily every 12 hours starting from day 16 of cycle 1 through day 1 of cycle 2.
Participants received a single oral dose of 2 mg of midazolam syrup on day -1 and day 15 of cycle 1.
Participants received a single oral dose of 500 mg cephalexin tablet or capsule on day -1 and day 15 of cycle 1.
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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.
- +3 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (26)
Site US10021
Birmingham, Alabama, 35294, United States
Site US10023
Scottsdale, Arizona, 85259, United States
Site US10022
Duarte, California, 91010, United States
Site US10008
Los Angeles, California, 90095-1678, United States
Site US10005
San Francisco, California, 94143, United States
Site US10001
Chicago, Illinois, 60611, United States
Site US10015
Chicago, Illinois, 60637, United States
Site US10012
Baltimore, Maryland, 21201, United States
Site US10003
Baltimore, Maryland, 21287, United States
Site US10006
Minneapolis, Minnesota, 55455, United States
Site US10011
Rochester, Minnesota, 55905, United States
Site US10020
Hackensack, New Jersey, 07601, United States
Site US10010
Buffalo, New York, 14263, United States
Site US10009
New York, New York, 10022, United States
Site US10013
New York, New York, 10032, United States
Site US10019
New York, New York, 10065, United States
Site US10014
Cleveland, Ohio, 44195, United States
Site US10018
Hershey, Pennsylvania, 17033, United States
Site US10004
Philadelphia, Pennsylvania, 19104, United States
Site US10017
Charleston, South Carolina, 29425-8900, United States
Site US10007
Nashville, Tennessee, 37232, United States
Site US10002
Houston, Texas, 77030, United States
Site US10026
Fairfax, Virginia, 22031, United States
Site DE49002
Berlin, 12203, Germany
Site DE49004
Dresden, 01307, Germany
Site IT39001
Bologna, 40138, Italy
Related Publications (3)
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.
PMID: 32304015DERIVEDPerl 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.
PMID: 28645776DERIVEDKasi 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.
PMID: 26904404DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Clinical Trial Disclosure
- Organization
- Astellas Pharma Global Development, Inc.
Study Officials
- STUDY DIRECTOR
Executive Medical Director
Astellas Pharma Global Development
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
- Expanded Access
- Yes
Study Record Dates
First Submitted
November 6, 2013
First Posted
December 18, 2013
Study Start
October 9, 2013
Primary Completion
August 4, 2017
Study Completion
March 7, 2018
Last Updated
December 3, 2024
Results First Posted
February 20, 2019
Record last verified: 2024-10
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, CSR
- Time Frame
- Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
- Access Criteria
- Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.