Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of ASP2215 in Japanese Patients With Relapsed or Refractory Acute Myeloid Leukemia

A Phase 1 Open-label, Dose-escalation Study Investigating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ASP2215 in Japanese Patients With Relapsed or Refractory Acute Myeloid Leukemia

The objectives of this study are to determine the safety and tolerability of ASP2215 as well as the maximum tolerated dose (MTD) based on the onset of dose limiting toxicity (DLT) and/or determine the recommended dose (RD) of ASP2215 for the next phase in subjects with relapsed or treatment-refractory acute myeloid leukemia (AML).

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: Gilteritinib

Detailed Description

This study will be conducted to determine the safety, tolerability, PK, PD, and efficacy of single and repeated oral dosing of ASP2215 once daily in patients with relapsed or refractory AML. After the determination of the MTD and/or RD, an expansion cohort might be set to further investigate the safety and efficacy of ASP2215.

This study will consist of a single-dose period (Cycle 0, 2 days) and a repeated-dose period (Cycle 1 and subsequent cycles, each cycle consisting of 28 days). The enrolled subjects will orally receive their assigned single dose in Cycle 0 (Day -2), followed by a 2-day observation period (dosing day inclusive). In Cycle 1 and subsequent cycles (one cycle is defined as 28 days), the subjects will receive oral ASP2215 once daily repeatedly until one of the discontinuation criteria is met. Another dosing regimen may be considered such as dosing twice daily based on the safety and PK data that will become available.

In this study, the Bayesian-Continual Reassessment Method (hereinafter, Bayesian-CRM) will be used as a reference for dose-escalation procedures, and based on the onset of DLTs, the RD level of the subsequent cohort will be set higher or lower. DLTs will be assessed during Cycle 0 and Cycle 1 (30 days).

ASP2215 may be escalated by one dose level if the subject meets the criteria at the end of each cycle after Cycle 1 and the investigator/sub-investigator judges escalation of ASP2215 is of clinical benefit. Dose reduction of ASP2215 will be considered if study drug-related toxicities are observed in a subject.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Aichi, Japan
    • Site JP00002
  • Fukuoka, Japan
    • Site JP00003
  • Gunma, Japan
    • Site JP00001
  • Tokyo, Japan
    • Site JP00004
  • Tokyo, Japan
    • Site JP00005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject is defined as morphologically documented primary or secondary acute myeloid leukemia (AML) according to the World Health Organization (WHO) criteria (2008) and fulfills one of the following:

  • Refractory to prior induction chemotherapy
  • Relapsed after achieving remission with prior therapy
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Subject's interval from prior treatment to the time of study drug administration is at least 14 days for antineoplastic agents other than ASP2215 (except for hydroxyurea, which is given to control blast cells).
• Subject's interval from prior treatment to the time of study drug (ASP2215) administration is at least 5 half-lives (if the half-life is unknown, 14 days) for other investigational products or drugs used for immunosuppressive therapy posthematopoietic stem cell transplantation (HSCT).

Exclusion Criteria:

• 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 persistent non-hematological toxicities of ≥ Grade 2 (CTCAE v4), with symptoms and objective findings, due to prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, investigational products, radiation therapy, and surgery)

• Subject has received hematopoietic stem cell transplant (HSCT) and falls under either of the following:

  • Is within 2 months of transplant
  • Has persistent and clinically significant graft-versus-host disease requiring treatment
  • Has persistent non-hematological toxicities of ≥ Grade 2 related to the transplant
• Subject has clinically active central nervous system leukemia
• Subject has disseminated intravascular coagulation (DIC)
• Subject has had major surgery within 28 days prior to the first study drug administration
• Subject has had radiation therapy within 28 days prior to the first study drug administration
• Subject has congestive heart failure of NYHA class 3 or 4, or subject with a past history of congestive heart failure of NYHA class 3 or 4 and in whom echocardiogram or Multiple Gate Acquisition (MUGA) scan performed within 3 months prior to screening or at screening showed a left ventricular ejection fraction (LVEF) of < 45%.
• Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of CYP3A4 or of P-gp with such exceptions of antibiotics, antifungals, and antivirals that are considered absolutely essential for prevention or treatment of infections and for which the physician judged that there are no interchangeable drugs.
• Subject requires treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR receptors or sigma nonspecific receptors, with the exception of drugs that are considered absolutely essential for treatment of the subject.
• Subject has an active uncontrollable infection
• Subject is known to have human immunodeficiency virus (HIV) infection
• Subject has active hepatitis B or C or other active hepatic disorders

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation Cohort; ASP2215	Drug: Gilteritinib; oral; Other Names: ASP2215

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and Tolerability assessed through adverse events to determine maximum tolerated dose	Up to 17 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	Response Rate includes following parameters; CR rate, composite CR [CR + CRp + CRi] rate, overall response rate [CRc + PR], duration of response	Up to 16 months
Pharmacokinetics of ASP2215 in plasma: AUCinf	Area under the concentration-time curve from the time of dosing extrapolated to time infinity	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: AUClast	Area under the concentration-time curve from the time of dosing to the last measurable concentration	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: AUC24	Area under the plasma concentration time curve from time 0 to 24 hours	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: AUC48	Area under the plasma concentration time curve from time 0 to 48 hours	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: Cmax	Maximum concentration	Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: C24	Concentration at 24 hours	Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: CLF	Oral clearance	Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Lambda z	Terminal first order elimination rate constant	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215: tmax	Time to attain Cmax	Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: t1/2	Apparent terminal elimination half-life	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: Vz/F	Apparent volume of distribution during the terminal elimination phase after oral dosing	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: AUCtau	Area under the plasma concentration time curve during a dosing interval	Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: PTR	Peak-trough ratio	Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Rac(AUC)	Accumulation ratio calculated using the area under the concentration-time curve	Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Rac(Cmax)	Accumulation ratio calculated using the maximum concentration	Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Rac derived t1/2	t1/2 derived from accumulation index	Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Ctrough	Plasma trough concentration	Cycle 1 Day 8, Day 15, Day 22, Day 28 and Day 29
Pharmacokinetics of ASP2215 in urine: Ae24	Amount of drug excreted in urine from time 0 to 24 hours	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in urine: Ae48	Amount of drug excreted in urine from time 0 to 48 hours	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in urine: Ae24%	Fraction of drug excreted into urine from time 0 to 24 hours as % of dose	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in urine: Ae48%	Fraction of drug excreted into urine from time 0 to 48 hours as % of dose	Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in urine: CLR	Renal clearance	Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in urine: Aetau	Amount of drug excreted in urine during a dosing interval	Cycle 1 Day 28
Pharmacokinetics of ASP2215 in urine: Aetau %	Fraction of drug excreted in urine during a dosing interval	Cycle 1 Day 28

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Investigators: Study Director: Medical Director, Astellas Pharma Inc

Publications and helpful links

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2014
• Primary Completion (Actual): June 27, 2016
• Study Completion (Actual): June 27, 2016

Study Registration Dates

• First Submitted: July 2, 2014
• First Submitted That Met QC Criteria: July 2, 2014
• First Posted (Estimated): July 4, 2014

Study Record Updates

• Last Update Posted (Actual): November 6, 2024
• Last Update Submitted That Met QC Criteria: November 5, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: AML; Acute myeloid leukemia; ASP2215; Gilteritinib
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Tyrosine Kinase Inhibitors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Gilteritinib
• Other Study ID Numbers: 2215-CL-0102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.