Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics of ASP2215 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Astellas

Status and phase: Completed; Phase 2; Phase 1

Conditions: Acute Myeloid Leukemia

Treatments: Drug: Voriconazole; Drug: Cephalexin; Drug: Midazolam; Drug: Gilteritinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT02014558

2215-CL-0101

Details and patient eligibility

About

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.

Enrollment: 265 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

265 participants in 13 patient groups

Gilteritinib 20 mg in Escalation Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Drug: Voriconazole

Gilteritinib 40 mg in Escalation Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 80 mg in Escalation Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 120 mg in Escalation Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 200 mg in Escalation Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 300 mg in Escalation Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 450 mg in Escalation Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 20 mg in Expansion Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 40 mg in Expansion Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 80 mg in Expansion Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 120 mg in Expansion Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Gilteritinib 200 mg in Expansion Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Drug: Cephalexin

Gilteritinib 300 mg in Expansion Phase

Experimental group

Description:

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.

Treatment:

Drug: Gilteritinib

Drug: Midazolam