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

• Conditions: Relapsed or Refractory Acute Myeloid Leukemia; MedDRA version: 18.1Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2014-002217-31-FR
• Lead Sponsor: Astellas Pharma Global Development, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2015-01-07
• Last Update Posted: 14 December 2015

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 230

Inclusion Criteria

1) Subject is =18 years of age at the time of obtaining informed consent.
2) Subject is defined as morphologically documented primary or secondary AML by the World Health Organization (WHO) criteria (2008) and fulfills one of the followings:
• Refractory to at least 1 cycle of induction chemotherapy
• Relapsed after achieving remission with a prior therapy
3) Subject has an Eastern Cooperative Oncology Group (ECOG) performance status =2.
4) 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, including immunosuppressive therapy post hematopoietic stem cell transplantation (HSCT).
5) 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 =1.5 x 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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 115
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 115

Exclusion Criteria

1. Subject was diagnosed as acute promyelocytic leukemia (APL).
2. Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
3. Subject has active malignant tumors other than AML or Myelodysplastic Syndrome (MDS).
4. Subject has persistent non-hematological toxicities of= Grade 2 (CTC AE v4), with symptoms and objective findings, from prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery).
5. 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.
6. Subject has clinically active central nervous system leukemia.
7. Subject has disseminated intravascular coagulation abnormality (DIC).
8. Subject has had major surgery within 4 weeks prior to the first study dose.
9. Subject has had radiation therapy within 4 weeks prior to the first study dose.
10. Subject has congestive heart failure 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%.
11. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of
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.
12. Subject requires 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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Assess the safety and tolerability, including determination of the maximum tolerated dose (MTD) of oral ASP2215 in subjects with relapsed or treatment-refractory AML. <br>Determine the pharmacokinetic (PK) parameters of ASP2215.;Secondary Objective: Investigate the anti-leukemic activity of various doses of ASP2215 in subjects with AML.<br>Evaluate the effect of strong or moderate cytochrome P450-isozyme3A4 (CYP3A4) inhibitors on the PK of ASP2215.<br>Evaluate the potential induction of CYP3A4 by ASP2215 by assessment of midazolam PK.;Primary end point(s): Safety and Tolerability (Determine Maximum tolerated dose)<br>Pharmacokinetics (ASP2215);Timepoint(s) of evaluation of this end point: (Unknown as dose escalation study)

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Efficacy of ASP2215 in AML<br>• CR rate<br>• Composite CR rate (CR + CRp + CRi)<br>• Best response rate (CRc + partial remission (PR))<br>• Duration of response<br>• Overall survival<br>• Event free survival<br>• Leukemia free survival<br>Pharmacokinetics of ASP2215, effect of strong or moderate CYP3A4 inhibitors<br>Pharmacokinetics of midazolam, potential induction of CYP3A4 by ASP2215;Timepoint(s) of evaluation of this end point: (Unknown as dose escalation study)<br>