A Phase 2/3 Multicenter, Open-label, 3-arm, 2-stage Randomized Study ofASP2215 (Gilteritinib), Combination of ASP2215 Plus Azacitidine andAzacitidine Alone in the Treatment of Newly Diagnosed Acute MyeloidLeukemia with FLT3 Mutation in Patients Not Eligible for Intensive Induction Chemotherapy

Phase 1

• Conditions: ewly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation in Patients Not Eligible for Intensive Induction Chemotherapy; MedDRA version: 19.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-001790-41-ES
• Lead Sponsor: Astellas Pharma Global Development, Inc. (APGD)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-04-20
• Last Update Posted: 13 June 2016

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 1803

Inclusion Criteria

1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] Authorization for United States [US] sites) must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Subject is considered an adult according to local regulation at the time of obtaining informed consent.
3. Subject has a diagnosis of previously-untreated AML according to World Health Organization (WHO) classification [Swerdlow et al, 2008] as determined by pathology review at the treating institution.
4. Subject is positive for FLT3 mutation (ITD or TKD [D835/I836] mutation) in bone marrow or whole blood as determined by central laboratory.
5. Subject is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
a. Subject is > = 75 years of age.
b. Subject has any of the following comorbidities:
i. Congestive heart failure or ejection fraction (Ef) < = 50%;
ii. Creatinine > 2 mg/dL (177 ?mol/L), dialysis or prior renal transplant;
iii. ECOG performance status > = 3;
iv. Prior or current malignancy that does not require concurrent treatment;
v. Subject has received a cumulative anthracycline dose above 400 mg/m2.
6. Subject must meet the following criteria as indicated on the clinical laboratory tests:
-Serum AST and ALT <=2.5 x upper limit of normal (ULN)
-Serum total bilirubin <=1.5 x ULN
- Serum potassium >=lower limit of normal (LLN)
-Serum magnesium>= LLN
7. Subject is suitable for oral administration of study drug.
8. Female subject must either:
-Be of nonchildbearing potential:
Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
-Or, if of childbearing potential,
Agree not to try to become pregnant during the study and for 45 days after the final study drug administration
And have a negative urine pregnancy test at screening
And, if heterosexually active, agree to consistently use 2 forms of effective contraception per locally accepted standards, 1 of which must be a barrier method, starting at screening and throughout the study period and for 45 days after the final study drug administration.
9. Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 45 days after the final study drug administration.
10. Female subject must not donate ova starting at screening and throughout the study period, and for 45 days after the final study drug administration.
11. Male subject and their female partners who are of childbearing potential must be using 2 forms of effective contraception per locally accepted standards, 1 of which must be a barrier method, starting at screening and continue throughout the study period, and for 105 days after the final study drug administration.
12. Male subject must not donate sperm starting at screening and throughout the study period and for 105 days after the final study drug administration.
13. Subject agrees not to participate in another interventional study while on treatment.
Waivers to the inclusion criteria will NOT be allowed.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) y

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 received previous therapy for AML, with the exception of the following:
-Emergency leukapheresis
-Hydroxyurea for <=14 days
-Preemptive treatment with retinoic acid prior to exclusion of APL <=7 days
-Growth factor or cytokine support
-Steroids for the treatment of hypersensitivity or transfusion reactions
4. Subject has clinically active central nervous system leukemia.
5. Subject has been diagnosed with another malignancy that requires concurrent treatment or hepatic malignancy regardless of need for treatment.
6. Subject has clinically significant coagulation abnormality unless secondary to AML in the opinion of the investigator.
7. Subject has had major surgery within 4 weeks prior to the first study dose.
8. Subject has radiation therapy within 4 weeks prior to the first study dose.
9. Subject requires treatment with concomitant drugs that are strong inducers of CYP3A4.
10. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P-gp with the exception of drugs that are considered absolutely essential for the care of the subject.
11. Subject requires treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
12. Subject has congestive heart failure classified as New York Hearth Association Class IV.
13. Subject with mean Fridericia-corrected QT interval (QTcF) > 450 ms at screening based on central reading.
14. Subject with Long QT Syndrome at screening.
15. Subject has known pulmonary disease with diffusion capacity of lung for carbon monoxide (DLCO) <=65%, forced expiratory volume in the first second (FEV1) <=65%, dyspnea at rest or requiring oxygen or any pleural neoplasm.
16. Subject has an active uncontrolled infection. If an infection is present, the patient must be receiving definitive therapy and have no signs of progressing infection. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
17. Subject is known to have human immunodeficiency virus infection.
18. Subject has active hepatitis B or C or other active hepatic disorder.
19. Subject has any condition which, in the investigator?s opinion, makes the subject unsuitable for study participation.
Waivers to the exclusion criteria will NOT be allowed.

Study & Design

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

Primary Outcome Measures

Name	Time	Method
Main Objective: Determine the efficacy superiority of ASP2215 and/or ASP2215 plus azacitidine versus azacitidine as measured by overall survival (OS).;Secondary Objective: Determine the efficacy superiority of ASP2215 and/or ASP2215 plus azacitidine versus azacitidine as measured by event-free survival (EFS).;Primary end point(s): - Overall Survival;Timepoint(s) of evaluation of this end point: Please refer to section E.5.1 and also the protocol.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Key Secondary Efficacy Endpoint:<br>- Event-free survival<br><br>Secondary Efficacy Endpoints:<br>- Best Response<br>- Leukemia-free survival<br>- Duration of remission<br>- Patient reported fatigue from BFI<br>Safety Endpoints:<br>- AEs<br>- Clinical laboratory results<br>- Vital sign measurements<br>- Ophthalmology assessments<br>- ECGs<br>- ECOG performance scores;Timepoint(s) of evaluation of this end point: Please refer to section E.5.2 and also the protocol.