A Phase 2/3 Multicenter, Open-label, 3-arm, 2-stage Randomized Study of ASP2215 (Gilteritinib), Combination of ASP2215 Plus Azacitidine and Azacitidine Alone in the Treatment of Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation in Patients Not Eligible for Intensive Induction Chemotherapy
The goal of this clinical research study is to compare ASP2215 (gilteritinib) alone, ASP2215 in combination with azacitidine, and azacitidine alone in the treatment of AML. The safety of the drugs will also be studied.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: ASP2215,Azacitidine
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
Primary Objective The primary objective is to determine the efficacy superiority of ASP2215 and/or ASP2215 plus azacitidine versus azacitidine as measured by overall survival (OS). Secondary Objectives Key Secondary Objective The key secondary objective is to determine the efficacy superiority of ASP2215 and/or ASP2215 plus azacitidine versus azacitidine as measured by event-free survival (EFS). Additional Secondary Objectives The additional secondary objectives are to evaluate the safety and efficacy of ASP2215 therapy and/or ASP2215 plus azacitidine versus azacitidine in terms of: Complete remission (CR) rate Leukemia-free survival (LFS) Duration of remission Composite complete remission (CRc) rate Patient reported fatigue (Brief Fatigue Inventory [BFI]) Adverse events (AEs), clinical laboratory results, physical examinations, vital signs, electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) performance scores Exploratory Objectives The exploratory objectives are to: Evaluate the efficacy of ASP2215 and/or ASP2215 plus azacitidine versus azacitidine in terms of: Transplantation rate Minimal residual disease (MRD) FLT3 gene mutation status Mutation types and frequency Relationship to efficacy and safety Mechanisms of acquired resistance Exploratory (predictive) biomarkers of ASP2215 activity Patient reported dyspnea (Functional Assessment of Chronic Illness Therapy-Dyspnea-Short Form [FACIT-Dys-SF]) Patient reported signs, symptoms and impacts of AML (Functional Assessment of Cancer Therapy-Leukemia [FACT-Leu] and dizziness and mouth sores items) Health-related quality of life assessed by the EuroQol Group 5-dimension 5-level (EQ-5D-5L) instrument Resource utilization including hospitalization, blood transfusion, antibiotic intravenous infusions, medication for AEs and opioid usage Characterize the pharmacokinetics of ASP2215 and azacitidine given as single agents and as combination treatment Evaluate and compare the pharmacokinetics of ASP2215 and azacitidine in a subset of Non-Japanese and Japanese subjects
IRB Review and Approval Date: 04/25/2017
Recruitment Status: Open
Projected Accrual: 540
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 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 [New York Heart Assosication (NYHA) class </=3] or ejection fraction [E(F)] </= 50%; ii. Creatinine > 2 mg/dL (177 umol/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/m(2).
6) Subject must meet the following criteria as indicated on the clinical laboratory tests: Serum AST and ALT </= 2.5 x institutional upper limit of normal (ULN); Serum total bilirubin </= 1.5 x institutional ULN; Serum potassium >/= institutional lower limit of normal (LLN); Serum magnesium >/= institutional LLN
7) Subject is suitable for oral administration of study drug.
8) Female subject must either: Be of non childbearing potential: Post menopausal (defined as at least 1 year without any menses) prior to screening, or Documented surgically sterile or status post hysterectomy (at least 1 month prior to screening); Or, if of childbearing potential, Agree not to try to become pregnant during the study and for 60 days after the final study drug administration And have a negative urine or serum 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 60 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 60 days after the final study drug administration.
10) Female subject must not donate ova starting at screening and throughout the study period, and for 60 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 120 days after the final study drug administration.
12) Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration.
13) Subject agrees not to participate in another interventional study while on treatment.
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 cytochrome P450 (CYP)3A.
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 Heart Association Class IV.
13) Subject with mean Fridericia-corrected QT interval (QTcF) > 450 ms at screening based on central reading.
14) Subject with a history of 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, including any contraindications of azacitidine listed in the country package insert.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
Phase II/Phase III
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