A Phase 3 Open-label, Multicenter, Randomized Study of ASP2215 versus Salvage Chemotherapy in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) with FLT3 Mutation
You are being asked to participate in this study because you have acute myeloid leukemia (AML) that is either relapsed (has come back) or refractory (has not responded to treatment). The goal of this clinical research study is to compare the effects of the study drug ASP2215 to those of standard-of-care chemotherapies in patients with AML with mutations in the FLT3 gene. The safety of these drugs will also be compared.
Disease Group: Leukemia
Treatment Agent: ASP2215
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Astellas Pharma Global Development, Inc.
Primary Objective The primary objective is to determine the clinical benefit of ASP2215 therapy in subjects with FLT3-mutated AML who are refractory to or have relapsed after first-line AML therapy as shown with OS compared to salvage chemotherapy. Secondary Objectives The key secondary objectives are to: Determine the overall efficacy in event-free survival (EFS) of ASP2215 compared to salvage chemotherapy. Determine the overall efficacy in CR rate of ASP2215 compared to salvage chemotherapy. The secondary objectives are to evaluate the safety and efficacy of ASP2215 therapy versus salvage chemotherapy in terms of: Leukemia-free survival (LFS) duration of remission CRc rate transplantation rate patient reported fatigue (Brief Fatigue Inventory [BFI]) adverse events (AEs), safety labs, vital signs, ophthalmologic exams, electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) performance scores Exploratory Objectives Evaluate the safety and efficacy of ASP2215 therapy versus salvage chemotherapy in terms of: pharmacogenomics (PGx) FLT3 gene mutation status mutation types and frequency relationship to efficacy and safety mechanisms of acquired resistance exploratory (predictive) biomarkers of ASP2215 activity resource utilization in this study population including hospitalization, blood transfusion, antibiotic iv infusions, medication for AEs and opioid usage patient reported dyspnea (Functional Assessment of Chronic Illness Therapy-Dyspnea-Short Forms [FACIT-Dys-SF]) patient reported signs, symptoms and impacts of AML (Functional Assessment of Cancer Therapy-Leukemia [FACT-Leu], dizziness and mouth sore items) EuroQol Group-5 Dimension-5 Level Instrument (EQ-5D-5L)
IRB Review and Approval Date: 05/27/2016
Recruitment Status: Open
Projected Accrual: 369
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 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 signing informed consent.
3) Subject has a diagnosis of primary AML or AML secondary to MDS according to World Health Organization (WHO) classification as determined by pathology review at the treating institution.
4) Subject is refractory to or relapsed after first-line AML therapy (with or without HSCT). Refractory to first-line AML therapy is defined as: Subject did not achieve CR/CRi/CRp under initial therapy. A subject eligible for standard therapy must receive at least 1 cycle of an anthracycline containing induction block in standard dose for the selected induction regimen. A subject not eligible for standard therapy must have received at least 1 complete block of induction therapy seen as the optimum choice of therapy to induce remission for this subject as per investigator’s assessment.; Untreated first hematologic relapse is defined as: Subject must have achieved a CR/CRi/CRp with first-line treatment and has hematologic relapse.
5) Subject is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. In the investigator’s opinion, a subject with rapidly proliferative disease and unable to wait for the central lab results can be enrolled based on local test performed after completion of the last interventional treatment. Subjects can be enrolled from a locl test result if they have any of the following FLT3 mutations: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/1836.
6) Subject has an ECOG performance status </= 2.
7) Subject is eligible for preselected salvage chemotherapy according to investigator assessment.
8) 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 (TBL) </= 1.5 x ULN; Serum creatinine </= 1.5 x ULN or an estimated glomerular filtration rate of > 50 mL/min as calculated by the Modification of Diet in Renal Disease equation.
9) Subject is suitable for oral administration of study drug.
10) Female subject must either: Be of non child-bearing potential; Postmenopausal (defined as at least 1 year without any menses) prior to screening, or; Documented surgically sterile (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 pregnancy test at screening; And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 60 days after the final study drug administration.
11) Female subject must agree not to breastfeed at screening and throughout the study period and for 60 days after the final study drug administration.
12) Female subject must not donate ova starting at screening and throughout the study period and for 60 days after the final study drug administration.
13) Male subject and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and continue throughout the study period and for 120 days after the final study drug administration.
14) Male subject must not donate sperm starting at screening and throughout the study period and 120 days after the final study drug administration.
15) Subject agrees not to participate in another interventional study while on treatment.
1) Subject was diagnosed as acute promyelocytic leukemia.
2) Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
3) Subject has AML secondary to prior chemotherapy for other neoplasms (except for MDS).
4) Subject is in second or later hematologic relapse or has received salvage therapy for refractory disease.
5) Subject has clinically active central nervous system leukemia.
6) Subject has been diagnosed with another malignancy, unless disease-free for at least 5 years. Subjects with treated nonmelanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. Subjects with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy.
7) Subject has received prior treatment with ASP2215 or other FLT3 inhibitors (with the exception of sorafenib and midostaurin used in first-line therapy regimen as part of induction, consolidation and/or maintenance).
8) Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation.
9) Subject has had major surgery within 4 weeks prior to the first study dose.
10) Subject has radiation therapy within 4 weeks prior to the first study dose.
11) 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 (ECHO) performed within 1 month prior to study entry results in a left ventricular ejection fraction (LVEF) that is >/= 45%.
12) Subject with mean of triplicate QTcF > 450 ms at Screening based on central reading.
13) Subject with Long QT Syndrome at Screening.
14) Subject with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal [LLN]).
15) Subject requires treatment with concomitant drugs that are strong inducers of CYP3A.
16) 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.
17) 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.
18) Subject has an active uncontrolled infection.
19) Subject is known to have human immunodeficiency virus infection.
20) Subject has active hepatitis B or C or other active hepatic disorder.
21) Subject has any condition which, in the investigator’s opinion, makes the subject unsuitable for study participation.
22) Subject has active clinically significant GVHD or is on treatment with systemic corticosteroids for GVHD.
23) Subject has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.
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