Study of FF-10101-01 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

A First-in-Human Phase 1 Study to Assess the Safety, Tolerability, Efficacy, and Pharmacokinetics of FF-10101-01 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia

A Phase 1 dose escalation and dose ranging study of FF-10101-01 in subjects with relapsed or refractory acute myeloid leukemia to determine the safety, tolerability, PK and preliminary efficacy. A total of 9 cohorts will be enrolled in Phase 1 to establish the Maximum Tolerated Dose (MTD).

Subjects will receive FF-10101-01 orally once a day repeated every 28 days =1 cycle Frequent blood draws will be collected to measure pharmacodynamic parameters and pharmacodynamic activity.

Disease assessments, including bone marrow aspirates, will be performed at the beginning of cycles 1-3, and every 3 months thereafter. Subjects who demonstrate objective response or stable disease will be allowed to continue therapy with FF-10101-01 until , observation of unacceptable adverse events, or until the subject is no longer deriving benefit based on the opinion of the investigator.

Subjects who are able and willing to give written informed consent

• Documented primary or secondary AML, as defined by the WHO criteria (2008), by histopathology refractory to previous induction chemotherapy and/or relapsed after achieving remission with a prior chemotherapy and who are not candidates for other available therapy likely to confer clinical benefit.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• In the absence of rapidly progressing disease, the interval from prior treatment to time of FF-10101-01 administration should be at least 14 days for cytotoxic agents other than hydroxyurea, at least 5 half-lives for non-cytotoxic agents, and 14 days for monoclonal antibody therapies. Hydroxyurea may be continued for a maximum of 14 days from the start of FF-10101-01 dosing, through Cycle 1 Day 14, with a maximal dose of 5 grams/day
• Persistent chronic clinically significant toxicities from prior chemotherapy or surgery must be ≤Grade 2
• If subject has had a hematopoietic stem cell transplant, subject must be ≥60 days post-transplant with no clinically significant GVHD requiring systemic therapy
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤3 times the upper limit of normal and total bilirubin of ≤1.5x the upper limit of normal. If total bilirubin is equal to or exceeds 1.5x the upper limit of normal, the subject can still be included if direct bilirubin is ≤1.5x the upper limit of normal
• Calculated creatinine clearance of ≥60 mL/min
• Female subjects of childbearing potential and sexually mature male subjects must agree to use a medically accepted method of contraception other than an oral contraceptive for the duration of the study.

Exclusion Criteria:

• Subjects diagnosed with acute promyelocytic leukemia
• Subjects with Bcr-Abl positive leukemia (chronic myelogenous leukemia in blast crisis)
• Subjects with clinically active CNS leukemia
• Subjects with major surgery within 28 days prior to the first administration of FF-10101-01
• Subjects with radiation therapy within 28 days prior to the first administration of FF-10101-01
• Subjects with active malignant disease requiring therapy other than AML or myelodysplastic syndrome with transformation into AML
• Subjects with an active uncontrolled infection
• Subjects with a medical condition, serious intercurrent illness, or other circumstance that, in the Investigator's judgment, could jeopardize the subject's safety as a study subject, or that could interfere with the study objectives
• Subjects known to have human immunodeficiency virus infection, or who have active hepatitis B or C infection as determined by serological testing
• Subjects with congestive heart failure, New York Heart Association (NYHA) Class 3 or 4, or subjects with a past history of congestive heart failure NYHA Class 3 or 4 and in whom echocardiogram or multiple gate acquisition (MUGA) scan performed within 3 months prior to screening or at screening showed a LVEF <40%
• Female subjects who are pregnant or breast feeding
• Subjects on 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) or other drugs known to have muscle toxicity
• Subjects taking strong inhibitors of CYP3A4 will be excluded from the study unless therapeutic substitution is possible
• Subjects taking strong inducers of CYP3A4 will be excluded from the study unless therapeutic substitution is possible
• Use of systemic immunosuppressive agents within 14 days prior to first dose of FF-10101
• Subjects taking drugs known to cause Torsades de Pointes will be excluded from the study unless therapeutic substitution is possible
• Subjects known to have long QT syndrome
• Subjects with mean QTcF values following 3 ECGs conducted 5 minutes apart of >470 msec