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

Study Overview
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Brief Summary
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A Phase 1/2a 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). Phase 2a will consist of up to 3 dose levels (high, medium, and low) of which subjects with FLT3 mutations will randomly be assigned.

Detailed Description
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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. For Phase 2a long term phone follow-up for assessment of overall survival will also occur.

Official Title
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A First-in-Human Phase 1/2a Study to Assess the Safety, Tolerability, Efficacy, and Pharmacokinetics of FF-10101-01 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia

Conditions
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AML, Adult

Intervention / Treatment
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* Drug: FF-10101-01


Participation Criteria
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Eligibility Criteria
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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. For Phase 2a only: in addition to inclusion criteria 2 above, patients must have a FLT3 mutation of any type 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: 10 mg<br>Orally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 2: 20 mg<br>Orally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 3: 35 mg<br>Orally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 4: 50 mg<br>Orally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 5: 75 mg<br>Orally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 6: 100 mg<br>Orally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 7: 150 mg<br>Orally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 8: 225 mg<br>Orally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 20: 50 mg<br>Orally twice daily (BID) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 21: 75 mg<br>Orally twice daily (BID) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|
| Experimental: Cohort 22: 100 mg<br>Orally twice daily (BID) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 | Drug: FF-10101-01<br>* FF-10101-01 will be administered orally once a day on Days 1-28 of a 28-day cycle. In Phase 1, the dose escalation will proceed until MTD is reached. In Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until, intolerable toxicity, or investigation/subject decision.<br>* Other names: FF-10101 succinate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1/2a: Frequency of adverse events | Safety Assessments include frequency of adverse events (AEs) in percentage (%) | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2a Clinical response of FF-10101-01 to AML | RFS: Defined as the time from CR to recurrence or death due to any cause. DOR: Defined as time from CR, CRp or CRi to recurrence. OS: Defined as time from the first FF-10101-01 administration to the time of death, censored (if appropriate) at the date last known to be alive. Recurrence (Relapse after confirmed CR): Reappearance of leukemia blats in peripheral blood or ≥5% blasts in the bone marrow not attributable in the Investigator's opinion to any other cause (e.g., bone marrow regeneration after consolidation therapy) or appearance of new dysplastic changes. PR: Defined as ≥50% decrease in bone marrow blasts to 5% to 25 % abnormal cells in the bone marrow, or CR with ≤5% blasts if Auer rods are present Treatment failure: defined as failure to achieve CR, CRi, CRp or PR | Response and survival assessments at the beginning Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1 and every 3 months for 2 year | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Maximum observed concentration (Cmax) | Maximum observed concentration (Cmax) | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Time to maximum concentration (tmax) | Time to maximum concentration (tmax) | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Area under the plasma concentration-time curve in the sampled matrix during a 24-hour dosing interval (AUC(τ)) | Area under the plasma concentration-time curve in the sampled matrix during a 24-hour dosing interval (AUC(τ)) | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite -Plasma concentration-time curve (AUC(0-last)) | Area under the plasma concentration-time curve in the sampled matrix from time zero to the last quantifiable concentration, if concentrations are not quantifiable over the entire 24-hour dosing interval (AUC(0-last)) | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Dose normalized AUC(τ) (AUC(τ)/dose) | Dose normalized AUC(τ) (AUC(τ)/dose) | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Dose normalized Cmax (Cmax/dose) | Dose normalized Cmax (Cmax/dose) | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Accumulation ratio for AUC | Accumulation ratio for AUC [RaccAUC ie, ratio of Day 29/Day 1 of the PK parameter] | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Accumulation ratio for Cmax | Accumulation ratio for Cmax [RaccCmax ie, ratio of Day 29/Day 1 of the PK parameter] | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Oral clearance (CL/F) for FF-10101 | Oral clearance (CL/F) for FF-10101 | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Average concentrations (Cavg) | Average concentrations (Cavg) | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Minimum observed concentration (Cmin) | Minimum observed concentration (Cmin) | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Fluctuation index | Fluctuation index | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for Cmax | Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for Cmax | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for AUC(τ) | Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for AUC(τ) | Cycle 1, Day 1 through Cycle 2, Day 1 | 
| Phase 1/2a: Frequency of Serious Adverse Events | Safety Assessments include frequency of Serious adverse events (SAEs) | 12 Months | 
| Phase 1/2a: Frequency of Dose Limiting Toxicities | Safety Assessments include frequency of dose-limiting toxicities (DLTs), dose reductions, delays, or withdrawals due to toxicity. | 12 Months | 
| Phase 1/2a: Frequency of adverse events including assessment of Hematology laboratory parameters | Safety assessments also include assessment of clinical laboratory parameters Hematology | 12 Months | 
| Phase 1/2a: Frequency of adverse events including assessment of serum chemistry laboratory parameters | Safety assessments also include assessment of clinical laboratory parameters serum chemistry | 12 Months | 
| Phase 1/2a: Frequency of adverse events including assessment of urinalysis laboratory parameters | Safety assessments also include assessment of clinical laboratory parameters urinalysis | 12 Months | 
| Phase 1/2a: Frequency of Adverse events including assessment of vital signs | Safety assessments also include assessment of Vital signs (Heart Rate and BP) | 12 Months | 
| Phase 1/2a: Frequency of Adverse events including assessment of vital signs - Heart Rate | Safety assessments also include assessment of Vital signs Heart Rate | 12 Months | 
| Phase 1/2a: Frequency of Adverse events including assessment of vital signs - Blood Pressure | Safety assessments also include assessment of Vital signs BP) | 12 Months | 
| Phase 1/2a: Frequency of Adverse events including assessment of 12 lead ECG. | Safety assessments also include assessment of 12 lead ECG. | 12 Months | 
| Phase 1/2a: Composite complete remission rate (CRc) including CR | Composite complete remission rate (CRc) which includes CR | 12 Months | 
| Phase1/2a: Composite complete remission rate (CRc) including CR with incomplete platelet recovery (CRp) | Composite complete remission rate (CRc) which includes CR with incomplete platelet recovery (CRp) | 12 Months | 
| Phase1/2a: Composite complete remission rate (CRc) including CR with incomplete neutrophil recovery with or without platelet recovery (CRi)) | Composite complete remission rate (CRc) which includes CR with incomplete neutrophil recovery with or without platelet recovery (CRi)) | 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia