Clinical trial NCT03194685: Study of FF-10101-01 in Patients With Relapsed or Refractory Acute Myeloid Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: AML, Adult
Keywords: Acute Myeloid Leukemia
Lead sponsor: Fujifilm Pharmaceuticals U.S.A., Inc.
Sponsor class: INDUSTRY
First posted: 2017-06-21
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase 1: Frequency of adverse events
timeFrame: 12 months
Secondary outcomes:
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Maximum observed concentration (Cmax)
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Time to maximum concentration (tmax)
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: 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))
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite -Plasma concentration-time curve (AUC(0-last))
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Dose normalized AUC(τ) (AUC(τ)/dose)
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Dose normalized Cmax (Cmax/dose)
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Accumulation ratio for AUC
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Accumulation ratio for Cmax
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Oral clearance (CL/F) for FF-10101
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Average concentrations (Cavg)
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Minimum observed concentration (Cmin)
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Fluctuation index
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for Cmax
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: 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)
timeFrame: Cycle 1, Day 1 through Cycle 2, Day 1
measure: Phase 1: Frequency of Serious Adverse Events
timeFrame: 12 Months
measure: Phase 1: Frequency of Dose Limiting Toxicities
timeFrame: 12 Months
measure: Phase 1: Frequency of adverse events including assessment of Hematology laboratory parameters
timeFrame: 12 Months
measure: Phase 1: Frequency of adverse events including assessment of serum chemistry laboratory parameters
timeFrame: 12 Months
measure: Phase 1: Frequency of adverse events including assessment of urinalysis laboratory parameters
timeFrame: 12 Months
measure: Phase 1: Frequency of Adverse events including assessment of vital signs
timeFrame: 12 Months
measure: Phase 1: Frequency of Adverse events including assessment of vital signs - Heart Rate
timeFrame: 12 Months
measure: Phase 1: Frequency of Adverse events including assessment of vital signs - Blood Pressure
timeFrame: 12 Months
measure: Phase 1: Frequency of Adverse events including assessment of 12 lead ECG.
timeFrame: 12 Months
measure: Phase 1: Composite complete remission rate (CRc) including CR
timeFrame: 12 Months
measure: Phase 1: Composite complete remission rate (CRc) including CR with incomplete platelet recovery (CRp)
timeFrame: 12 Months
measure: Phase 1: Composite complete remission rate (CRc) including CR with incomplete neutrophil recovery with or without platelet recovery (CRi))
timeFrame: 12 Months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles, David Geffen School of Medicine
state: California
city: San Francisco
country: United States
facility: University Of California, San Francisco School of Medicine
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Hospital - Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
References: