Clinical Trials /

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

NCT03194685

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of FF-10101-01 in Patients With Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: FF-10101-US101/201
  • NCT ID: NCT03194685

Conditions

  • AML, Adult

Interventions

DrugSynonymsArms
FF-10101-01FF-10101 succinatePhase 1 Cohort 1: 10 mg

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 Cohort 1: 10 mgExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . The dose escalation will proceed until MTD is reached.
  • FF-10101-01
Phase 1 Cohort 2: 20 mgExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . The dose escalation will proceed until MTD is reached.
  • FF-10101-01
Phase 1 Cohort 3: 35 mgExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . The dose escalation will proceed until MTD is reached.
  • FF-10101-01
Phase 1 Cohort 4: 50 mgExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . The dose escalation will proceed until MTD is reached.
  • FF-10101-01
Phase 1 Cohort 5: 75 mgExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . The dose escalation will proceed until MTD is reached.
  • FF-10101-01
Phase 1 Cohort 6: 100 mgExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . The dose escalation will proceed until MTD is reached.
  • FF-10101-01
Phase 1 Cohort 7: 150 mgExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . The dose escalation will proceed until MTD is reached.
  • FF-10101-01
Phase 1 Cohort 8: 225 mgExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . The dose escalation will proceed until MTD is reached.
  • FF-10101-01
Phase 1 Cohort 9: 300 mgExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . The dose escalation will proceed until MTD is reached.
  • FF-10101-01
Phase 2a Group 1: High DoseExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until disease progression, intolerable toxicity, or investigation/subject decision.
  • FF-10101-01
Phase 2a Group 2: Middle DoseExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until disease progression, intolerable toxicity, or investigation/subject decision.
  • FF-10101-01
Phase 2a Group 3: Low DoseExperimentalOrally once a day (QD) on Days 1-28 of a 28-day cycle. Drug: FF-10101-01 . Phase 2a, subjects will be randomly assigned to 1 of 3 dose levels in a balanced fashion. The treatment will continue until disease progression, intolerable toxicity, or investigation/subject decision.
  • FF-10101-01

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.

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Phase 2a Clinical response of FF-10101-01 to AML
Time Frame: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
Safety Issue:
Description: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
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Maximum observed concentration (Cmax)
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Maximum observed concentration (Cmax)
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Time to maximum concentration (tmax)
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Time to maximum concentration (tmax)
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))
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Area under the plasma concentration-time curve in the sampled matrix during a 24-hour dosing interval (AUC(τ))
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite -Plasma concentration-time curve (AUC(0-last))
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description: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))
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Dose normalized AUC(τ) (AUC(τ)/dose)
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Dose normalized AUC(τ) (AUC(τ)/dose)
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Dose normalized Cmax (Cmax/dose)
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Dose normalized Cmax (Cmax/dose)
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Accumulation ratio for AUC
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Accumulation ratio for AUC [RaccAUC ie, ratio of Day 29/Day 1 of the PK parameter]
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Accumulation ratio for Cmax
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Accumulation ratio for Cmax [RaccCmax ie, ratio of Day 29/Day 1 of the PK parameter]
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Oral clearance (CL/F) for FF-10101
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Oral clearance (CL/F) for FF-10101
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Average concentrations (Cavg)
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Average concentrations (Cavg)
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Minimum observed concentration (Cmin)
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Minimum observed concentration (Cmin)
Measure:Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Fluctuation index
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Fluctuation index
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
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for Cmax
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)
Time Frame:Cycle 1, Day 1 through Cycle 2, Day 1
Safety Issue:
Description:Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for AUC(τ)
Measure:Phase 1/2a: Frequency of Serious Adverse Events
Time Frame:12 Months
Safety Issue:
Description:Safety Assessments include frequency of Serious adverse events (SAEs)
Measure:Phase 1/2a: Frequency of Dose Limiting Toxicities
Time Frame:12 Months
Safety Issue:
Description:Safety Assessments include frequency of dose-limiting toxicities (DLTs), dose reductions, delays, or withdrawals due to toxicity.
Measure:Phase 1/2a: Frequency of adverse events including assessment of Hematology laboratory parameters
Time Frame:12 Months
Safety Issue:
Description:Safety assessments also include assessment of clinical laboratory parameters Hematology
Measure:Phase 1/2a: Frequency of adverse events including assessment of serum chemistry laboratory parameters
Time Frame:12 Months
Safety Issue:
Description:Safety assessments also include assessment of clinical laboratory parameters serum chemistry
Measure:Phase 1/2a: Frequency of adverse events including assessment of urinalysis laboratory parameters
Time Frame:12 Months
Safety Issue:
Description:Safety assessments also include assessment of clinical laboratory parameters urinalysis
Measure:Phase 1/2a: Frequency of Adverse events including assessment of vital signs
Time Frame:12 Months
Safety Issue:
Description:Safety assessments also include assessment of Vital signs (Heart Rate and BP)
Measure:Phase 1/2a: Frequency of Adverse events including assessment of vital signs - Heart Rate
Time Frame:12 Months
Safety Issue:
Description:Safety assessments also include assessment of Vital signs Heart Rate
Measure:Phase 1/2a: Frequency of Adverse events including assessment of vital signs - Blood Pressure
Time Frame:12 Months
Safety Issue:
Description:Safety assessments also include assessment of Vital signs BP)
Measure:Phase 1/2a: Frequency of Adverse events including assessment of 12 lead ECG.
Time Frame:12 Months
Safety Issue:
Description:Safety assessments also include assessment of 12 lead ECG.
Measure:Phase 1/2a: Composite complete remission rate (CRc) including CR
Time Frame:12 Months
Safety Issue:
Description:Composite complete remission rate (CRc) which includes CR
Measure:Phase1/2a: Composite complete remission rate (CRc) including CR with incomplete platelet recovery (CRp)
Time Frame:12 Months
Safety Issue:
Description:Composite complete remission rate (CRc) which includes CR with incomplete platelet recovery (CRp)
Measure:Phase1/2a: Composite complete remission rate (CRc) including CR with incomplete neutrophil recovery with or without platelet recovery (CRi))
Time Frame:12 Months
Safety Issue:
Description:Composite complete remission rate (CRc) which includes CR with incomplete neutrophil recovery with or without platelet recovery (CRi))

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fujifilm Pharmaceuticals U.S.A., Inc.

Trial Keywords

  • Acute Myeloid Leukemia

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