AML, Adult
Conditions
Keywords
Acute Myeloid Leukemia
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.
Interventions
DRUGFF-10101-01
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.
Sponsors
Fujifilm Pharmaceuticals U.S.A., Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open Label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Frequency of adverse events | 12 months | Safety Assessments include frequency of adverse events (AEs) in percentage (%) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Time to maximum concentration (tmax) | Cycle 1, Day 1 through Cycle 2, Day 1 | Time to maximum concentration (tmax) |
| 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)) | Cycle 1, Day 1 through Cycle 2, Day 1 | Area under the plasma concentration-time curve in the sampled matrix during a 24-hour dosing interval (AUC(τ)) |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite -Plasma concentration-time curve (AUC(0-last)) | Cycle 1, Day 1 through Cycle 2, Day 1 | 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)) |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Dose normalized AUC(τ) (AUC(τ)/dose) | Cycle 1, Day 1 through Cycle 2, Day 1 | Dose normalized AUC(τ) (AUC(τ)/dose) |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Dose normalized Cmax (Cmax/dose) | Cycle 1, Day 1 through Cycle 2, Day 1 | Dose normalized Cmax (Cmax/dose) |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Accumulation ratio for AUC | Cycle 1, Day 1 through Cycle 2, Day 1 | Accumulation ratio for AUC \[RaccAUC ie, ratio of Day 29/Day 1 of the PK parameter\] |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Accumulation ratio for Cmax | Cycle 1, Day 1 through Cycle 2, Day 1 | Accumulation ratio for Cmax \[RaccCmax ie, ratio of Day 29/Day 1 of the PK parameter\] |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Oral clearance (CL/F) for FF-10101 | Cycle 1, Day 1 through Cycle 2, Day 1 | Oral clearance (CL/F) for FF-10101 |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Average concentrations (Cavg) | Cycle 1, Day 1 through Cycle 2, Day 1 | Average concentrations (Cavg) |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Minimum observed concentration (Cmin) | Cycle 1, Day 1 through Cycle 2, Day 1 | Minimum observed concentration (Cmin) |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Fluctuation index | Cycle 1, Day 1 through Cycle 2, Day 1 | Fluctuation index |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for Cmax | Cycle 1, Day 1 through Cycle 2, Day 1 | Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for Cmax |
| Phase 1: Evaluate the Pharmacokinetic profile of FF-10101-01 and its Metabolite - Maximum observed concentration (Cmax) | Cycle 1, Day 1 through Cycle 2, Day 1 | Maximum observed concentration (Cmax) |
| Phase 1: Frequency of Serious Adverse Events | 12 Months | Safety Assessments include frequency of Serious adverse events (SAEs) |
| Phase 1: Frequency of Dose Limiting Toxicities | 12 Months | Safety Assessments include frequency of dose-limiting toxicities (DLTs), dose reductions, delays, or withdrawals due to toxicity. |
| Phase 1: Frequency of adverse events including assessment of Hematology laboratory parameters | 12 Months | Safety assessments also include assessment of clinical laboratory parameters Hematology |
| Phase 1: Frequency of adverse events including assessment of serum chemistry laboratory parameters | 12 Months | Safety assessments also include assessment of clinical laboratory parameters serum chemistry |
| Phase 1: Frequency of adverse events including assessment of urinalysis laboratory parameters | 12 Months | Safety assessments also include assessment of clinical laboratory parameters urinalysis |
| Phase 1: Frequency of Adverse events including assessment of vital signs | 12 Months | Safety assessments also include assessment of Vital signs (Heart Rate and BP) |
| Phase 1: Frequency of Adverse events including assessment of vital signs - Heart Rate | 12 Months | Safety assessments also include assessment of Vital signs Heart Rate |
| Phase 1: Frequency of Adverse events including assessment of vital signs - Blood Pressure | 12 Months | Safety assessments also include assessment of Vital signs BP) |
| Phase 1: Frequency of Adverse events including assessment of 12 lead ECG. | 12 Months | Safety assessments also include assessment of 12 lead ECG. |
| Phase 1: Composite complete remission rate (CRc) including CR | 12 Months | Composite complete remission rate (CRc) which includes CR |
| Phase 1: Composite complete remission rate (CRc) including CR with incomplete platelet recovery (CRp) | 12 Months | Composite complete remission rate (CRc) which includes CR with incomplete platelet recovery (CRp) |
| Phase 1: Composite complete remission rate (CRc) including CR with incomplete neutrophil recovery with or without platelet recovery (CRi)) | 12 Months | Composite complete remission rate (CRc) which includes CR with incomplete neutrophil recovery with or without platelet recovery (CRi)) |
| 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) | Cycle 1, Day 1 through Cycle 2, Day 1 | Metabolite (FF-10101M1) to parent (FF-10101) exposure ratios for AUC(τ) |
Countries
United States
Outcome results
None listed