Study of FF-10501-01 in Patients With Relapsed or Refractory Hematological Malignancies

Study Overview
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Brief Summary
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A Phase 1/2a Dose Escalation Study of FF-10501-01 in Patients with Relapsed or Refractory Hematological Malignancies to determine the safety and tolerability. A total of 6 cohorts will be enrolled in Phase 1 to establish the MTD. A total of 20 subjects with MDS/CMML treated at the RP2D are planned, including MDS/CMML subjects treated at the RP2D in Phase 1.

Detailed Description
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Subjects will receive FF-10501-01 orally on a twice daily schedule for 14, 21 or 28 days repeated every 28 days (=1 cycle). Disease assessments, including analysis of blood and bone marrow aspirates, will be performed at the end of Cycle 1 and every 2 cycles thereafter. Subjects who demonstrate objective response or stable disease will be allowed to continue therapy with FF-10501-01 until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in condition that prevent further study participation.

Official Title
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A Phase 1/2a, Dose Escalation Study of FF-10501-01 for the Treatment of Advanced Hematologic Malignancies

Conditions
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AML, CMML, MDS

Intervention / Treatment
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* Drug: FF-10501-01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed advanced hematologic malignancies; Phase 1: High-risk MDS/CMML (defined as ≥ 10% peripheral blood or marrow blasts and/or IPSS score ≥ 1.5) and relapsed or refractory to prior therapy AML relapsed or refractory to prior therapy, or ≥ 60 years of age and not a candidate for other therapies Phase 2a: MDS/CMML, relapsed from, or refractory to, prior HMA therapy; the latter defined as failure to achieve clinical remission (CR), partial remission (PR) or hematologic improvement (HI) after previous HMA therapy (≥ 4 cycles of azacitidine or decitabine), or progression during, or toxicity to previous HMA therapy precluding further HMA treatment, and, Bone marrow blast count ≥ 10% or peripheral blast count ≥ 5%, or IPSS-R score ≥ 3.5. At least 3 weeks beyond the last chemotherapy, targeted anticancer agent, major surgery or experimental treatment and recovered from all acute toxicities (≤ Grade 1). Hydroxyurea used to control peripheral blast counts is permitted up to Day 7 of treatment on study. Adequate performance status: ECOG ≤ 2; Adequate renal and hepatic function: creatinine ≤ 2.0 mg/dL, or calculated creatinine clearance ≥ 45 mL/min total bilirubin ≤ 2 times the upper limit of normal (ULN) ALT/AST ≤ 2 times ULN Negative serum pregnancy test Ability to provide written informed consent Exclusion Criteria: Known history of coronary artery disease, angina, myocardial infarction, congestive heart failure, cardiac arrhythmia or any other type of heart disease present within the last 6 months Known family history of hereditary heart disease QT interval corrected for rate (QTc) > 450 msec on the electrocardiogram (ECG) obtained at Screening Concomitant medication(s) that may cause QTc prolongation or induce Torsades de Pointes, with the exception of anti-microbials that are used as standard of care to prevent or treat infections and other such drugs that are considered by the Investigator to be essential for the care of the patient. Presence of active central nervous system (CNS) leukemia. Subjects adequately treated for CNS leukemia documented by 2 consecutive cerebrospinal fluid samples negative for leukemia cells are eligible. Subjects with no history of CNS leukemia will not be required to undergo cerebrospinal fluid sampling for eligibility. Known positive for HIV, hepatitis B virus surface antigen (HBsAg), or hepatitis C virus (HCV). Active infection requiring IV anti-infective usage within the last 7 days prior to study treatment. Any other medical intervention or condition which could compromise adherence to study requirements or confound the interpretation of study results. Pregnant or breast-feeding. Treatment with any investigational product within 28 days prior to Screening.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Lowest dose of FF-10501-01<br>FF-10501-01 tablets BID every 14 days of a 28 day cycle. | Drug: FF-10501-01<br>* FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle. The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.<br>* Other names: Drug FF-10501-01;|
| Experimental: Phase 1: 2x lowest dose of FF-10501-01<br>2x lowest dose of FF-10501-01 tablets BID every 14 days of a 28 day cycle. | Drug: FF-10501-01<br>* FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle. The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.<br>* Other names: Drug FF-10501-01;|
| Experimental: Phase 1: 4x lowest dose of FF-10501-01<br>4x lowest dose of FF-10501-01 tablets BID every 14 days of a 28 day cycle. | Drug: FF-10501-01<br>* FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle. The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.<br>* Other names: Drug FF-10501-01;|
| Experimental: Phase 1: 6x lowest dose of FF-10501-01<br>6x lowest dose of FF-10501-01 tablets BID every 14 days of a 28 day cycle. | Drug: FF-10501-01<br>* FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle. The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.<br>* Other names: Drug FF-10501-01;|
| Experimental: Phase 1: 8x lowest dose of FF-10101-01<br>8x lowest dose of FF-10501-01 tablets BID every 14 days of a 28 day cycle. | Drug: FF-10501-01<br>* FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle. The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.<br>* Other names: Drug FF-10501-01;|
| Experimental: Ph 2a: FF-10501-01 at 8x in MDS/CMML<br>FF-10501-01 tablets BID every 21 days of a 28 day cycle. | Drug: FF-10501-01<br>* FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle. The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.<br>* Other names: Drug FF-10501-01;|
| Experimental: Ph1:8x lowest dose FF10101-01 for 21 day<br>FF-10501-01 tablets BID every 21 days of a 28 day cycle. | Drug: FF-10501-01<br>* FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle. The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.<br>* Other names: Drug FF-10501-01;|
| Experimental: Ph1: 8x lowest dose FF-10101-01 28 day<br>FF-10501-01 tablets BID every 28 days of a 28 day cycle. | Drug: FF-10501-01<br>* FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle. The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.<br>* Other names: Drug FF-10501-01;|
| Experimental: Ph1: 10X lowest dose FF-10501-01 14 day<br>10x lowest dose of FF-10501-01 tablets BID every 14 days of a 28 day cycle. | Drug: FF-10501-01<br>* FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle. The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.<br>* Other names: Drug FF-10501-01;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessed by adverse events | Safety and tolerability assessed by adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicity (DLT), dose reductions, delays or withdrawals due to toxicity | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of overall response rates. | Response criteria by IWG Response Criteria for AML (AML subjects) or IWG Response Criteria for MDS (MDS and CMML subjects) | Responses and survival assessed at end of Cycle 1 and every 2 cycles thereafter through 6 months following last dose of study drug. Each cycle is 28 days in length. | 
| Evaluate the pharmacokinetic profile of FF-10501-01 and its metabolite. | Cmax, Tmax, Half-life, AUC, Clearance, Volume of Distribution | Evaluated at three timepoints: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1. Each cycle is 28 days in length. | 
| Changes from baseline in xanthosine monophosphate (XMP) as a pharmacodynamic marker. | Xanthosine monophosphate (XMP) | Evaluated at three timepoints: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1. Each cycle is 28 days in length. | 
| Evaluate the proportion of subjects who achieve hematologic improvement in peripheral blood or bone marrow blast count. | Response Criteria by IWG Response Criteria for AML (AML subjects) or IWG Response Criteria for MDS (MDS and CMML subjects). | Responses and survival assessed at the end of Cycle 1 and every 2 cycles thereafter through 6 months following last dose of study drug. Each cycle is 28 days in length. | 
| Evaluate progression-free survival (PFS). | Response Criteria by IWG Response Criteria for AML (AML subjects) or IWG Response Criteria for MDS (MDS and CMML subjects). | Responses and survival assessed at end of Cycle 1 and every 2 cycles thereafter through 6 months following last dose of study drug. Each cycle is 28 days in length. | 
| Evaluate overall survival (OS). | Response criteria by IWG Response Criteria for AML (AML subjects) or IWG Response Criteria for MDS (MDS and CMML subjects). | Responses and survival assessed at end of Cycle 1 and every 2 cycles thereafter through 6 months following last dose of study drug. Each cycle is 28 days in length. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome