Study of a Novel BET Inhibitor FT-1101 in Patients With Relapsed or Refractory Hematologic Malignancies

Study Overview
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Brief Summary
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This is an open-label, multicenter, dose-escalation Phase 1/1b study in patients with acute myelogenous leukemia (AML)/MDS or non-Hodgkin Lymphoma (NHL), intended to investigate safety, pharmacokinetics, and the pharmacodynamic effects of FT-1101 administered via one or more intermittent dosing schedules alone and in combination with azacitidine. Once the MTD has been established for a treatment cohort, up to 20 additional patients may be enrolled in up to 4 expansion cohorts each of select populations of patients with either AML/MDS or NHL at the recommended dose for future studies to confirm safety.

Official Title
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A Phase 1/1b Dose Escalation, Multicenter, Open-label, Safety, Pharmacokinetic and Pharmacodynamic Study of FT-1101 as a Single Agent and in Combination With Azacitidine in Patients With Relapsed or Refractory Hematologic Malignancies

Conditions
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Acute Myeloid Leukemia, Acute Myelogenous Leukemia, Myelodysplastic Syndrome, Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: FT-1101
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Single agent (SA) Dose Escalation: Histologically or cytologically proven acute leukemia or high-risk MDS as defined by the World Health Organization (WHO) criteria and IPSS-R, respectively, that is relapsed or refractory (R/R) to standard therapy or for whom standard treatments are contraindicated, OR Mature B-Cell non-Hodgkin Lymphoma that is Relapsed/Refractory to standard therapy AML SA expansion group 1: histologically or cytologically proven AML with a FLT3 ITD or TKD mutation previously determined by local testing that is R/R to standard therapy or for whom standard treatments are contraindicated AML SA expansion group 2: histologically or cytologically proven AML with intermediate or unfavorable risk cytogenetics in the absence of a detectable FLT3 ITD or TKD mutation as previously determined by local testing that is R/R to standard therapy or for whom standard treatments are contraindicated NHL SA expansion: Mature B-cell NHL with the following histologies: primary mediastinal lymphoma, DLBCL, and B-cell lymphoma not specified that is R/R to standard therapy and for whom standard treatments are contraindicated or unavailable AML/MDS combination treatment (dose escalation and expansion): histologically or cytologically proven AML or MDS as defined by WHO criteria and IPSS-R, respectively, that is: R/R to standard therapy, or AML: who are unfit for, or unwilling to receive standard induction therapy, or MDS: eligible to receive azacitidine Patients ≥ 18 years old Good kidney and liver function No prior organ allograft For fertile men and women, agreement to use effective contraceptive methods duration of study participation and 90 days after Key Exclusion Criteria: History of prior malignancy unless disease free for > or equal to 12 months or considered surgically cured. Patients with symptomatic central nervous system (CNS) metastases or other tumor location (such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.) necessitating an urgent therapeutic intervention, palliative care, surgery or radiation therapy Treatment with major surgery (requiring general anesthesia) within one month prior to study entry Previous treatment with any prior BET inhibitor therapy Patients unable to swallow oral medications, or patients with gastrointestinal conditions (e.g. malabsorption, gastric or small bowel resection, etc.) deemed to jeopardize intestinal absorption Congestive heart failure (New York Heart Association Class III or IV) or unstable angina pectoris. Previous history of myocardial infarction within 1 year prior to study entry, uncontrolled hypertension or uncontrolled arrhythmias Pulmonary disease (e.g. COPD, asthma, etc) that is not controlled (moderate to severe symptoms) with current medication Known HIV positivity Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation FT-1101<br>Following a 3+3 dose escalation strategy, the first cohort of patients will be administered FT-1101 at 10 mg, oral capsules, once weekly on a continuous basis. Subsequent cohorts dose and frequency will be determined by investigators and sponsor following observations of previous cohorts. Dose escalation will continue until the MTD is determined. | Drug: FT-1101<br>* FT-1101 will be supplied as 5 mg, 20 mg or 100 mg capsules and will be administered per the protocol defined frequency and dose level<br>* Other names: FT1101;|
| Experimental: Dose Expansion FT-1101<br>Once the MTD is determined, the Recommended Phase 2 Dose (RP2D) will be identified. 3 Expansion cohorts of up to 20 patients each will be treated with the RP2D of FT-1101 | Drug: FT-1101<br>* FT-1101 will be supplied as 5 mg, 20 mg or 100 mg capsules and will be administered per the protocol defined frequency and dose level<br>* Other names: FT1101;|
| Experimental: Dose Escalation FT-1101 + azacitidine<br>Following a 3+3 dose escalation strategy, the first cohort of AML/MDS patients will be administered FT-1101 at approximately 50% or lower than the MTD identified for the single agent FT-1101. Subsequent cohorts dose will be determined by investigators and sponsor following observations of previous cohorts. Dose escalation will not exceed the dose determined to be the single agent MTD for that schedule. | Drug: FT-1101<br>* FT-1101 will be supplied as 5 mg, 20 mg or 100 mg capsules and will be administered per the protocol defined frequency and dose level<br>* Other names: FT1101;Drug: Azacitidine<br>* Azacitidine will be administered per site's standard of care<br>|
| Experimental: Dose Expansion FT-1101 + azacitidine<br>Once the MTD is determined, the Recommended Phase 2 Dose (RP2D) will be identified. 1 Expansion cohorts of up to 20 AML/MDS patients each will be treated with the RP2D of FT-1101 in combination with azacitidine. | Drug: FT-1101<br>* FT-1101 will be supplied as 5 mg, 20 mg or 100 mg capsules and will be administered per the protocol defined frequency and dose level<br>* Other names: FT1101;Drug: Azacitidine<br>* Azacitidine will be administered per site's standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) |  | Within first 4 weeks of treatment | 
| Dose Limiting Toxicities (DLT) |  | Within first 4 weeks of treatment | 
| Recommended Phase 2 Dose (RP2D) |  | Participants to be followed for duration of participation, an expected average of 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) |  | PK collected at multiple visits during the first 30 days of treatment | 
| Peak Plasma Concentration (Cmax) |  | PK collected at multiple visits during the first 30 days of treatment | 
| Time of peak plasma concentration (TMax) |  | PK collected at multiple visits during the first 30 days of treatment | 
| Time for half of the drug to be absent in blood stream following dose (T 1/2) |  | PK collected at multiple visits during the first 30 days of treatment | 
| Rate at which drug is removed from blood stream (CL/F) |  | PK collected at multiple visits during the first 30 days of treatment | 
| Rate of drug distribution within the blood stream (Vd/F) |  | PK collected at multiple visits during the first 30 days of treatment | 
| Observe patients for any evidence of anti-leukemic or anti-myelodysplastic activity of FT-1101 |  | Assessed for duration of participation, an expected average of 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, BET Inhibitor, FT-1101, Acute Leukemia, Myelodysplastic Syndrome, NHL, Non-Hodgkin Lymphoma