Open-label Study of FT-2102 With or Without Azacitidine or Cytarabine in Patients With AML or MDS With an IDH1 Mutation

Study Overview
=================
Brief Summary
-----------------
This Phase 1/2 study will evaluate the safety, efficacy, PK, and PD of FT-2102 (olutasidenib) as a single agent or in combination with azacitidine or cytarabine. The Phase 1 stage of the study is split into 2 distinct parts: a dose escalation part, which will utilize an open-label design of FT-2102 (olutasidenib) (single agent) and FT-2102 (olutasidenib) + azacitidine (combination agent) administered via one or more intermittent dosing schedules followed by a dose expansion part. The dose expansion part will enroll patients in up to 5 expansion cohorts, exploring single-agent FT-2102 (olutasidenib) activity as well as combination activity with azacitidine or cytarabine. Following the completion of the relevant Phase 1 cohorts, Phase 2 will begin enrollment. Patients will be enrolled across 8 different cohorts, examining the effect of FT-2102 (olutasidenib) (as a single agent) and FT-2102 (olutasidenib) + azacitidine (combination) on various AML/MDS disease states.

Official Title
-----------------
A Phase 1/2, Multicenter, Open-label Study of FT-2102 as a Single Agent and in Combination With Azacitidine or Cytarabine in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome With an IDH1 Mutation

Conditions
-----------------
Acute Myeloid Leukemia, Acute Myelogenous Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
-----------------
* Drug: FT-2102 (olutasidenib)
* Drug: Azacitidine
* Drug: Cytarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically proven acute myeloid leukemia (AML) (except acute promyelocytic leukemia [APL] with the t(15;17) translocation) or intermediate, high-risk, or very high risk Myelodysplastic Syndrome (MDS) as defined by the World Health Organization (WHO) criteria or Revised International Prognostic Scoring System (IPSS-R) which is relapsed or refractory (R/R) to standard therapy and/or for which standard therapy is contraindicated or which has not adequately responded to standard therapy. Patients must have documented IDH1-R132 gene-mutated disease as evaluated by the site Good performance status Good kidney and liver function Exclusion Criteria: 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 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 Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: PH1 Dose Escalation & Expansion FT-2102 (olutasidenib)<br> | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>|
| Experimental: PH1 Esc. and Exp. FT-2102 (olutasidenib)+Azacitidine<br> | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>Drug: Azacitidine<br>* azacitidine will be administered per site's standard of care<br>* Other names: Vidaza;|
| Experimental: PH1 Esc. and Exp. FT-2102 (olutasidenib)+Cytarabine<br> | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>Drug: Cytarabine<br>* low-dose cytarabine will be administered per site's standard of care<br>|
| Experimental: PH2 Cohort 1 FT-2102 (olutasidenib) Single Agent<br>Relapsed or Refractory (R/R) AML | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>|
| Experimental: PH2 Cohort 2 FT-2102 (olutasidenib) Single Agent<br>AML in morphologic complete remission or complete remission with incomplete blood count recovery (CR/CRi) after prior therapy with residual IDH1-R132 mutation | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>|
| Experimental: PH2 Cohort 3 FT-2102 (olutasidenib) Single Agent<br>R/R AML/MDS, previously treated with FT-2102 | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>|
| Experimental: PH2 Cohort 4 FT-2102 (olutasidenib)+Azacitidine<br>R/R AML/MDS that are naïve to prior hypomethylating therapy and IDH1 inhibitor therapy | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>Drug: Azacitidine<br>* azacitidine will be administered per site's standard of care<br>* Other names: Vidaza;|
| Experimental: PH2 Cohort 5 FT-2102 (olutasidenib)+Azacitidine<br>R/R AML/MDS that have inadequately responded to or have progressed on prior hypomethylating therapy | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>Drug: Azacitidine<br>* azacitidine will be administered per site's standard of care<br>* Other names: Vidaza;|
| Experimental: PH2 Cohort 6 FT-2102 (olutasidenib)+Azacitidine<br>R/R AML/MDS that have been previously treated with single-agent FT-2102 as their last therapy prior to study enrollment | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>Drug: Azacitidine<br>* azacitidine will be administered per site's standard of care<br>* Other names: Vidaza;|
| Experimental: PH2 Cohort 7 FT-2102 (olutasidenib) Single Agent<br>Treatment naïve AML for whom standard treatments are contraindicated | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>|
| Experimental: PH2 Cohort 8 FT-2102 (olutasidenib)+Azacitidine<br>Treatment naïve AML who are candidates for azacitidine first line treatment | Drug: FT-2102 (olutasidenib)<br>* FT-2102 (olutasidenib) will be supplied as 50 mg or 150 mg capsules and will be administered per the protocol defined frequency and dose level<br>Drug: Azacitidine<br>* azacitidine will be administered per site's standard of care<br>* Other names: Vidaza;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Doses (MTDs) or Maximum Evaluated Doses (MEDs) [Phase 1] |  | Within first 4 weeks of treatment | 
| Number of Participants with a Dose Limiting Toxicity (DLT) [Phase 1] |  | Within first 4 weeks of treatment | 
| Doses recommended for future studies [Phase 1] |  | Within first 4 weeks of treatment | 
| Complete Response (CR and CRh) Rate of FT-2102 (olutasidenib) single-agent or in combination with Azacitidine in patients with AML/MDS [Phase 2 Cohorts 1, 3-8] |  | As per modified IWG Response Assessment Guidelines for AML and MDS based on investigator's assessment on day 1 of each cycle through study completion | 
| 4-Month Relapse Free Survival (RFS) of FT-2102 (olutasidenib) single-agent [Phase 2 Cohort 2] |  | From time of entry on study through progression, up to 30 weeks, on average | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) [Phase 1 and Phase 2] |  | Blood samples for PK analysis collected at multiple visits during the first 60 days of treatment and on day 1 of all cycles following the first 30 days | 
| Peak Plasma Concentration (Cmax) [Phase 1 and Phase 2] |  | Blood samples for PK analysis collected at multiple visits during the first 60 days of treatment and on day 1 of all cycles following the first 30 days | 
| Time of peak plasma concentration Tmax [Phase 1 and Phase 2] |  | Blood samples for PK analysis collected at multiple visits during the first 60 days of treatment and on day 1 of all cycles following the first 30 days | 
| Time for half of the drug to be absent in blood stream following dose (T 1/2) [Phase 1 and Phase 2] |  | Blood samples for PK analysis collected at multiple visits during the first 60 days of treatment and on day 1 of all cycles following the first 30 days | 
| Rate at which drug is removed from blood stream (CL/F) [Phase 1 and Phase 2] |  | Blood samples for PK analysis collected at multiple visits during the first 60 days of treatment and on day 1 of all cycles following the first 30 days | 
| Rate of drug distribution within the blood stream (Vd/F) [Phase 1 and Phase 2] |  | Blood samples for PK analysis collected at multiple visits during the first 60 days of treatment and on day 1 of all cycles following the first 30 days | 
| Evidence of antileukemic or antimyelodysplastic activity of FT-2102 (olutasidenib) as determined by CR, CRh, CRi, MLFS, Marrow CR, PR, and SD as a single-agent or in combination with azacitidine or cytarabine [Phase 1] |  | As per modified IWG Response Assessment Guidelines for AML and MDS based on investigator's assessment on day 1 of each cycle through study completion | 
| Incidence and severity of adverse events, clinical laboratory abnormalities, and changes in ECG parameters as assessed by CTCAE v4.0 as a single-agent or in combination with azacitidine [Phase 2] |  | Safety will be assessed from time of first dose through 28 days post last dose. | 
| Additional measures of antileukemic or antimyelodysplastic activity as determined by CRi, MLFS, Marrow CR, PR, Overall Response (OR), and Stable Disease (SD) of FT-2102 (olutasidenib) alone or in combination with azacitidine [Phase 2] |  | As per modified IWG Response Assessment Guidelines for AML and MDS based on investigator's assessment on day 1 of each cycle through study completion | 
| Time to Response (TTR) [Phase 2] |  | From first dose of study drug through time of first response by blood recovery count, up to 30 weeks, on average | 
| Duration of Response (DOR) [Phase 2] |  | From time of first response by blood recovery count through relapse, up to 30 weeks, on average | 
| Event-Free Survival (EFS) [Phase 2] |  | From time of entry on study through progression, up to 30 weeks, on average | 
| Overall Survival (OS) [Phase 2] |  | From time of entry on study through death or date last known alive at end of follow-up, up to 30 weeks, on average | 
| Relapse Free Survival (RFS) [Phase 2] |  | From time of entry on study through progression, up to 30 weeks, on average | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AML, MDS, IDH1, IDH