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

Phase 1

Completed

Conditions: Acute Myelogenous Leukemia
Myelodysplastic Syndrome
Acute Myeloid Leukemia

Interventions: Drug: FT-2102 (olutasidenib)
Drug: Azacitidine
Drug: Cytarabine

Registration Number: NCT02719574

Lead Sponsor: Forma Therapeutics, Inc.

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 336

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PH1 Dose Escalation & Expansion FT-2102 (olutasidenib)	FT-2102 (olutasidenib)	-
PH2 Cohort 6 FT-2102 (olutasidenib)+Azacitidine	FT-2102 (olutasidenib)	R/R AML/MDS that have been previously treated with single-agent FT-2102 as their last therapy prior to study enrollment
PH1 Esc. and Exp. FT-2102 (olutasidenib)+Azacitidine	FT-2102 (olutasidenib)	-
PH1 Esc. and Exp. FT-2102 (olutasidenib)+Cytarabine	FT-2102 (olutasidenib)	-
PH2 Cohort 1 FT-2102 (olutasidenib) Single Agent	FT-2102 (olutasidenib)	Relapsed or Refractory (R/R) AML
PH2 Cohort 2 FT-2102 (olutasidenib) Single Agent	FT-2102 (olutasidenib)	AML in morphologic complete remission or complete remission with incomplete blood count recovery (CR/CRi) after prior therapy with residual IDH1-R132 mutation
PH2 Cohort 3 FT-2102 (olutasidenib) Single Agent	FT-2102 (olutasidenib)	R/R AML/MDS, previously treated with FT-2102
PH2 Cohort 4 FT-2102 (olutasidenib)+Azacitidine	FT-2102 (olutasidenib)	R/R AML/MDS that are naïve to prior hypomethylating therapy and IDH1 inhibitor therapy
PH2 Cohort 5 FT-2102 (olutasidenib)+Azacitidine	FT-2102 (olutasidenib)	R/R AML/MDS that have inadequately responded to or have progressed on prior hypomethylating therapy
PH2 Cohort 7 FT-2102 (olutasidenib) Single Agent	FT-2102 (olutasidenib)	Treatment naïve AML for whom standard treatments are contraindicated
PH2 Cohort 8 FT-2102 (olutasidenib)+Azacitidine	FT-2102 (olutasidenib)	Treatment naïve AML who are candidates for azacitidine first line treatment
PH1 Esc. and Exp. FT-2102 (olutasidenib)+Azacitidine	Azacitidine	-
PH1 Esc. and Exp. FT-2102 (olutasidenib)+Cytarabine	Cytarabine	-
PH2 Cohort 4 FT-2102 (olutasidenib)+Azacitidine	Azacitidine	R/R AML/MDS that are naïve to prior hypomethylating therapy and IDH1 inhibitor therapy
PH2 Cohort 6 FT-2102 (olutasidenib)+Azacitidine	Azacitidine	R/R AML/MDS that have been previously treated with single-agent FT-2102 as their last therapy prior to study enrollment
PH2 Cohort 5 FT-2102 (olutasidenib)+Azacitidine	Azacitidine	R/R AML/MDS that have inadequately responded to or have progressed on prior hypomethylating therapy
PH2 Cohort 8 FT-2102 (olutasidenib)+Azacitidine	Azacitidine	Treatment naïve AML who are candidates for azacitidine first line treatment

Primary Outcome Measures

Name	Time	Method
Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Phase 1: From start of drug administration (Day 1) up to 28 days after last dose of study drug (up to 82 months)	A TEAE was defined as an adverse event (AE) that emerges during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, or is life-threatening, or requires inpatient hospitalization or causes prolongation of existing hospitalization results in persistent or significant disability/incapacity, or may have caused a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. Number of participants with TEAEs and SAEs is reported. Safety analysis set (SAS) included all the participants who have received at least one dose of study drug (FT-2102, azacitidine, or cytarabine).
Phase 1: Number of Participants With Change From Baseline in Clinically Significant Abnormal Laboratory Values	Phase 1: From Baseline up to 28 days after last dose of study drug (up to 82 months)	Number of participants with change from baseline in clinically significant abnormal laboratory values for hematology, chemistry and coagulation with Grade \<1 to 4 is reported. National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 toxicity grade used to determine severity of AE. Grade 1: mild;asymptomatic/mild symptoms; Grade 2: moderate; minimal; Grade 3: severe/medically significant; Grade 4: life-threatening consequences, Grade 5: death.
Phase 1: Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG)	Phase 1: From Baseline up to 28 days after last dose of study drug (up to 82 months)	Number of participants with change from baseline in clinically significant abnormal ECG parameter (QTcF) is reported. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate.
Phase 2, Cohort 1: Percentage of Participants With Complete Remission (CR) Plus Complete Remission With Partial Hematological Recovery (CRh) for Acute Myeloid Leukemia Assessed by Investigator Based on International Working Group (IWG) Response Criteria	Phase 2: up to 3 weeks post last dose of study drug or until the introduction of new anticancer therapy, whichever is earlier (up to 82 months)	Percentage of participants with CR plus CRh (CR, Molecular CR \[CRm\], Cytogenetic CR \[CRc\], CRh) is re-ported. CR is defined as bone marrow blasts less than (\<) 5 percent (%) (in aspirate with spicules and 200 nucleated cells), no blasts with auer rods, no extramedullary disease, absolute neutrophil count (ANC) greater than or equal to (\>=) 1000/μL, platelet count \>=100,000/μL and transfusion independ-ence. CRc is defined as CR with no residual cytogenetic abnormalities. CRm is defined as CR with unde-tectable IDH1m minimal residual disease (MRD) and CRh is defined as bone marrow blasts and partial recovery of peripheral blood counts (platelet count \>50 × 10\^9/L and ANC \> 0.5 × 10\^9/L).
Phase 2, Cohort 3, 4, 5, 6, 7, 8: Percentage of Participants With CR Plus CRh for Acute Myeloid Leukemia Assessed by Investigator Based on IWG Response Criteria	Phase 2: up to 3 weeks post last dose of study drug or until the introduction of new anticancer therapy, whichever is earlier (up to 82 months)	Percentage of participants with CR plus CRh (CR, Molecular CR \[CRm\]), Cytogenetic CR \[CRc\], CRh) is re-ported. CR is defined as bone marrow blasts \<5 % (in aspirate with spicules and 200 nucleated cells), no blasts with auer rods, no extramedullary disease, ANC \>=1000/μL, platelet count \>=100,000/μL and transfusion independ-ence. CRc is defined as CR with no residual cytogenetic abnormalities. CRm is de-fined as CR with undetectable IDH1m MRD and CRh is defined as bone marrow blasts and partial recovery of peripheral blood counts (platelet count \>50 × 10\^9/L and ANC \> 0.5 × 10\^9/L).
Phase 2, Cohort 4 and 5: Percentage of Participants With CR for MDS Assessed by IWG Response Criteria	Phase 2: up to 3 weeks post last dose of study drug or until the introduction of new anticancer therapy, whichever is earlier (up to 82 months)	Percentage of participants with complete remission (CR) is reported. CR is defined as bone marrow blast ≤ 5% myeloblasts with normal maturation of all cell lines, peripheral blood: Hgb ≥11 grams per deciliter (g/dL), platelets ≥ 100 × 10\^9/L, neutrophils ≥ 1.0 × 10\^9/L and blasts 0%.
Phase 2, Cohort 2: Four-month Relapse Free Survival (RFS) Rate	Phase 2: From the date of first dose until relapse or death from any cause, whichever occurs first (up to 4 months)	RFS is defined as the time between the date of first dose until relapse or death from any cause, whichever occurs first. RFS is calculated for all participants in Phase 2 Cohort 2. 4-Month RFS rate is defined as the percentage of participants in Phase 2 Cohort 2 who have not relapsed or died on or before their 4-month response evaluation.

Secondary Outcome Measures

Name	Time	Method
Phase 1: Area Under the Curve (AUClast) for FT-2102	Phase 1: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)	Area under the plasma concentration-time curve from zero time until the last measurable concentration is presented.
Phase 1: Maximum Plasma Concentration (Cmax) for FT-2102	Phase 1: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)	Maximum plasma concentration (Cmax) for FT-2102 is presented.
Phase 1: Time to Maximum Plasma Concentration (Tmax) for FT-2102	Phase 1: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)	Time to reach the maximum plasma concentration (Tmax) is presented.
Phase 1: Time to Response (TTR) for AML	Phase 1: Time from first dose of study drug until documentation of the first overall response (up to 82 months)	TTR is the time in months between the first dose of study drug and documentation of the first overall response for participants who achieve a PR or better. This analysis was performed only on participants who have achieved PR or better as a best overall response.
Phase 1: Time to Response (TTR ) for MDS	Phase 1: Time from first dose of study drug until documentation of the first overall response (up to 82 months)	TTR is the time in months between the first dose of study drug and documentation of the first overall response for participants who achieve a PR or better. This analysis was performed only on participants who have achieved PR or better as a best overall response.
Phase 2: Time to Response (TTR) for Acute Myeloid Leukemia (AML)	Phase 2: Time from first dose of study drug until documentation of the first overall response (up to 82 months)	TTR is the time in months between the first dose of study drug and documentation of the first overall response for participants who achieve a PR or better. This analysis was performed only on participants who have achieved PR or better as a best overall response.
Phase 2: Duration of Overall Response for Acute Myeloid Leukemia (AML)	Phase 2: From the date of the first response to the date of the relapse or death (up to 82 months)	Duration of overall response is defined as the time from the date of the first response to the date of the relapse or death. The estimation of median duration of overall response was done by Kaplan-Meier method.
Phase 2, Cohort 4 and Cohort 5: Time to Response (TTR) for Myelodysplastic Syndrome (MDS)	Phase 2: Time from first dose of study drug until documentation of the first overall response (up to 82 months)	TTR is the time in months between the first dose of study drug and documentation of the first overall response for participants who achieve a PR or better. This analysis was performed only on participants who have achieved PR or better as a best overall response.
Phase 2, Cohort 4 and Cohort 5: Duration of Overall Response for Myelodysplastic Syndrome (MDS)	Phase 2: From the documentation of the first response of PR or better until the date of relapse, death, whichever is earlier (up to 82 months)	Duration of overall response was calculated similarly to DCR but was assessed the time in months between documentation of the first response of PR or better until the date of relapse, death, whichever is earlier. The estimation of median duration of overall response was done by Kaplan-Meier method. The median duration of overall response is defined as the time at which 50% of the participants in a study have experienced the event of interest (relapse or death). Given the presence of only a single participant in the sample, there is an absence of variability in outcomes, and therefore, it was not possible to ascertain a time point at which half of the participants have experienced the event. Hence, median value could not be calculated.
Phase 2, Cohort 2: Time to Relapse-Free Survival (RFS)	Phase 2: From the date of first dose until relapse or death from any cause, whichever occurs first (up to 82 months)	RFS was calculated for all participants in Phase 2 Cohort 2. RFS is defined as the time (in months) between the date of first dose until relapse or death from any cause, whichever occurs first. Relapse free survival time to event is reported for all participants in Cohort 2.
Phase 2: Overall Survival (OS)	Phase 2: From first dose of study drug until death from any cause (up to 82 months)	OS is defined as the time in months from the first dose of study drug until death from any cause. For the participants who are not known to have died by the end of study follow-up, OS will be censored on the date the participants was last known to be alive. OS is calculated using Kaplan-Meier method.
Phase 2: Event-free Survival (EFS)	Phase 2: From first dose of study drug to disease progression, relapse, death from any cause, treatment failure, or start of other (non-protocol study drug) new antileukemia therapy (up to 82 months)	EFS is defined as the time in months between first dose of study drug and disease progression, relapse, death from any cause, treatment failure, or start of other (non-protocol study drug) new antileukemia therapy, whichever occurs first.
Phase 2: Transfusion Independence	Phase 2: From baseline (8 weeks prior to first dose) up to treatment period (up to 82 months)	Transfusion independence is defined as the number of participants who experience at least a 56-day period during any point on treatment without requiring a transfusion of RBC and/or platelet transfusion. Participants are classified as either "dependent" or "independent" at baseline based on their transfusion history. Those who received either platelets or pRBC or both within 8 weeks prior to the first dose of FT-2102 are considered "dependent". Number of participants with transfusion independent is reported here.
Phase 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Phase 2: From start of drug administration (Day 1) up to 28 days after last dose of study drug (up to 82 months)	A TEAE was defined as an AE that emerges during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. A SAE is defined as any untoward medical occur-rence that at any dose results in death, or is life-threatening, or requires inpatient hospitalization or causes prolongation of existing hospitalization results in persistent or significant disability/incapacity, or may have caused a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. Number of participants with TEAEs and SAEs is reported.
Phase 1: Duration of Overall Response for AML	Phase 1: From date of the first response to the date of the relapse or death (up to 82 months)	Duration of response is defined as the time from the date of the first response to the date of the relapse or death. The estimation of median duration of overall response was done by Kaplan-Meier method.
Phase 2: Number of Participants With Change From Baseline in Clinically Significant Abnormal Laboratory Values	Phase 2: From Baseline up to 28 days after last dose of study drug (up to 82 months)	Number of participants with change from baseline in clinically significant abnormal laboratory values for hematology, chemistry and coagulation with Grade \<1 to 4 is reported. National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 toxicity grade used to determine severity of AE. Grade 1: mild;asymptomatic/mild symptoms; Grade 2: moderate; minimal; Grade 3: severe/medically significant; Grade 4: life-threatening consequences, Grade 5: death.
Phase 2: Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG)	Phase 2: From Baseline up to 28 days after last dose of study drug (up to 82 months)	Number of participants with change from baseline in clinically significant abnormal ECG parameter (QTcF) is reported. QT interval was the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTcF was the QT interval corrected for heart rate using Fridericia's formula: QTcF = QT divided by cube root of 60/heart rate.
Phase 2: Area Under the Curve (AUClast) for FT-2102	Phase 2: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)	Area under the plasma concentration-time curve from zero time until the last measurable concentration is presented.
Phase 2: Maximum Plasma Concentration (Cmax) for FT-2102	Phase 2: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)	Maximum Plasma Concentartion (Cmax) for FT-2102 is presented.
Phase 2: Time to Maximum Plasma Concentration (Tmax) for FT-2102	Phase 2: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)	Time to reach the maximum plasma concentration (Tmax) for FT-2102 is presented.

Trial Locations

Locations (60): UCLA Medical Center
🇺🇸
Los Angeles, California, United States
UC Davis Comprehensive Cancer Center
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Sacramento, California, United States
Yale University
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New Haven, Connecticut, United States
University of Miami
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Miami, Florida, United States
Emory Winship Cancer Institute
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Atlanta, Georgia, United States
Northwestern University Feinberg School of Medicine
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Chicago, Illinois, United States
University of Maryland Greenebaum Cancer Center
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Baltimore, Maryland, United States
Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Roswell Park Cancer Institute
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Buffalo, New York, United States
New York Medical College
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Hawthorne, New York, United States
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UCLA Medical Center
🇺🇸Los Angeles, California, United States