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

Phase 2CompletedNCT02719574

Forma Therapeutics, Inc.336 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

336

Conditions

Acute Myeloid Leukemia Acute Myelogenous Leukemia Myelodysplastic Syndrome

Interventions

FT-2102 (olutasidenib)DRUG

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

AzacitidineDRUG

azacitidine will be administered per site's standard of care

CytarabineDRUG

low-dose cytarabine will be administered per site's standard of care

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (60)

UCLA Medical Center

Los Angeles, California, United States

UC Davis Comprehensive Cancer Center

Sacramento, California, United States

Yale University

New Haven, Connecticut, United States

University of Miami

Miami, Florida, United States

Emory Winship Cancer Institute

Atlanta, Georgia, United States

Outcomes

Primary Outcomes

Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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).

Time frame: Phase 1: From start of drug administration (Day 1) up to 28 days after last dose of study drug (up to 82 months)

Phase 1: Number of Participants With Change From Baseline in Clinically Significant Abnormal Laboratory Values

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.

Time frame: Phase 1: From Baseline up to 28 days after last dose of study drug (up to 82 months)

Phase 1: Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG)

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.

Time frame: Phase 1: From Baseline up to 28 days after last dose of study drug (up to 82 months)

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

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).

Time frame: 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)

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

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).

Time frame: 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)

Phase 2, Cohort 4 and 5: Percentage of Participants With CR for MDS Assessed by IWG Response Criteria

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%.

Time frame: 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)

Phase 2, Cohort 2: Four-month Relapse Free Survival (RFS) Rate

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.

Time frame: Phase 2: From the date of first dose until relapse or death from any cause, whichever occurs first (up to 4 months)

Secondary Outcomes

Phase 1: Area Under the Curve (AUClast) for FT-2102

Area under the plasma concentration-time curve from zero time until the last measurable concentration is presented.

Time frame: Phase 1: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)

Phase 1: Maximum Plasma Concentration (Cmax) for FT-2102

Maximum plasma concentration (Cmax) for FT-2102 is presented.

Time frame: Phase 1: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)

Phase 1: Time to Maximum Plasma Concentration (Tmax) for FT-2102

Time to reach the maximum plasma concentration (Tmax) is presented.

Time frame: Phase 1: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)

Phase 1: Time to Response (TTR) for AML

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.

Time frame: Phase 1: Time from first dose of study drug until documentation of the first overall response (up to 82 months)

Phase 1: Duration of Overall Response for AML

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.

Time frame: Phase 1: From date of the first response to the date of the relapse or death (up to 82 months)

Phase 1: Time to Response (TTR ) for MDS

Time frame: Phase 1: Time from first dose of study drug until documentation of the first overall response (up to 82 months)

Data from ClinicalTrials.gov

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Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

University of Maryland Greenebaum Cancer Center

Baltimore, Maryland, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

New York Medical College

Hawthorne, New York, United States

...and 50 more locations

Phase 2: Time to Response (TTR) for Acute Myeloid Leukemia (AML)

Time frame: Phase 2: Time from first dose of study drug until documentation of the first overall response (up to 82 months)

Phase 2: Duration of Overall Response for Acute Myeloid Leukemia (AML)

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.

Time frame: Phase 2: From the date of the first response to the date of the relapse or death (up to 82 months)

Phase 2, Cohort 4 and Cohort 5: Time to Response (TTR) for Myelodysplastic Syndrome (MDS)

Time frame: Phase 2: Time from first dose of study drug until documentation of the first overall response (up to 82 months)

Phase 2, Cohort 4 and Cohort 5: Duration of Overall Response for Myelodysplastic Syndrome (MDS)

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.

Time frame: 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)

Phase 2, Cohort 2: Time to Relapse-Free Survival (RFS)

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.

Time frame: Phase 2: From the date of first dose until relapse or death from any cause, whichever occurs first (up to 82 months)

Phase 2: Overall Survival (OS)

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.

Time frame: Phase 2: From first dose of study drug until death from any cause (up to 82 months)

Phase 2: Event-free Survival (EFS)

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.

Time frame: 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)

Phase 2: Transfusion Independence

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.

Time frame: Phase 2: From baseline (8 weeks prior to first dose) up to treatment period (up to 82 months)

Phase 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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.

Time frame: Phase 2: From start of drug administration (Day 1) up to 28 days after last dose of study drug (up to 82 months)

Phase 2: Number of Participants With Change From Baseline in Clinically Significant Abnormal Laboratory Values

Time frame: Phase 2: From Baseline up to 28 days after last dose of study drug (up to 82 months)

Phase 2: Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG)

Time frame: Phase 2: From Baseline up to 28 days after last dose of study drug (up to 82 months)

Phase 2: Area Under the Curve (AUClast) for FT-2102

Area under the plasma concentration-time curve from zero time until the last measurable concentration is presented.

Time frame: Phase 2: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)

Phase 2: Maximum Plasma Concentration (Cmax) for FT-2102

Maximum Plasma Concentartion (Cmax) for FT-2102 is presented.

Time frame: Phase 2: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)

Phase 2: Time to Maximum Plasma Concentration (Tmax) for FT-2102

Time to reach the maximum plasma concentration (Tmax) for FT-2102 is presented.

Time frame: Phase 2: Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle length= 28 days)