A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 and/or Ras Mutations

Study Overview
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Brief Summary
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This is a Phase 1/2a dose-escalation study of E6201, a dual mitogen-activated protein kinase/extracellular-signal regulated kinase 1 (MEK1) and FMS-like tyrosine kinase 3 (FLT3) inhibitor, in subjects with advanced hematologic malignancies with documented FLT3 and/or rat sarcoma (Ras) mutations. The Phase1 portion of the study will be a safety run-in (up to 30 subjects) to establish a recommended Phase 2 dose (RP2D). The Ph. 2a portion of the study will evaluate three specific patients groups: Cohort 1 will enroll patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure to a FLT3 inhibitor; Cohort 2 will enroll patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3 inhibitor; Cohort 3 will enroll patients with relapsed or refractory AML with a confirmed Ras mutation and no FLT3 mutation.

Detailed Description
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Phase 1 (Safety Run-In): Following Screening, a total of up to 30 subjects in up to 5 dose cohorts to establish the RP2D. The safety run-in phase will be a standard 3+3 cohort design. Phase 2a (Expansion): Once the Phase 1 Safety Run-In portion of the study is complete and an RP2D is established, additional subjects will be enrolled into the Phase 2 Expansion portion in three cohorts. Cohort 1 will enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure to a FLT3 inhibitor. Cohort 2 will enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3 inhibitor. Cohort 3 will enroll up to 10 patients with relapsed or refractory AML with a confirmed Ras mutation and no FLT3 mutation. Cohort 1 and 2 of the Expansion Phase will incorporate a Simon 2-stage optimal design. Subjects with AML enrolled in the Phase 1 portion of the study at the RP2D will count towards the Phase 2a accrual for the appropriate cohort. Subjects will receive E6201 weekly or bi-weekly on a 28-day schedule, with the schedule and dose level established in the Safety Run-In portion of the study. Disease assessments, including analysis of blood and bone marrow samples, will be performed at the end of Cycles 1 and 3 and every 2 cycles thereafter. Disease assessments may be made at other time points at the discretion of the Investigator. Subjects who demonstrate clinical benefit (objective response or stable disease) will be allowed to continue therapy with E6201 until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the patient's condition that prevents further study participation. During the study, ECGs will be performed, blood will be collected for hematology, serum chemistry, pharmacokinetics and pharmacodynamics assessments, and bone marrow will be collected for the assessment of disease response and mutational status.

Official Title
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A Phase 1/2a Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 and/or Ras Mutations, Including Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Conditions
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AML, MDS, CMML

Intervention / Treatment
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* Drug: E6201


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ≥ 18 years of age Phase 1: Confirmed relapsed or refractory AML with a documented FLT3 and/or Ras mutation, or ≥ 60 years with newly diagnosed FLT3+ and/or Ras+ AML and not eligible for standard induction chemotherapy or FLT3+ and/or Ras+ higher-risk MDS/CMML (defined as ≥ 10% marrow blasts or ≥ 5% peripheral blood blasts or Revised International Prognostic Scoring System [IPSS-R] score ≥ 3.5) and relapsed or refractory to prior therapy Phase 2: Confirmed relapsed or refractory AML with a documented FLT3 and/or Ras mutation, or age ≥ 60 years with newly diagnosed FLT3+ and/or Ras+ AML and not eligible for standard induction chemotherapy At least 3 weeks beyond the last cancer treatment for the disease under study, major surgery and recovered from all acute toxicities (≤ Grade 1) by first dose of study drug (C1D1). Hydroxyurea used to control peripheral blast counts is permitted during the first 2 cycles. Adequate performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2 Adequate renal and hepatic function: creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance ≥ 45 mL/minute total bilirubin ≤ 2 times the upper limit of normal (ULN) unless due to Gilbert's disease or thought to be due to underlying AML ALT and AST ≤ 5 times ULN Negative serum pregnancy test within 14 days prior to the first dose of study therapy for women of child-bearing potential (WCBP). Sexually active WCBP and male subjects must agree to use adequate methods to avoid pregnancy throughout the study and for 28 days after completion of study treatment. Ability to provide written informed consent Exclusion Criteria: History of clinically significant cardiac impairment, congestive heart failure (CHF) New York Heart Association (NYHA) Class III or IV, unstable angina, or myocardial infarction during the previous 6 months, or serious cardiac arrhythmia QT interval corrected for rate (QTc) ≥ 450 msec for males and ≥ 460 msec for females on the ECG obtained at Screening using Fridericia method for QTc calculation (average of 3 readings) Concomitant medication(s) that may cause QTc prolongation or induce Torsades de Pointes with the exception of anti-microbials 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. However, if such medications are deemed to be necessary during the study, more extensive ECG monitoring will be added during the period of concomitant drug administration. 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 human immunodeficiency virus (HIV), hepatitis B virus surface antigen (HBsAg), or hepatitis C virus HCV) Active, uncontrolled infection Known hypersensitivity to any study drug component History of another malignancy; Exception: Patients disease-free for 2 years or treated in situ carcinoma Any other medical intervention or other condition which, in the opinion of the Principal Investigator, could compromise adherence to study requirements or confound the interpretation of study results Pregnancy or lactation

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E6201 240 mg/m^2 IV weekly<br>E6201 240 mg/m^2 administered IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) | Drug: E6201<br>* Single Group Assignment<br>* Other names: Dual inhibitor of FLT3 and MEK1;|
| Experimental: E6201 320 mg/m^2 IV weekly<br>E6201 320 mg/m^2 administered IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle) | Drug: E6201<br>* Single Group Assignment<br>* Other names: Dual inhibitor of FLT3 and MEK1;|
| Experimental: E6201 160 mg/m^2 IV twice weekly<br>E6201 160 mg/m^2 administered IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) | Drug: E6201<br>* Single Group Assignment<br>* Other names: Dual inhibitor of FLT3 and MEK1;|
| Experimental: E6201 240 mg/m^2 IV twice weekly<br>E6201 240 mg/m^2 administered IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle) | Drug: E6201<br>* Single Group Assignment<br>* Other names: Dual inhibitor of FLT3 and MEK1;|
| Experimental: E6201 320 mg/m^2 IV twice weekly<br>E6201 320 mg/m^2 administered IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22, and 25, repeated every 28 days (= 1 cycle) | Drug: E6201<br>* Single Group Assignment<br>* Other names: Dual inhibitor of FLT3 and MEK1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of E6201 | Phase 1 (Safety Run-In) was conducted in 5 dose cohorts in up to 30 subjects in a standard 3+3 dose-escalation design to establish an MTD and recommended Phase 2 dose (RP2D). Safety assessed through the monitoring of adverse events (AEs), serious adverse events (SAEs), clinical laboratory parameters (hematology and serum chemistry), vital sign measurements, electrocardiograms (ECGs) and physical examinations. | Up to 6 weeks for each dose cohort | 
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | A DLT was defined as any one of the following events: prolonged myelosuppression (as defined by the National Cancer Institute [NCI] criteria specific for leukemia, i.e., marrow cellularity < 5% at ≥ 6 weeks from start of therapy without evidence of leukemia); ≥ Grade 3 non-hematologic toxicity (excluding Grade 3 nausea, vomiting or diarrhea that is adequately controlled with supportive care and resolves to ≤ Grade 2 within 48 hours, or Grade 3 electrolyte disturbances responsive to correction within 24 hours); ≥ Grade 3 liver function tests (LFTs) lasting > 7 days; treatment interruption > 14 days due to toxicity; or other important medical event. DLTs were collected to determine the MTD which is defined as the dose level below the dose at which ≥ 2 of 6 patients in a dose cohort experienced a DLT. | Up to 6 weeks for each dose cohort | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | For acute myeloid leukemia (AML): Revised Recommendations of the International Working Group (IWG) Response Criteria for AML: CR: Free of leukemia-related symptoms, absolute neutrophil count (ANC) > 1.0 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal bone marrow with < 5% blasts and no Auer rods. CRi: As per CR but w/ residual thrombocytopenia (platelet count <100 x 10^9/L) or residual neutropenia (ANC <1.0 x 10^9/L). PR: ≥50% decrease bone marrow blasts to 5 - 25% abnormal cells, or CR w/ ≤ 5% blasts if Auer rods present. For myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML): Modified IWG Response Criteria for MDS: CR: Free of leukemia-related symptoms, ANC ≥1.0 x 10^9/L, platelet count ≥100 x 10^9/L, bone marrow ≤5% myeloblasts, normal maturation of all cell lines, hemoglobin ≥ 11g/dL, no blasts in the peripheral blood. PR: All CR criteria w/ ≥50% decrease in bone marrow blasts over pre-treatment, but still > 5%. | At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug | 
| Duration of Response | Length of time from the first evidence of objective response to the first evidence of progression | At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug | 
| Progression-Free Survival | Length of time from the date of first administration of study drug to the first evidence of disease progression or death, whichever is earlier | From Cycle 1 Day 1 (C1D1) until death or study closure, up to 26 months | 
| Overall Survival | Length of time from the date of first administration of study drug to the date of death from any cause | From C1D1 until death or study closure, up to 26 months | 
| Pharmacokinetic Profile of E6201 in Plasma: Cmax | Cmax: Maximum measured plasma concentration over the collection period | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. | 
| Pharmacokinetics of E6201 in Plasma: Tmax | Tmax: Time to maximum measured plasma concentration | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. | 
| Pharmacokinetic Profile of E6201 in Plasma: AUCT | Area under the plasma concentration versus time curve (AUC) to the last measurable concentration over the sampling time-interval. | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. | 
| Pharmacokinetic Profile of E6201 in Plasma: AUCI | AUCI: The area under the concentration versus time curve from time 0 to infinity | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. | 
| Pharmacokinetic Profile of E6201 in Plasma: T1/2 | T1/2: The apparent first-order elimination half-life | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. | 
| Pharmacokinetic Profile of E6201 in Plasma: CLobs | Clearance observed (CLobs): Total body clearance for extravascular administration | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. | 
| Pharmacokinetic Profile of E6201 in Plasma: VDobs | Measurement of apparent volume of distribution observed (VDobs) | Assessed at Cycle 1 Days 1 and 15, Cycle 2 Day 1, pre-dose, 5 minutes following the end of the 2-hour infusion, 2, 4, 8 and 24 hours post-infusion. Summary PK parameters for Cycle 1 Day 1 reported. | 
| Number of Participants With Suppression of pERK at 4 Hours Post-dose | phospho-ERK (pERK) in blood assessed by Western blot at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. | 
| Number of Participants With Suppression of pERK at 24 Hours Post-dose | Measurement of phospho-ERK (pERK) in blood assessed by Western blot at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. | 
| Number of Participants With Suppression of pFLT3 at 4 Hours Post-dose | phospho-FLT3 (pFLT3) in blood assessed by Western blot at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. | 
| Number of Participants With Suppression of pFLT3 at 24 Hours Post-dose | phospho-FLT3 (pFLT3) in blood assessed by Western blot at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. | 
| Number of Participants With Suppression of pAKT at 4 Hours Post-dose | phospho-AKT (pAKT) in blood assessed by Western blot at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. | 
| Number of Participants With Suppression of pAKT at 24 Hours Post-dose | phospho-AKT (pAKT) in blood assessed by Western blot at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. | 
| Number of Participants With Suppression of pERK by PIA at 4 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pERK in blood at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. | 
| Number of Participants With Suppression of in pERK by PIA 24 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pERK in blood at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. | 
| Number of Participants With Suppression of pFLT3 by PIA at 4 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pFLT3 in blood at 4 hours post-dose | Cycle 1 Day 1, 4 hours post-dose. | 
| Number of Participants With Suppression of pFLT3 by PIA at 24 Hours Post-dose | Blood assay: Plasma inhibitory assay (PIA) measuring pFLT3 in blood at 24 hours post-dose | Cycle 1 Day 1, 24 hours post-dose. |