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

Phase 1

Terminated

Conditions: AML
MDS
CMML

Interventions: Drug: E6201

Registration Number: NCT02418000

Lead Sponsor: Spirita Oncology, LLC

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 27

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
E6201 240 mg/m^2 IV twice weekly	E6201	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)
E6201 320 mg/m^2 IV twice weekly	E6201	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)
E6201 240 mg/m^2 IV weekly	E6201	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)
E6201 160 mg/m^2 IV twice weekly	E6201	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)
E6201 320 mg/m^2 IV weekly	E6201	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)

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)	Up to 6 weeks for each dose cohort	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.
Maximum Tolerated Dose (MTD) of E6201	Up to 6 weeks for each dose cohort	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.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic Profile of E6201 in Plasma: T1/2	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.	T1/2: The apparent first-order elimination half-life
Number of Participants With Suppression of pERK at 4 Hours Post-dose	Cycle 1 Day 1, 4 hours post-dose.	phospho-ERK (pERK) in blood assessed by Western blot at 4 hours post-dose
Number of Participants With Suppression of pFLT3 at 4 Hours Post-dose	Cycle 1 Day 1, 4 hours post-dose.	phospho-FLT3 (pFLT3) in blood assessed by Western blot at 4 hours post-dose
Number of Participants With Suppression of pFLT3 at 24 Hours Post-dose	Cycle 1 Day 1, 24 hours post-dose.	phospho-FLT3 (pFLT3) in blood assessed by Western blot at 24 hours post-dose
Duration of Response	At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug	Length of time from the first evidence of objective response to the first evidence of progression
Progression-Free Survival	From Cycle 1 Day 1 (C1D1) until death or study closure, up to 26 months	Length of time from the date of first administration of study drug to the first evidence of disease progression or death, whichever is earlier
Overall Survival	From C1D1 until death or study closure, up to 26 months	Length of time from the date of first administration of study drug to the date of death from any cause
Pharmacokinetics of E6201 in Plasma: Tmax	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.	Tmax: Time to maximum measured plasma concentration
Pharmacokinetic Profile of E6201 in Plasma: AUCT	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.	Area under the plasma concentration versus time curve (AUC) to the last measurable concentration over the sampling time-interval.
Pharmacokinetic Profile of E6201 in Plasma: AUCI	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.	AUCI: The area under the concentration versus time curve from time 0 to infinity
Pharmacokinetic Profile of E6201 in Plasma: CLobs	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.	Clearance observed (CLobs): Total body clearance for extravascular administration
Pharmacokinetic Profile of E6201 in Plasma: 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.	Measurement of apparent volume of distribution observed (VDobs)
Number of Participants With Suppression of pAKT at 4 Hours Post-dose	Cycle 1 Day 1, 4 hours post-dose.	phospho-AKT (pAKT) in blood assessed by Western blot at 4 hours post-dose
Overall Response Rate	At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug	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%.
Number of Participants With Suppression of pERK at 24 Hours Post-dose	Cycle 1 Day 1, 24 hours post-dose.	Measurement of phospho-ERK (pERK) in blood assessed by Western blot at 24 hours post-dose
Pharmacokinetic Profile of E6201 in Plasma: Cmax	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.	Cmax: Maximum measured plasma concentration over the collection period
Number of Participants With Suppression of pAKT at 24 Hours Post-dose	Cycle 1 Day 1, 24 hours post-dose.	phospho-AKT (pAKT) in blood assessed by Western blot at 24 hours post-dose
Number of Participants With Suppression of pERK by PIA at 4 Hours Post-dose	Cycle 1 Day 1, 4 hours post-dose.	Blood assay: Plasma inhibitory assay (PIA) measuring pERK in blood at 4 hours post-dose
Number of Participants With Suppression of in pERK by PIA 24 Hours Post-dose	Cycle 1 Day 1, 24 hours post-dose.	Blood assay: Plasma inhibitory assay (PIA) measuring pERK in blood at 24 hours post-dose
Number of Participants With Suppression of pFLT3 by PIA at 4 Hours Post-dose	Cycle 1 Day 1, 4 hours post-dose.	Blood assay: Plasma inhibitory assay (PIA) measuring pFLT3 in blood at 4 hours post-dose
Number of Participants With Suppression of pFLT3 by PIA at 24 Hours Post-dose	Cycle 1 Day 1, 24 hours post-dose.	Blood assay: Plasma inhibitory assay (PIA) measuring pFLT3 in blood at 24 hours post-dose

Trial Locations

Locations (4): Texas Transplant Institute
🇺🇸
San Antonio, Texas, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
H. Lee Moffitt Cancer Center & research Institute
🇺🇸
Tampa, Florida, United States
Colorado Blood Cancer Institute
🇺🇸
Denver, Colorado, United States