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

NCT02418000 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: BSC-101-01
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 4

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.

Conditions

AML; MDS; CMML

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (21)

• Overall Response Rate

  At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug

• Duration of Response

  At the end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug

• Progression-Free Survival

  From Cycle 1 Day 1 (C1D1) until death or study closure, up to 26 months

• Overall Survival

  From C1D1 until death or study closure, up to 26 months

• 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.

Study Arms (5)

E6201 240 mg/m^2 IV weekly

EXPERIMENTAL

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

E6201 320 mg/m^2 IV weekly

EXPERIMENTAL

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

E6201 160 mg/m^2 IV twice weekly

EXPERIMENTAL

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

E6201 240 mg/m^2 IV twice weekly

EXPERIMENTAL

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

E6201 320 mg/m^2 IV twice weekly

EXPERIMENTAL

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

Interventions

E6201 DRUG

Single Group Assignment

Also known as: Dual inhibitor of FLT3 and MEK1

E6201 160 mg/m^2 IV twice weekly; E6201 240 mg/m^2 IV twice weekly; E6201 240 mg/m^2 IV weekly; E6201 320 mg/m^2 IV twice weekly; E6201 320 mg/m^2 IV weekly

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Spirita Oncology, LLC: lead

Study Sites (4)

Colorado Blood Cancer Institute

Denver, Colorado, 80218, United States

Location

H. Lee Moffitt Cancer Center & research Institute

Tampa, Florida, 33612, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Texas Transplant Institute

San Antonio, Texas, 78229, United States

Location

Related Links

• Responsible Party URL

MeSH Terms

Interventions

14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione

Limitations and Caveats

Although E6201 exhibited an acceptable safety profile when administered at doses up to the MTD of 320 mg/m\^2 IV twice weekly, insufficient efficacy was observed during the Phase 1 portion of the study. Thus, the Phase 2a portion was not initiated.

Results Point of Contact

• Title: Chief Development Officer
• Organization: Spirita Oncology, LLC

linda.paradiso@spiritaoncology.com

+1 (713) 898-8965

Study Officials

• Gautam Borthakur, MD

  MD Anderson Cancer Center Houston, TX 77030

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 18, 2015
• First Posted: April 16, 2015
• Study Start: April 10, 2015
• Primary Completion: June 8, 2017
• Study Completion: June 8, 2017
• Last Updated: March 20, 2019
• Results First Posted: March 5, 2019

Record last verified: 2019-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)