Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies (Zotatifin)

A Phase 1-2 Dose-Escalation and Cohort-Expansion Study of Intravenous Zotatifin (eFT226) in Subjects With Selected Advanced Solid Tumor Malignancies

This clinical trial is a Phase 1-2, open-label, sequential-group, dose-escalation and cohort-expansion study evaluating the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of Zotatifin (eFT226) in subjects with selected advanced solid tumor malignancies.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor, Adult
• Intervention / Treatment: Drug: Trastuzumab; Drug: eFT226; Drug: Fulvestrant; Drug: Sotorasib; Drug: Abemaciclib

Detailed Description

Part 1 (Dose Escalation): Completed; Recommended Phase 2 Dose (RP2D) and Maximum Tolerated Dose (MTD) identified

Part 1a (Dose Escalation) This cohort will enroll patients with an advanced breast cancer that is refractory or intolerant to SOC therapy.

Part 1b (Dose Escalation) This cohort will enroll patients with an advanced breast cancer that is refractory or intolerant to SOC therapy.

Part 2 (Expansion Cohort) provides defined expansion cohorts to further explore the safety, pharmacology, and clinical activity of eFT226 monotherapy and in various combinations in subjects with previously treated advanced solid tumor malignancies.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Mark Densel; Phone Number: 858-925-8215; Email: clinicaltrials@effector.com

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • University of Southern California
      • Principal Investigator: Anthony El-Khoueiry, MD
      • Contact: Xiomara Menendez; Phone Number: 323-409-4638; Email: menendez_x@med.usc.edu
    • Los Angeles, California, United States, 90067
      • Recruiting
      • Valkyrie Clinical Trials
      • Principal Investigator: David Berz, MD
      • Contact: Chemyn Cortez; Phone Number: 559-360-3707; Email: chemyn.cortez@valkyrieclinicaltrials.com
    • Newport Beach, California, United States, 92663
      • Completed
      • Hoag Memorial Hospital Presbyterian
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford University
      • Principal Investigator: Jennifer Caswell-Jin, MD
      • Contact: Kaushali Thakore-Shah; Email: kthakore@stanford.edu
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • Recruiting
      • Start Midwest
      • Principal Investigator: Manish Sharma, MD
      • Contact: Abigail Van Kirk; Phone Number: 1824 616-954-5550; Email: abigail.vankirk@startmidwest.com
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Completed
      • Comprehensive Cancer Centers of Nevada
  • New Jersey
    • Middletown, New Jersey, United States, 07748
      • Recruiting
      • Memorial Sloan Kettering Cancer Center- Monmouth
      • Contact: Ezra Rosen; Email: rosene1@mskcc.org
      • Contact: Colleen Wenzel; Email: WenzelC1@mskcc.org
      • Principal Investigator: Ezra Rosen, MD
  • New York
    • Commack, New York, United States, 11725
      • Recruiting
      • Memorial Sloan Kettering Cancer Center- Commack
      • Contact: Colleen Wenzel; Email: WenzelC1@mskcc.org
      • Principal Investigator: Ezra Rosen, MD
      • Contact: Ezra Rosen, MD; Email: rosene1@mskcc.org
    • Harrison, New York, United States, 10604
      • Recruiting
      • Memorial Sloan Kettering Cancer Center- Westchester
      • Contact: Ezra Rosen; Email: rosene1@mskcc.org
      • Contact: Colleen Wenzel; Email: WenzelC1@mskcc.org
      • Principal Investigator: Ezra Rosen, MD
    • New York, New York, United States, 11101
      • Recruiting
      • Memorial Sloan Kettering Cancer Center- David H. Koch Center for Cancer Care
      • Contact: Colleen Wenzel; Email: WenzelC1@mskcc.org
      • Principal Investigator: Ezra Rosen, MD
      • Contact: Ezra Rosen, MD; Email: rosene1@mskcc.org
  • Ohio
    • Toledo, Ohio, United States, 43614
      • Completed
      • University of Toledo Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
      • Principal Investigator: Funda Meric-Bernstam, MD
      • Contact: Amanda Ekert; Phone Number: 713-745-8074; Email: ACEckert@mdanderson.org
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • New Experimental Therapeutics of San Antonio - NEXT Oncology
      • Principal Investigator: David Sommerhalder, MD
      • Contact: Nicole Klein; Phone Number: 210-580-9543; Email: nklein@nextoncology.com
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Virginia Cancer Specialists
      • Principal Investigator: Alexander Spira, MD
      • Contact: Karina Castillo-Grady; Phone Number: 703-280-5390; Email: Karina.CastilloGrady@usoncology.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Criteria:

Parts 1a and 1b (Dose Escalation + Fulvestrant):

• Patient has histological or cytological confirmation of breast cancer.
• Patient has metastatic disease or locoregionally recurrent disease which is refractory or intolerant to existing therapy(ies) known to provide clinical benefit.

• Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows:

  • Minimum of one prior line of therapy for advanced/metastatic disease.
  • Maximum of five prior lines of therapy for advanced/metastatic disease.
  • Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting.
  • Prior treatment has included a CDK4/6 inhibitor.
• Tumor is ER+ (defined as ER IHC staining > 0%).

Cohort EMNK:

• Patient has undergone treatment with platinum-based chemotherapy and an anti-PD-1/L1 agent, if appropriate.
• Tumor has a known KRAS-activating mutation; Patients with KRAS G12C mutations are excluded.

Cohort EMBF:

• Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows:

  • Minimum of one prior line of therapy for advanced/metastatic disease.
  • Maximum of five prior lines of therapy for advanced/metastatic disease.
  • Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting, which may include combination therapy (eg, with a CDK4/6 inhibitor).
• Tumor is ER+ (defined as ER IHC staining > 0%) and has FGFR amplification.

Cohort EMBH:

• Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows:

  • Minimum of one prior line of therapy for advanced/metastatic disease.
  • Minimum of one line of HER2-directed therapy Note: Prior treatment with CDK4/6 inhibitors is permitted.
• Tumor is ER+ (defined as ER IHC staining > 0%) and HER2+ (defined as HER2 3+ IHC staining or HER2 2+ and FISH+).

Cohort ECNS:

• Patient has histologically or cytologically confirmed stage IIIB (pleural or pericardial effusion) or stage IV NSCLC.
• Patient has undergone treatment with platinum-based chemotherapy and an anti-PD-1/L1 agent, if appropriate. Note: Patients who have declined approved therapy(ies) or who per treating physician are not eligible for approved therapy(ies) (eg, due to intolerance) may be eligible following discussion with the Medical Monitor.
• Tumor has a known G12C KRAS-activating mutation. Note: Patients who have been previously treated with KRAS-specific therapy are excluded.

Cohort ECBF:

• Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows:

  • Minimum of one prior line of therapy for advanced/metastatic disease.
  • Maximum of five prior lines of therapy for advanced/metastatic disease.
  • Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting.
  • Prior treatment has included a CDK4/6 inhibitor.
• Tumor is ER+ (defined as ER IHC staining > 0%).

Cohort ECBF+A:

• Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows:

  • Minimum of one prior line of therapy for advanced/metastatic disease.
  • Maximum of five prior lines of therapy for advanced/metastatic disease.
  • Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting.
• Tumor is ER+ (defined as ER IHC staining > 0%) and HER2- (defined as absence of HER2 3+ IHC staining and/or absence of FISH+).

Cohort ECBT:

• Patient has progressed after treatment with at least one approved anti-HER2 agent and has been administered at least one line of chemotherapy.
• Tumor is HER2+ (defined as HER2 3+ IHC staining or HER2 2+ and FISH+). Cohorts EMBF, EMBH, ECBF, ECBF+A: There is no limit on the number of lines of prior endocrine therapies.

Cohort ECBF-D1:

• Patient has metastatic disease or locoregionally recurrent disease which is refractory or intolerant to existing therapy(ies) known to provide clinical benefit.

• Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows:

  • Minimum of one prior line of therapy for advanced/metastatic disease.
  • Maximum of five prior lines of therapy for advanced/metastatic disease.
  • Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting.
  • Prior treatment has included a CDK4/6 inhibitor.
• Tumor is ER+ (defined as ER IHC staining > 0%).
• Tumor has amplification of Cyclin D1 as determined by next generation sequencing or in situ hybridization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Sequential escalation (Completed); eFT226 administered IV weekly in 21-day cycles; dose escalated in sequential cohorts after subjects enrolled in a given cohort have completed DLT evaluation period.	Drug: eFT226; eFT226 is a novel small-molecule, investigational drug being developed by eFFECTOR Therapeutics as an anticancer therapy. eFT226 is a potent and selective inhibitor of eIF4A1-mediated translation and selectively regulates the translation of a subset of mRNAs based on sequence specific recognition motifs in their 5'-UTR. eIF4A1 inhibition by eFT226 downregulates expression of receptor tyrosine kinases and KRAS, leading to decreased signaling through the PI3K/AKT and MAPK pathways. Preclinical efficacy testing of eFT226 demonstrates activity across models of solid tumor cancers with amplifications in HER2, FGFR1/2 and mutations in KRAS (including breast, NSCLC and CRC).; Other Names: Selective translation inhibitor
Experimental: Part 2: Cohort Expansion, Monotherapy, NSCLC, KRAS (EMNK); Cohort EMNK	Drug: eFT226; eFT226 is a novel small-molecule, investigational drug being developed by eFFECTOR Therapeutics as an anticancer therapy. eFT226 is a potent and selective inhibitor of eIF4A1-mediated translation and selectively regulates the translation of a subset of mRNAs based on sequence specific recognition motifs in their 5'-UTR. eIF4A1 inhibition by eFT226 downregulates expression of receptor tyrosine kinases and KRAS, leading to decreased signaling through the PI3K/AKT and MAPK pathways. Preclinical efficacy testing of eFT226 demonstrates activity across models of solid tumor cancers with amplifications in HER2, FGFR1/2 and mutations in KRAS (including breast, NSCLC and CRC).; Other Names: Selective translation inhibitor
Experimental: Part 2: Cohort Expansion, Monotherapy, Breast, FGFR (EMBF); Cohort EMBF	Drug: eFT226; eFT226 is a novel small-molecule, investigational drug being developed by eFFECTOR Therapeutics as an anticancer therapy. eFT226 is a potent and selective inhibitor of eIF4A1-mediated translation and selectively regulates the translation of a subset of mRNAs based on sequence specific recognition motifs in their 5'-UTR. eIF4A1 inhibition by eFT226 downregulates expression of receptor tyrosine kinases and KRAS, leading to decreased signaling through the PI3K/AKT and MAPK pathways. Preclinical efficacy testing of eFT226 demonstrates activity across models of solid tumor cancers with amplifications in HER2, FGFR1/2 and mutations in KRAS (including breast, NSCLC and CRC).; Other Names: Selective translation inhibitor
Experimental: Part 2: Cohort Expansion, Monotherapy, Breast, HER2 (EMBH); Cohort EMBH	Drug: eFT226; eFT226 is a novel small-molecule, investigational drug being developed by eFFECTOR Therapeutics as an anticancer therapy. eFT226 is a potent and selective inhibitor of eIF4A1-mediated translation and selectively regulates the translation of a subset of mRNAs based on sequence specific recognition motifs in their 5'-UTR. eIF4A1 inhibition by eFT226 downregulates expression of receptor tyrosine kinases and KRAS, leading to decreased signaling through the PI3K/AKT and MAPK pathways. Preclinical efficacy testing of eFT226 demonstrates activity across models of solid tumor cancers with amplifications in HER2, FGFR1/2 and mutations in KRAS (including breast, NSCLC and CRC).; Other Names: Selective translation inhibitor
Experimental: Part 2: Cohort Expansion, Combination, Breast, Fulvestrant (ECBF); Cohort ECBF; Combination therapy partner administered per SOC at the approved dose.	Drug: Fulvestrant; 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter; Other Names: Faslodex
Experimental: Part 2: Cohort Expansion, Combination, NSCLC, Sotorasib (ECNS); Cohort ECNS; Combination therapy partner administered per SOC at the approved dose.	Drug: Sotorasib; Recommended dosage: 960 mg orally once daily; Other Names: Lumarkus
Experimental: Part 2: Cohort Expansion, Combination, Breast, Fulvestrant+Abemaciclib (ECBF+A); Cohort ECBF+A; Combination therapy partner administered per SOC at the approved dose.	Drug: Fulvestrant; 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter; Other Names: Faslodex; Drug: Abemaciclib; Dose in combination with fulvestrant: 150 mg twice daily; Other Names: Verzenia
Experimental: Part 2: Cohort Expansion, Combination, Breast, Trastuzumab (ECBT); Cohort ECBT; Combination therapy partner administered per SOC at the approved dose.	Drug: Trastuzumab; 600 mg every 3 weeks; Other Names: Herceptin
Experimental: Part 1a: Dose Escalation, Combination, Breast; eFT226 administered IV weekly in 21-day cycles. Fulvestrant will also be given. Dose escalations per protocol.	Drug: Fulvestrant; 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter; Other Names: Faslodex
Experimental: Part 1b Dose Escalation, Combination, Breast; eFT226 administered IV every other week in 14-day cycles. Fulvestrant will also be given. Dose escalations per protocol.	Drug: Fulvestrant; 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter; Other Names: Faslodex
Experimental: Part 2 Cohort Expansion, Combination, Breast, Fulvestrant, Cyclin D1; ECBF-D1; Combination therapy partner administered per SOC at the approved dose.	Drug: Fulvestrant; 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter; Other Names: Faslodex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parts 1a and 1b: MTD	determined by occurrence of first cycle DLTs within a 3+3 or 3+3+3 clinical trial design	Through study completion, approximately 12 months
Parts 1a and 1b; incidence of AEs, serious adverse events (SAEs), and DLTs	according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)	Through study completion, approximately 12 months
Parts 1a and 1b: RP2D	determined by Incidence and type of DLTs	Through study completion, approximately 12 months
Parts 1a and 1b: RP2D	determine by Incidence, type, and severity of AEs and SAEs graded as per NCI CTCAE	Through study completion, approximately 12 months
Part 2: Objective Response Rate- Efficacy	defined as confirmed Complete Response (CR) or Partial Response (PR)	Through study completion, approximately 12 months
Part 2: (Combination Cohorts) Determine MTD	determined by occurrence of first cycle Dose Limiting Toxicities (DLTs) within the study design	Through study completion, approximately 12 months
Part 2: (Combination Cohorts) Incidence, type, and severity of AEs and SAEs	via adverse event monitoring	Through study completion, approximately 12 months
Part 2: (Combination Cohorts) Determine RP2D	determined by incidence and type of DLTs, and incidence, type, and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Through study completion, approximately 12 months
Part 2: Percent change in tumor dimensions of target lesions- Efficacy	calculated by the percentage change from baseline in the sum of the LD of target lesions	Through study completion, approximately 12 months
Part 2: Time to Response (TTR)- Efficacy	defined as the interval from the start of study therapy to the first documentation of an objective response	Through study completion, approximately 12 months
Part 2: Duration of Response (DOR)- Efficacy	defined as the interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause	Through study completion, approximately 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parts 1a and 1b: Objective response	determined by confirmed CR or PR	Through study completion, approximately 12 months
Parts 1a and 1b: Percent change in tumor dimensions of target lesions	calculated by the percentage change from baseline in the sum of the LD of target lesions	Through study completion, approximately 12 months
Parts 1a and 1b: TTR	defined as the interval from the start of study therapy to the first documentation of an objective response	Through study completion, approximately 12 months
Parts 1a and 1b: DOR	defined as the interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause	Through study completion, approximately 12 months
Parts 1a and 1b: PFS	defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause	Through study completion, approximately 12 months
Part 2: (Monotherapy and Combination Cohorts) Incidence and severity of AEs, SAEs, and additional safety parameters	via adverse event monitoring	Through study completion, approximately 12 months
Part 2: Progression Free Survival	defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause	Through study completion, approximately 12 months
Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including area under the plasma concentration-time curve	Through study completion, approximately 12 months
Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including maximum concentration	Through study completion, approximately 12 months
Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including terminal phase rate constant	Through study completion, approximately 12 months
Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including estimated steady-state volume of distribution [Vss]	Through study completion, approximately 12 months
Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including half-life (t½)	Through study completion, approximately 12 months
Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including total body clearance	Through study completion, approximately 12 months
Evaluate plasma Pharmacokinetic (PK) parameters of eFT226including terminal state volume of distribution	including terminal state volume of distribution	Through study completion, approximately 12 months
Evaluate plasma Pharmacokinetic (PK) parameters of eFT226 including terminal phase rate constant	including terminal phase rate constant	Through study completion, approximately 12 months

Collaborators and Investigators

• Sponsor: Effector Therapeutics
• Investigators: Study Director: Douglas Warner, MD, EFFECTOR Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2019
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: September 10, 2019
• First Submitted That Met QC Criteria: September 13, 2019
• First Posted (Actual): September 17, 2019

Study Record Updates

• Last Update Posted (Estimated): December 20, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Hormone Antagonists; Immune Checkpoint Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; Trastuzumab; Fulvestrant; Sotorasib
• Other Study ID Numbers: eFT226-0002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is not a plan to make IPD available

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No