Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies

Solid Tumor, Adult Clinical Trial

— Zotatifin  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04092673
• Other study ID #: eFT226-0002
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 25, 2019
• Est. completion date: March 31, 2025

Study information

• Verified date: December 2023
• Source: Effector Therapeutics
• Contact: Mark Densel
• Phone: 858-925-8215
• Email: clinicaltrials[@]effector.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: March 31, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumor, Adult

Intervention

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).
• Sotorasib
Recommended dosage: 960 mg orally once daily
• Fulvestrant
500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter
• Abemaciclib
Dose in combination with fulvestrant: 150 mg twice daily
• Trastuzumab
600 mg every 3 weeks

Locations

Country	Name	City	State
United States	Memorial Sloan Kettering Cancer Center- Commack	Commack	New York
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	START Midwest	Grand Rapids	Michigan
United States	Memorial Sloan Kettering Cancer Center- Westchester	Harrison	New York
United States	MD Anderson Cancer Center	Houston	Texas
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	University of Southern California	Los Angeles	California
United States	Valkyrie Clinical Trials	Los Angeles	California
United States	Memorial Sloan Kettering Cancer Center- Monmouth	Middletown	New Jersey
United States	Memorial Sloan Kettering Cancer Center- David H. Koch Center for Cancer Care	New York	New York
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	Stanford University	Palo Alto	California
United States	New Experimental Therapeutics of San Antonio - NEXT Oncology	San Antonio	Texas
United States	University of Toledo Medical Center	Toledo	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Effector Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Parts 1a and 1b: RP2D	determined by Incidence and type of DLTs	Through study completion, approximately 12 months
Primary	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
Primary	Part 2: Objective Response Rate- Efficacy	defined as confirmed Complete Response (CR) or Partial Response (PR)	Through study completion, approximately 12 months
Primary	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
Primary	Part 2: (Combination Cohorts) Incidence, type, and severity of AEs and SAEs	via adverse event monitoring	Through study completion, approximately 12 months
Primary	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
Primary	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
Primary	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
Primary	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	Parts 1a and 1b: Objective response	determined by confirmed CR or PR	Through study completion, approximately 12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including area under the plasma concentration-time curve	Through study completion, approximately 12 months
Secondary	Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including maximum concentration	Through study completion, approximately 12 months
Secondary	Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including terminal phase rate constant	Through study completion, approximately 12 months
Secondary	Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including estimated steady-state volume of distribution [Vss]	Through study completion, approximately 12 months
Secondary	Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including half-life (t½)	Through study completion, approximately 12 months
Secondary	Evaluate plasma Pharmacokinetic (PK) parameters of eFT226	including total body clearance	Through study completion, approximately 12 months
Secondary	Evaluate plasma Pharmacokinetic (PK) parameters of eFT226including terminal state volume of distribution	including terminal state volume of distribution	Through study completion, approximately 12 months
Secondary	Evaluate plasma Pharmacokinetic (PK) parameters of eFT226 including terminal phase rate constant	including terminal phase rate constant	Through study completion, approximately 12 months