Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Solid Tumor, Adult

Intervention / Treatment
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* Drug: eFT226
* Drug: Sotorasib
* Drug: Fulvestrant
* Drug: Abemaciclib
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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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.

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
Interventional Model Description: Dose Escalation, 3+3, 3+3+3
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Sequential escalation (Completed)<br>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<br>* 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).<br>* Other names: Selective translation inhibitor;|
| Experimental: Part 2: Cohort Expansion, Monotherapy, NSCLC, KRAS (EMNK)<br>Cohort EMNK | Drug: eFT226<br>* 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).<br>* Other names: Selective translation inhibitor;|
| Experimental: Part 2: Cohort Expansion, Monotherapy, Breast, FGFR (EMBF)<br>Cohort EMBF | Drug: eFT226<br>* 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).<br>* Other names: Selective translation inhibitor;|
| Experimental: Part 2: Cohort Expansion, Monotherapy, Breast, HER2 (EMBH)<br>Cohort EMBH | Drug: eFT226<br>* 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).<br>* Other names: Selective translation inhibitor;|
| Experimental: Part 2: Cohort Expansion, Combination, Breast, Fulvestrant (ECBF)<br>Cohort ECBF; Combination therapy partner administered per SOC at the approved dose. | Drug: Fulvestrant<br>* 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter<br>* Other names: Faslodex;|
| Experimental: Part 2: Cohort Expansion, Combination, NSCLC, Sotorasib (ECNS)<br>Cohort ECNS; Combination therapy partner administered per SOC at the approved dose. | Drug: Sotorasib<br>* Recommended dosage: 960 mg orally once daily<br>* Other names: Lumarkus;|
| Experimental: Part 2: Cohort Expansion, Combination, Breast, Fulvestrant+Abemaciclib (ECBF+A)<br>Cohort ECBF+A; Combination therapy partner administered per SOC at the approved dose. | Drug: Fulvestrant<br>* 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter<br>* Other names: Faslodex;Drug: Abemaciclib<br>* Dose in combination with fulvestrant: 150 mg twice daily<br>* Other names: Verzenia;|
| Experimental: Part 2: Cohort Expansion, Combination, Breast, Trastuzumab (ECBT)<br>Cohort ECBT; Combination therapy partner administered per SOC at the approved dose. | Drug: Trastuzumab<br>* 600 mg every 3 weeks<br>* Other names: Herceptin;|
| Experimental: Part 1a: Dose Escalation, Combination, Breast<br>eFT226 administered IV weekly in 21-day cycles. Fulvestrant will also be given. Dose escalations per protocol. | Drug: Fulvestrant<br>* 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter<br>* Other names: Faslodex;|
| Experimental: Part 1b Dose Escalation, Combination, Breast<br>eFT226 administered IV every other week in 14-day cycles. Fulvestrant will also be given. Dose escalations per protocol. | Drug: Fulvestrant<br>* 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter<br>* Other names: Faslodex;|
| Experimental: Part 2 Cohort Expansion, Combination, Breast, Fulvestrant, Cyclin D1<br>ECBF-D1; Combination therapy partner administered per SOC at the approved dose. | Drug: Fulvestrant<br>* 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter<br>* Other names: Faslodex;|

What is the study measuring?
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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 |