A PD Study of Oral eFT508 in Subjects With Advanced TNBC and HCC

Study Overview
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Brief Summary
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This study will evaluate the pharmacodynamic (PD), safety, antitumor activity, and PK of eFT508 in female subjects who have pathologically documented, radiographically measurable, metastatic or locally advanced and unresectable TNBC and have received prior cancer therapy regimen for metastatic disease, and in male and female subjects who have histologically or cytologically confirmed advanced HCC not amenable to surgical resection and have failed systemic therapy.

Official Title
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A Pharmacodynamic Study of Oral eFT508 in Subjects With Advanced Triple Negative Breast Cancer and Hepatocellular Carcinoma

Conditions
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Triple Negative Breast Cancer, Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: eFT508


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (TNBC Cohort Only): Women ≥18 years of age Pathologically documented diagnosis of TNBC that is metastatic or locally advanced and unresectable Adequate hepatic function and coagulation profile Negative HIV, HBV and HCV Inclusion Criteria (HCC Cohort Only): Men or Women ≥18 years of age Histological or cytological confirmed diagnosis of HCC with Barcelona Clinic Liver Cancer Stage B or C who cannot benefit from resection, local ablation, or chemoembolization ECOG performance status of 0 or 1 Has at least 1 measurable lesion based on irRECIST 1.1. Negative HIV tests Inclusion Criteria (Either Cohort): subject agrees to undergo a pre-treatment and an on-treatment biopsy of the tumor Completion of all previous therapy for the treatment of cancer ≥3 weeks before the start of study drug All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before the start of study drug Adequate bone marrow and renal function Life expectancy of ≥3 months Exclusion Criteria (Either Cohort): Pregnant or breastfeeding History of another malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin; in situ cervical carcinoma; adequately treated, papillary, noninvasive bladder cancer; other adequately treated Stage 1 or 2 cancers currently in complete remission; or any other cancer that has been in complete remission for ≥2 years. Gastrointestinal disease that may interfere with drug absorption or with interpretation of GI AEs. Known symptomatic brain metastases requiring ≥10 mg/day of prednisolone (or its equivalent). Significant cardiovascular disease within 6 months prior to start of study drug Ongoing risk for bleeding due to active peptic ulcer disease or bleeding diathesis or requirement for systemic anticoagulation with unfractionated heparin, low-molecular-weight heparin or heparin fractions, or oral anticoagulants. Evidence of an ongoing systemic bacterial, fungal, or viral infection Has received a live vaccine within 30 days of planned start of study drug Major surgery within 4 weeks before the start of study drug Prior solid organ or bone marrow progenitor cell transplantation Prior therapy with any known inhibitor of MNK1 or MNK2 Prior high dose chemotherapy requiring stem cell rescue History of or active autoimmune disorders or other conditions that might impair or compromise the immune system Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids Use of a strong inhibitor or inducer of cytochrome P450 (CYP)3A4 within 7 days prior to the start of study drug or expected requirement for use of a strong CYP3A4 inhibitor or inducer during study participation Need for proton pump inhibitors and histamine H2 blockers Previously received investigational product in a clinical trial within 30 days or within 5 elimination half lives (whichever is longer) prior to the start of study drug, or is planning to take part in another clinical trial while participating in this study HCC Cohort Only: Portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TNBC Cohort<br>female subjects who have pathologically documented, radiographically measurable, metastatic or locally advanced and unresectable TNBC and have received >=1 prior cancer therapy regimen for metastatic disease | Drug: eFT508<br>* 200 mg eFT508 dosed BID for 3 week cycles<br>|
| Experimental: HCC Cohort<br>male and female subjects who have histologically or cytologically confirmed advanced HCC not amenable to surgical resection and have failed >=1 systemic therapy, which must include sorafenib, or are intolerant to multikinase inhibitor therapies | Drug: eFT508<br>* 200 mg eFT508 dosed BID for 3 week cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of biomarkers of antitumor activation | Biomarkers of antitumor immune activation in pre- and on treatment tumor biopsies and peripheral blood cells | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular profiling of circulating lymphocytes and tumor-infiltrating lymphocytes (TILs) | Includes determination of T cell clonality via T cell receptor sequencing | up to 3 years | 
| Levels of eIF4E and phospho-eIF4E | Assessment of eIF4E and phospho-eIF4E in tumor biopsies by immunohistochemistry, and in circulating peripheral blood cells by phospho-flow cytometry | up to 3 years | 
| Number of mutations | Assessment of mutations will be determined for a subset of known cancer driver genes by sequencing tumor DNA | up to 3 years | 
| Objective tumor response | determined by irRECIST 1.1, defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR) | up to 3 years | 
| Progression Free Survival | as determined by irRECIST 1.1, defined as the interval from the start of study drug to the earlier of the first documentation of disease progression or death from any cause | up to 3 years | 
| Proportion of subjects with TEAEs and SAEs |  | up to 3 years | 
| PK plasma concentrations | taken at the anticipated maximum and minimum plasma concentrations for eFT508 | up to 21 weeks |