FOG-001 in Locally Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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The goal of this clinical trial is to determine if FOG-001 is safe and effective in participants with locally advanced or metastatic cancer.

Detailed Description
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This first-in-human, Phase 1/2, multicenter, open-label, non-randomized dose escalation and expansion study will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of FOG-001 in participants with locally advanced or metastatic solid tumors. FOG-001 is a first-in-class direct inhibitor of Beta-catenin, which functions by blocking its interaction with the T-cell factor (TCF) family of transcription factors.

Official Title
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A Phase 1/2 Study of FOG-001 in Participants With Locally Advanced or Metastatic Solid Tumors

Conditions
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Cancer, Colorectal Cancer, Solid Tumor, Locally Advanced Solid Tumor, Metastatic Cancer, Gastric Cancer, Non-small Cell Lung Cancer, Non-small Cell Carcinoma, Non-small Cell Lung Cancer Metastatic, Non-small Cell Lung Cancer Stage IIIB, Non-Small Cell Carcinoma of Lung, TNM Stage 4, Gastroesophageal-junction Cancer, WNT Pathway, β-catenin, Beta-catenin, Adenomatous Polyposis Coli, APC

Intervention / Treatment
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* Drug: FOG-001
* Drug: FOG-001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate organ and marrow function. Additional Inclusion Criteria for Dose Escalation Cohorts (Part 1a): Diagnosis of treatment-refractory advanced/metastatic solid tumor that is non-MSI-H or non-dMMR colorectal cancer (CRC) or any other solid tumor with documented WNT- pathway activating mutations (WPAMs). Additional Inclusion Criteria for Dose Escalation Cohorts (Part 1b): Diagnosis of treatment-refractory advanced/metastatic non-MSI-H or non-dMMR CRC. At least one lesion that is suitable for a core needle biopsy. Additional Inclusion Criteria for Dose Expansion Cohort (Cohort 2a): Colorectal Cancer (CRC) Cohort Diagnosis of treatment-refractory advanced/metastatic non-MSI-H or non-dMMR CRC. Additional Inclusion Criteria for Dose Expansion Cohort (Cohort 2b): Non-small Cell Lung Cancer (NSCLC) Cohort Diagnosis of treatment-refractory advanced/metastatic NSCLC with documented WPAMs in adenomatous polyposis coli (APC) or Beta-catenin. Additional Inclusion Criteria for Dose Expansion Cohort (Cohort 2c): Gastric/Gastroesophageal junction (GEJ) Cohort Diagnosis of treatment-refractory advanced/metastatic gastric/GEJ cancer with documented WPAMs in APC or Beta-catenin. Additional Inclusion Criteria for Dose Expansion Cohort (Cohort 2d): Tumor Agnostic Cohort Diagnosis of treatment-refractory advanced/metastatic solid tumor with documented WPAMs. Exclusion Criteria: Known history of bone metastasis. Evidence of vertebral compression fracture or non-traumatic bone fracture within the past 12 months. Osteoporosis, which is defined as a T-score of <-2.0 at the lumbar spine (L1 - L4), left (or right) femoral neck, and left (or right) total hip as determined by DXA scan. Inflammatory bowel disease (i.e., ulcerative colitis or Crohn's disease) that is recently active or requires therapy currently. Unstable/inadequate cardiac function. Has known meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or symptomatic or unstable brain metastases. Pregnant, lactating, or planning to become pregnant.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a<br>Solid Tumors with Any WNT-Pathway Activating Mutations (WPAMs) or Microsatellite Stable (MSS) Colorectal Cancer (Irrespective of WPAM Status) | Drug: FOG-001<br>* FOG-001 will be administered IV once weekly at assigned doses in continuous cycles of 28 days<br>|
| Experimental: Part 1b<br>Microsatellite Stable Colorectal Cancer (Irrespective of WPAM Status) | Drug: FOG-001<br>* FOG-001 will be administered IV once weekly at assigned doses in continuous cycles of 28 days<br>|
| Experimental: Cohort 2a<br>Microsatellite Stable Colorectal Cancer (Irrespective of WPAM Status) | Drug: FOG-001<br>* FOG-001 will be administered IV once weekly at the RP2D dose in continuous cycles of 28 days<br>|
| Experimental: Cohort 2b<br>Non-Small Cell Lung Cancer with a WNT-Pathway Activating Mutation (WPAM) in Adenomatous Polyposis Coli (APC) or Beta-Catenin | Drug: FOG-001<br>* FOG-001 will be administered IV once weekly at the RP2D dose in continuous cycles of 28 days<br>|
| Experimental: Cohort 2c<br>Gastric Cancer/Gastroesophageal Junction Carcinoma (GEJ) with a WNT-Pathway Activating Mutation (WPAM) in Adenomatous Polyposis Coli (APC) or Beta-Catenin | Drug: FOG-001<br>* FOG-001 will be administered IV once weekly at the RP2D dose in continuous cycles of 28 days<br>|
| Experimental: Cohort 2d<br>Solid Tumors with Any WNT-Pathway Activating Mutations (WPAMs) | Drug: FOG-001<br>* FOG-001 will be administered IV once weekly at the RP2D dose in continuous cycles of 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| During dose escalation and dose expansion measure incidence and severity of treatment emergent adverse events by CTCAE v5.0 | Number and severity of treatment emergent adverse events as assessed by CTCAE v5.0 | Through study completion, an average of 4 months | 
| During dose escalation characterize dose-limiting toxicities (DLTs) | Incidence of DLTs | 1 treatment cycle (28 days) | 
| During dose expansion describe the Overall Response Rate using RECIST v1.1 | The rate of objective responses (Partial & Complete) using RECIST v1.1 | Every 56 days until study completion, approximately 4 months on average | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration (Cmax) of FOG-001 |  | During first 2 cycle (56 days) | 
| Time to achieve Cmax (Tmax) of FOG-001 in plasma |  | During first 2 cycle (56 days) | 
| Area under the plasma concentration-time curve (AUC) of FOG-001 |  | During first 2 cycle (56 days) | 
| Clearance (CL) of FOG-001 from the plasma |  | During first 2 cycle (56 days) | 
| Terminal half-life (t1/2) of FOG-001 in plasma |  | During first 2 cycle (56 days) | 
| During dose escalation select the recommended Phase 2 dose and dosing schedule of study drug | Rate of Dose Limiting Toxicities (DLTs) across dose levels | During Cycle 1 (28 days) | 
| During dose escalation Part 1b to evaluate the pharmacodynamic activity in tumors | Change in tumor Myc expression (on-study compared to baseline) | During first 2 cycles (56 days) | 
| During dose escalation and expansion to describe Best Overall Response Rate using RECIST v1.1 | Best response to treatment using RECIST v1.1 | Every 56 days until study completion, approximately 4 months on average | 
| During dose escalation and expansion to describe Duration of Response using RECIST v1.1 | Time from initial objective response (partial response or complete response) to disease progression | Every 56 days until study completion, approximately 4 months on average | 
| During dose expansion describe Progression Free Survival | Progression Free Survival (PFS) using RECIST v1.1 | From date of randomization until the date of first disease progression, an average of 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Colorectal Cancer, Solid Tumor, Locally Advanced Solid Tumor, Metastatic Cancer, WNT Pathway Activating Mutation (WPAM), Non-small Cell Lung Cancer (NSCLC), Gastric Cancer (GC), Gastroesophageal-junction Cancer (GEJ), Colorectal Cancer (CRC), Microsatellite Stable (MSS)