FOG-001 in Locally Advanced or Metastatic Solid Tumors

This is a FIH, Phase 1/2, multicenter, open-label, non-randomized, dose escalation, dose expansion, and multiple subcutaneous dose study to evaluate the safety, tolerability, PK, pharmacodynamics, and antitumor activity of FOG-001 as monotherapy and in combination with other anticancer agents in participants with advanced or metastatic solid tumors likely or known to have a Wnt pathway activating mutation (WPAM), and FAP, a disorder of this pathway characterized by a germline mutation in the APC gene.

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 and Part 1g):

• 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 Escalation and Dose Expansion Cohorts (Part 1c and Part 2c):

• Histologically, cytologically, or radiographically confirmed HCC with a documented WPAM (by local ctDNA or tumor NGS testing) in APC or CTNNB1

Additional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part 1d, Part 1h, and Part 2d):

• Desmoid tumor (aggressive fibromatosis)

Additional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part 1f-1 and Part 2f-1) FOG-001 + FOLFOX + Bevacizumab:

• Diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR CRC
• Participants with tumors known to be negative for APC LoF mutations or CTNNB1 GoF mutations (per NGS tests) are not eligible.
• One dose of mFOLFOX6 with or without bevacizumab in the unresectable or metastatic setting prior to enrollment is allowed.

Additional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part 1f-2 and Part 2f-2): FOG-001 + Nivolumab

• Non-MSI-H or non-dMMR (by local testing) CRC with or without liver metastases.
• MSI-H CRC or solid tumors that are WPAM and resistant to a-PD-1/PD-L1
• Participants with tumors known to be negative for APC LoF mutations or CTNNB1 GoF mutations (per NGS tests) are not eligible

Additional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part 1f-3 and Part 2f-3): FOG-001 + Trifluridine/Tipiracil + Bevacizumab

• Diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (by local testing) CRC
• Participants with tumors known to be negative for APC LoF mutations or CTNNB1 GoF mutations (per NGS tests) are not eligible.

Monotherapy Dose Optimization (Part 1i): FAP

• Diagnosis of phenotypic classical FAP with a documented APC mutation
• Post-colectomy >6 months prior to first dose of study drug administration with measurable duodenal polyp burden

Additional Inclusion Criteria for Dose Expansion Cohort (Part 2a):

• Diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (by local testing) CRC

Additional Inclusion Criteria for Dose Expansion Cohort (Part 2b):

• Diagnosis of advanced or metastatic solid tumors with a documented WPAM (by local testing) or equivalent evidence

Exclusion criteria

• Known history of bone metastasis. Bone metastasis are allowed for patients with mCRPC. For participants with FAP, osteomas are allowed.
• Evidence of vertebral compression fracture or non-traumatic bone fracture within the past 12 months and who are not receiving antiresorptive therapy.
• Osteoporosis, which is defined as a T-score of ≤-2.5 at the lumbar spine (L1 - L4), left (or right) femoral neck or left (or right) total hip as determined by DXA scan.
• Uncontrolled inflammatory bowel disease (i.e., ulcerative colitis or Crohn's disease)
• 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.
• Complete colectomy within 6 months of the first dose of study drug administration.