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.

• FOG-001 (Drug): FOG-001 will be administered IV at assigned doses in continuous cycles of 28 days
• mFOLFOX-6 (Drug), also known as Leucovorin, 5-fluorouracil, Oxaliplatin: mFOLFOX-6 will be administered per the prescribing information in combination with FOG-001
• Nivolumab (Drug), also known as Opdivo: Nivolumab will be administered per the prescribing information in combination with FOG-001
• Trifluridine/tipiracil (Drug), also known as Lonsurf: Trifluridine/tipiracil will be administered per the prescribing information in combination with FOG-001
• Bevacizumab (Drug), also known as Avastin: Bevacizumab will be administered per the prescribing information in combination with FOG-001
• FOG-001 (Drug): FOG-001 will be administered subcutaneous at assigned doses in continuous cycles of 28 days

Primary outcomes

• During dose escalation and dose expansion measure incidence and severity of treatment emergent adverse events by CTCAE v5.0 [Through study completion, an average of 10 months]: Number and severity of treatment emergent adverse events as assessed by CTCAE v5.0
• During dose escalation characterize dose-limiting toxicities (DLTs) [1 treatment cycle (28 days)]: Incidence of DLTs
• During dose expansion describe the Overall Response Rate using RECIST v1.1 [Every 63 days until study completion, approximately 10 months on average]: The rate of objective responses (Partial \& Complete) using RECIST v1.1
• During dose expansion describe the Disease Control Rate using RECIST v1.1 (Part 2a only) [4 months]: The rate of objective responses (Stable, Partial, \& Complete) using RECIST v1.1
• During dose expansion describe the PSA30 response rate for participants with prostate cancer [Baseline, weekly during the first 2 cycles (56 days), bi-weekly during the Cycle 3 (28 days), and then monthly (up to approximately 7 months)]: The response to treatment as a 30% or greater reduction in PSA levels from baseline

Secondary outcomes

• Maximum observed plasma concentration (Cmax) of FOG-001 and associated metabolites [During first 2 cycles (56 days)]
• Time to achieve Cmax (Tmax) of FOG-001 and associated metabolites in plasma [During first 2 cycles (56 days)]
• Area under the plasma concentration-time curve (AUC) of FOG-001 and associated metabolites [During first 2 cycles (56 days)]
• Plasma trough concentration (Ctrough) of FOG-001 and associated metabolites [During first 2 cycles (56 days)]
• Clearance (CL) of FOG-001 from the plasma [During first 2 cycles (56 days)]
• Volume of distribution of FOG-001 [During first 2 cycles (56 days)]
• During dose escalation select the preliminary recommended Phase 2 dose and dosing schedule of study drug [Through Part 1 study completion]
• Rate of DLTs across dose levels [During Cycle 1 (28 days)]
• During dose escalation Part 1b to evaluate the pharmacodynamic activity in tumors [During first 2 cycles (56 days)]: Change in tumor Myc expression (on-study compared to baseline)
• During dose escalation and expansion to describe Best Overall Response Rate using RECIST v1.1 [Every 63 days until study completion, approximately 10 months on average]: Best response to treatment using RECIST v1.1
• During dose escalation and expansion to describe Duration of Response using RECIST v1.1 [Every 63 days until study completion, approximately 10 months on average]: Time from initial objective response (partial response or complete response) to disease progression
• During dose escalation and expansion describe Progression Free Survival [From date of randomization until the date of first disease progression, an average of 10 months]: Progression Free Survival (PFS) using RECIST v1.1
• During dose escalation and expansion describe the Disease Control Rate using RECIST v1.1 [Every 63 days until study completion, approximately 10 months on average]: The rate of objective responses (Stable, Partial, \& Complete) using RECIST v1.1
• During dose escalation and expansion describe the Time To Progression using RECIST v1.1 [From date of randomization until the date of first disease progression, an average of 10 months]: Time To Progression (TTP) using RECIST v1.1
• During dose escalation and expansion describe radiographic Progression Free Survival for participants with prostate cancer [From date of randomization until the date of first disease progression, an average of 10 months]: Radiographic Progression Free Survival (rPFS) using PCWG3 assessment criteria

Sex: All, ages: 18 Years to any

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.

• Results publication: Habault J, Franco JL, Ha S, Schneider JA, Voisin M, Wise DR, Wong KK, Garabedian MJ, Kirshenbaum K, Logan SK. In Vivo Efficacy of a Macrocyclic Peptoid-Peptide Hybrid That Selectively Modulates the Beta-Catenin/TCF Interaction to Inhibit Prostate Cancer. Prostate. 2025 May;85(7):646-658. doi: 10.1002/pros.24868. Epub 2025 Feb 16. PMID 39956770

• Benjamin Oshrine, Study chair, Parabilis Medicines, Inc.