Cancer, Colorectal Cancer, Solid Tumor, Locally Advanced Solid Tumor, Metastatic Cancer, WNT Pathway, β-catenin, Beta-catenin, Adenomatous Polyposis Coli, APC, HCC, Desmoid, Microsatellite Stable Colorectal Cancer, Metastatic Castration-resistant Prostate Cancer, FAP, Endometrial Carcinoma, Prostate Cancer, Microsatellite Instability-High Colorectal Cancer, CTNNB1, Adamantinomatous Craniopharyngioma
Conditions
Keywords
Cancer, Solid Tumor, Locally Advanced Solid Tumor, Metastatic Cancer, WNT Pathway Activating Mutation (WPAM), Colorectal Cancer (CRC), Microsatellite Stable (MSS), Desmoid
Brief summary
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
This is a FIH, Phase 1/2, multicenter, open-label, non-randomized, dose escalation and dose expansion 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).
Interventions
DRUGFOG-001
FOG-001 will be administered IV at assigned doses in continuous cycles of 28 days
DRUGmFOLFOX-6
mFOLFOX-6 will be administered per the prescribing information in combination with FOG-001
DRUGNivolumab
Nivolumab will be administered per the prescribing information in combination with FOG-001
DRUGTrifluridine/tipiracil
Trifluridine/tipiracil will be administered per the prescribing information in combination with FOG-001
DRUGBevacizumab
Bevacizumab will be administered per the prescribing information in combination with FOG-001
Sponsors
Parabilis Medicines, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 1e): * 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): * Diagnosis of HCC with a documented WPAM (by local testing) in APC or CTNNB1. HCC that is radiographically confirmed without tissue biopsy may be enrolled with a documented CTNNB1 mutation (e.g., by ctDNA). Additional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part 1d 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 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. 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. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| 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 |
| 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) | — |
Countries
United States
Contacts
CONTACTClinical Trial Inquiries
STUDY_CHAIRJorge Ramos, DO
Parabilis Medicines, Inc.
Outcome results
None listed