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

Details

IRB Study Number 25-557

Status Recruiting

Phases Phase 1, Phase 2

Institute Taussig Cancer Institute

Description

Primary Objectives

Part 1

To assess the safety and tolerability of FOG-001 alone or in combination across a range of dose levels and dosing schedules in participants with locally advanced or metastatic solid tumors to determine the MTD or maximum feasible dose

Part 2

To further characterize the safety and tolerability of FOG-001 alone or in combination at the RP2D
To evaluate the preliminary antitumor activity of FOG-001 alone or in combination in advanced cancer participants with centrally-confirmed WPAM

Secondary Objectives

Part 1

To characterize the PK profile of FOG-001 and associated metabolites
To select the preliminary RP2D and dosing schedule of FOG-001 for participants with advanced or metastatic solid tumors
Evaluation of FOG-001 pharmacodynamic activity in tumors (Part 1b only)
To evaluate the preliminary antitumor activity of FOG-001 alone or in combination in advanced cancer participants by WPAM status and by tumor type

Part 2

To evaluate the preliminary antitumor activity of FOG-001 alone or in combination in advanced cancer participants, with centrally-confirmed WPAM
To evaluate the preliminary antitumor activity of FOG-001 alone or in combination in advanced cancer participants, with WPAM based on local testing
To evaluate the PK profile of FOG-001 and associated metabolites

Inclusion Criteria

Aged ≥18 years or the legal age of consent in the jurisdiction in which the study is taking place, unless specified otherwise, at the time of signing the informed consent form (ICF).
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Life expectancy >3 months.
Adequate organ and marrow function, as defined below:
a. Absolute neutrophil count (ANC) ≥1500/μL
b. Platelet count ≥100,000/μL
c. Hemoglobin ≥9 g/dL
d. Creatinine clearance ≥60 mL/min (either measured or calculated using Cockcroft-Gault formula)
e. Serum total bilirubin ≤ULN. Note: Participants with Gilbert syndrome with total bilirubin up to 1.5× ULN are allowed as long as direct bilirubin is ≤ULN.
f. AST, ALT, and alkaline phosphatase ≤2.5× ULN. Note: For participants with known liver metastases or who have HCC, AST, ALT, and alkaline phosphatase must be ≤5× ULN.
g. Albumin ≥3.0 g/dL
h. PT/international normalized ratio (INR) and activated partial thromboplastin time (aPTT)/PTT <1.5× ULN, or within a stable target range if taking prophylactic anticoagulant(s)
i. Plasma CK <1.5× ULN
j. Sodium ≥130 mmol/L
Resolution of all treatment-related toxicities, except alopecia, fatigue, anemia, endocrinopathies managed by hormone replacement, or peripheral neuropathy from any previous cancer therapy to Grade ≤1 or to values within those required for eligibility on this study prior to the first dose of study treatment.
-Participants with a history of immunotherapy-related colitis should no longer require corticosteroid or anti-motility therapy.
Male and female participants of childbearing potential who are sexually active with a non-sterilized partner must agree to use highly effective methods of birth control from the time of enrollment until at least 90 days (or at least 5 months if receiving nivolumab or at least 6 months if receiving bevacizumab or trifluridine/tipiracil) after the last dose of all study treatments; cessation of birth control after this point shall be discussed with a responsible physician. Highly effective methods of contraception are described in Appendix 3.
-Pregnant or lactating females are prohibited from enrolling in this study.
Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Additional Inclusion Criteria Specific to Dose Escalation Cohorts (Part 1) and Dose Expansion Cohorts (Part 2)

Monotherapy Dose Escalation Cohorts (Part 1a and Part 1e)

Adult participants with a histologically or cytologically proven diagnosis of locally advanced or metastatic 1) solid tumor with documented WPAM (by local testing) or 2) non-MSI-H or non-dMMR (by local testing) colorectal adenocarcinoma (irrespective of WPAM status) that have received at least one prior systemic therapy and either 1) has progressed on or was nonresponsive to available therapies or 2) is unfit for available therapies.
-Participants with CRC should have received prior 5-FU, oxaliplatin, irinotecan, and appropriate biologic therapy in the metastatic setting and should have no more than a maximum of 4 lines of therapy (including investigational agents) in the metastatic setting. Relapse within 6 months of completion of adjuvant therapy will be considered as a line of therapy in the metastatic setting.
Participants are ineligible for surgery or chemoradiation with curative intent.
Evaluable disease that may or may not meet Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) for measurable disease (except for participants with prostate cancer; see Section 5.1.1.8).

Monotherapy Pharmacodynamic Biomarker Cohorts (Part 1b)

Adult participants with a histologically or cytologically proven diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (by local testing) colorectal adenocarcinoma who received ≥1 line of fluoropyrimidine-containing chemotherapy and either 1) has progressed on or was nonresponsive to available therapies or 2) is unfit for available therapies. Refer to Appendix 10 for biomarker eligibility criteria.
a. Participants should have received prior 5-FU, oxaliplatin, irinotecan, and appropriate biologic therapy in the metastatic setting and should have no more than a maximum of 4 lines of therapy in the metastatic setting. Relapse within 6 months of completion of adjuvant therapy will be considered as a line of therapy in the metastatic setting.
Participants are ineligible for surgery or chemoradiation with curative intent.
At least one tumor lesion/lymph node that meets RECIST 1.1 for measurable disease.
At least one lesion that is suitable for core needle biopsy. Note: In general, RECIST target lesions should not be used for biopsy. However, a target lesion may be considered for the biopsy lesion if, in the opinion of the radiologist, the biopsy would not affect evaluability of the lesion for RECIST 1.1.

WPAM-Documented HCC Monotherapy Dose Escalation Cohorts (Part 1c) and WPAM-Documented HCC Monotherapy Dose Expansion Cohort (Part 2c)

Histologically or cytologically confirmed 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 APC or CTNNB1 pathogenic mutation (e.g., by ctDNA).
Barcelona Clinic Liver Cancer (BCLC) stage C or BCLC stage B not amenable to locoregional therapy or relapsed after locoregional therapy, and not amenable to a curative treatment approach (Appendix 12).
Child-Pugh A classification (Appendix 13).
Progressed on or intolerant to at least 1 line of systemic immune-based therapy or VEGF/tyrosine kinase inhibitor (TKI)-based therapy for unresectable HCC.
a. For Part 2c only, participants must have received at least 1 line, but no more than 2 lines, of systemic therapy for unresectable HCC. Additional prior systemic therapies used as adjuvant or local therapy are allowed and will not count as a prior line of systemic therapy.
At least 1 tumor lesion/lymph node that meets RECIST 1.1 for measurable disease
Participants with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection will be allowed if they meet the following criteria:
a. HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surface antigen) or chronic HBV infection (as evidenced by detectable HBV surface antigen or HBV DNA). Participants with chronic HBV infection must have HBV DNA <500 IU/mL and must be on antiviral therapy, per institutional practice to ensure adequate viral suppression. Participants with active or uncontrolled clinically serious HBV infections are excluded.
b. HCV-HCC: Resolved HCV infection (as evidenced by undetectable HCV RNA).

Desmoid Tumor Monotherapy Dose Escalation Cohorts (Part 1d) and Desmoid Tumor Monotherapy Dose Expansion Cohort (Part 2d)

Adult participants with a histologically confirmed desmoid tumor (aggressive fibromatosis).
An increase of ≥10% in the active component of the tumor per investigator assessment within 12 months prior to the first dose.
Meets one of the following:
a. Treatment-naïve participant for whom, in the opinion of the Investigator, the study treatment is deemed appropriate, OR
b. Recurrent/refractory disease following at least 1 line of therapy (including surgery, radiation, or systemic therapy).
At least 1 tumor lesion that meets RECIST 1.1 for measurable disease.

Combination Therapy Dose Escalation (Part 1f) and Combination Therapy Dose Expansion Cohorts (Part 2f)

Part 1f-1 and Part 2f-1: FOG-001 + FOLFOX + Bevacizumab

Adult participants with a histologically or cytologically proven diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (by local testing) colorectal adenocarcinoma. Refer to Appendix 10 for biomarker eligibility criteria.
Participants must have not received prior systemic therapy for unresectable or metastatic CRC.
a. Prior adjuvant/neoadjuvant therapy in the non-metastatic setting is permitted provided that the last treatment with adjuvant or neoadjuvant chemotherapy was >12 months prior to recurrence or metastases.
b. One dose of mFOLFOX-6 in the unresectable or metastatic setting prior to enrollment is allowed. The baseline tumor assessment scan must be performed prior to mFOLFOX-6 administration.
At least 1 tumor lesion/lymph node that meets RECIST 1.1 for measurable disease.

Part 1f-2 and Part 2f-2: FOG-001 + Nivolumab

Adult participants with a histologically or cytologically proven diagnosis of locally advanced or metastatic solid tumors who have:
a. Non-MSI-H or non-dMMR (by local testing) colorectal adenocarcinoma with liver metastases.
i. Participants should have received prior 5-FU, oxaliplatin, and irinotecan in the metastatic setting and should have no more than a maximum of 2 lines of therapy in the metastatic setting. Relapse within 6 months of completion of adjuvant therapy will be considered as a line of therapy in the metastatic setting.
ii. Refer to Appendix 10 for biomarker eligibility criteria. OR
b. Non-MSI-H or non-dMMR (by local testing) colorectal adenocarcinoma without liver metastases.
i. Participants should have received prior 5-FU, oxaliplatin, and irinotecan in the metastatic setting and should have no more than a maximum of 2 lines of therapy in the metastatic setting. Relapse within 6 months of completion of adjuvant therapy will be considered as a line of therapy in the metastatic setting.
ii. Refer to Appendix 10 for biomarker eligibility criteria.
Note: Sponsor will prioritize enrollment of patients who meet 1a criteria above.
Patients who meet criteria 1b above may be enrolled at the discretion of the Sponsor based on emerging data. OR
c. A documented WPAM by local testing (including MSI-H CRC) for which anti-PD-1/PD-L1 with or without anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy is SoC and have demonstrated primary or secondary resistance on anti-PD-1/PD-L1 therapy and have received or are ineligible for SoC therapy. Participants with secondary resistance must have received anti-PD-1/PD-L1 therapy within 6 months of C1D1.
Participants are ineligible for surgery or chemoradiation with curative intent.
At least 1 tumor lesion/lymph node that meets RECIST 1.1 for measurable disease.
Must be able to provide a fresh tumor biopsy during screening and on treatment, if feasible (e.g., accessible location that can be biopsied). Note: In general, RECIST target lesions should not be used for biopsy. However, a target lesion may be considered for the biopsy lesion if, in the opinion of the radiologist, the biopsy would not affect evaluability of the lesion for RECIST 1.1.

Part 1f-3 and Part 2f-3: FOG-001 + Trifluridine/Tipiracil + Bevacizumab

Adult participants with a histologically or cytologically proven diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (by local testing) colorectal adenocarcinoma. Refer to Appendix 10 for biomarker eligibility criteria.
Participants should have received prior 5-FU, oxaliplatin, irinotecan, and appropriate biologic therapy in the metastatic setting and should have no more than a maximum of 2 lines of therapy in the metastatic setting. Relapse within 6 months of completion of adjuvant therapy will be considered as a line of therapy in the metastatic setting.
Participants that have received trifluridine/tipiracil prior to study entry are ineligible.
Participants are ineligible for surgery or chemoradiation with curative intent.
At least 1 tumor lesion/lymph node that meets RECIST 1.1 for measurable disease.

CRC Monotherapy Dose Expansion Cohort (Part 2a)

Adult participants with a histologically or cytologically proven diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (by local testing) colorectal adenocarcinoma. Refer to Appendix 10 for biomarker eligibility criteria.
a. Participants should have received prior 5-FU, oxaliplatin, irinotecan, and appropriate biologic therapy in the metastatic setting and should have no more than a maximum of 2 lines of therapy in the metastatic setting. Relapse within 6 months of completion of adjuvant therapy will be considered as a line of therapy in the metastatic setting.
Participants are ineligible for surgery or chemoradiation with curative intent.
At least 1 tumor lesion/lymph node that meets RECIST 1.1 for measurable disease.

WPAM-Documented Tumor Agnostic Monotherapy Dose Expansion Cohort (Part 2b)

Adult participants with a proven diagnosis of advanced or metastatic solid tumors with a documented WPAM (by local testing) or equivalent evidence (see Appendix 10) that 1) are unfit for or do not have available systemic therapy options or 2) have received at least 1 prior systemic therapy and have progressed on or were nonresponsive to all available therapies known to provide meaningful clinical benefit.
Participants are ineligible for surgery or chemoradiation with curative intent.
At least 1 tumor lesion/lymph node that meets RECIST 1.1 for measurable disease (except for participants with prostate cancer; see Section 5.1.1.8).

WPAM-Documented mCRPC Monotherapy Dose Expansion Cohort (Part 2e)

Adult male participants with mCRPC with a documented WPAM (by local testing) in APC and/or CTNNB1. Additional WPAMs listed in Appendix 10 may be considered upon discussion with the Sponsor.
Have documented progressive mCRPC per Prostate Cancer Working Group 3 (PCWG3) based on at least one of the following criteria on or after the last prior therapy:
a. Prostate-specific antigen (PSA) progression defined by an increase in PSA with 2 consecutive rises above the nadir, separated by ≥1 week, with the last determination having a value of ≥2 ng/mL.
b. Soft tissue disease progression defined by new or progressive soft tissue disease documented by CT or MRI.
c. Bone disease progression.
Histologically or cytologically confirmed adenocarcinoma of the prostate.
Must have progressed on androgen deprivation therapy (ADT) and at least 1 of the following secondary hormonal therapies: abiraterone, enzalutamide, apalutamide, or darolutamide. Participants must have received prior taxane chemotherapy unless the participant is considered by the Investigator to be unfit for, intolerant of, or declines chemotherapy.
Must have castrate levels of serum testosterone <50 ng/dL and must continue ADT with a luteinizing hormone releasing hormone (LHRH) agonist/antagonist if they have not undergone bilateral orchiectomy.
Discontinuation of abiraterone acetate, rucaparib, or olaparib ≥2 weeks and enzalutamide flutamide, nilutamide, bicalutamide, and other approved secondary hormonal therapy, chemotherapy, immunotherapy, or investigational treatments (except treatments to maintain castrate status) ≥4weeks or ≥5 half-lives prior to the first dose, whichever is shorter.
Palliative procedures (e.g., surgery or radiation) performed after establishing progression must not impact the criteria used to determine progressive disease (e.g., PSA progression should be documented after the procedure).
Must have PSA ≥2 ng/mL at screening.
Participants with bone metastasis are eligible.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply. However, where tumor-specific criteria differ from the main criteria, the tumor-specific criteria should be applied.

Medical Conditions

Known history of bone metastasis, unless otherwise specified.
Participants with evidence of vertebral compression fracture or non-traumatic bone fracture within the past 12 months and who are not receiving antiresorptive therapy (e.g., bisphosphonates and denosumab).
Osteoporosis 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. For premenopausal females and males <50 years of age use Z scores and exclude if Z score ≤-2.5 at any site.
Any other current or previous malignancy within the past 2 years except neoplasm that, in the opinion of the Principal Investigator and with the agreement of the Sponsor’s Medical Monitor, will not interfere with study-specific endpoints. Exception: Participants with hereditary cancer known or suspected to be due to genetic activation of the Wnt pathway (e.g., familial adenomatous polyposis) are eligible.
Uncontrolled inflammatory bowel disease (i.e., ulcerative colitis or Crohn’s disease).
Symptomatic pleural effusion requiring intermittent thoracentesis. A participant who is clinically stable following treatment for pleural effusion (including therapeutic thoracentesis) is eligible upon review and approval by the Medical Monitor. Participants with any ascites requiring therapeutic paracentesis within 60 days of C1D1 are not eligible.
Biliary stenting for malignant obstruction within 3 weeks of C1D1.
Malignant bowel obstruction within 3 months of C1D1.
Unstable/inadequate cardiac function as defined as:
a. Myocardial infarction or symptomatic ischemia within the last 6 months.
b. Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular tachycardia on antiarrhythmics is excluded; first-degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block are eligible).
c. Congestive heart failure (New York Heart Association Class III to IV).
Known positivity for human immunodeficiency virus (HIV) or active hepatitis B or C (i.e., DNA test positivity). HCC participants may be eligible if they meet inclusion criteria regarding HBV and HCV infection (Section 5.1.1.3).
Major surgery within 6 weeks prior to first dose of study treatment.
Infection requiring parenteral antibiotics, antivirals, or antifungals within 2 weeks prior to C1D1. Antivirals are allowed for HCC participants per (Section 5.1.1.3).
Serious psychiatric or medical conditions that could interfere with treatment or protocol-related procedures.
Has known meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or symptomatic or unstable brain metastases. Note:
a. Participants with a small number (<5) of untreated asymptomatic, small (≤10 mm) brain metastases that do not require high dose or increasing dose of systemic corticosteroids will be permitted.
b. Participants with more significant brain metastases are permitted but must have completed treatment and recovered adequately from any associated toxicity and/or complications prior to eligibility assessment.
Pregnant, lactating, or planning to become pregnant.
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator.
Any CRC participants known to be positive for BRAF activating (gain-of-function) mutations.

Prior/Concomitant Therapy

Cytotoxic chemotherapy and tyrosine kinase inhibitor (or other targeted anticancer agent) within 14 days or 5 half-lives, whichever is longer, prior to C1D1 (42 days for nitrosoureas or mitomycin C). Radiation therapy within 14 days prior to C1D1.
Immunotherapy within 21 days prior to C1D1.
Biological therapy (e.g., monoclonal antibodies) with 21 days or 5 half-lives prior to C1D1, whichever is shorter.
Treatment with an unapproved investigational therapeutic agent within 21 days (or 5 half-lives for small molecule agents) prior to C1D1, except for permitted antiresorptive therapy per protocol.
Any concurrent investigational anticancer therapy, P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrates with narrow therapeutic index (NTI), organic anion transporting polypeptide (OATP)1B1 or OATP1B3 drug transporter substrate with NTI (see Section 6.9.2).
Any concurrent use of statins (see Section 6.9.2).
Any concurrent use of aldosterone antagonists (e.g., spironolactone, eplerenone) (see Section 6.9.2).

Additional Exclusion Criteria Specific to Dose Escalation Cohorts (Part 1) and Dose Expansion Cohorts (Part 2)