FHD-286 in Subjects With Metastatic Uveal Melanoma

Study Overview
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Brief Summary
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This Phase 1, multicenter, open-label, dose escalation and expansion study is designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FHD-286 oral monotherapy in subjects with metastatic Uveal Melanoma (UM).

Detailed Description
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This study is an ascending multiple dose clinical trial with expansion arms. It is primarily intended to evaluate the safety and tolerability of FHD-286 when administered orally to subjects with metastatic UM. The Dose Escalation Phase will allow for the determination of the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) in subjects with metastatic UM. This study will also evaluate the PK/PD profiles of multiple dose administration of FHD-286. The Dose Expansion Phase will allow a more robust evaluation of the safety profile of FHD-286, including less frequent toxicities and an assessment of antitumor activity. The data from this study in subjects with metastatic UM, including safety, tolerability, PK/PD findings, and antitumor activity, will form the basis for subsequent clinical development of FHD-286.

Official Title
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A Phase 1, Multicenter, Open-Label, Dose Escalation and Expansion Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered FHD-286 in Subjects With Metastatic Uveal Melanoma

Conditions
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Metastatic Uveal Melanoma

Intervention / Treatment
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* Drug: FHD-286


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female subjects ≥ 18 years of age Subject must have a diagnosis of metastatic histologically or cytologically confirmed UM. If histologic or cytologic confirmation of the primary tumor is not available, clinical confirmation of a diagnosis of metastatic UM, as per standard practice for UM, by the treating investigator can be obtained, and fall into any of the following categories: Newly diagnosed subject who has not yet received liver-directed or systemic treatment Subjects ineligible for any available therapy likely to convey clinical benefit Subjects who have disease progression after treatment with available therapies and/or who is intolerant to those treatments. Subject must have measurable disease by RECIST v1.1, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded) as ≥ 10 mm with calipers and/or CT scan. Measurable lesions cannot have undergone any local treatment (including liver-directed radio- or immune-therapies) or radiation, unless there has been interim progression of that lesion, nor can any local treatment or radiation involving measurable lesions be anticipated. Note: A malignant lymph node must be ≥ 15 mm on the short axis when assessed by CT scan to be considered pathologically enlarged and measurable. Willingness to provide newly obtained tumor tissue at baseline and on treatment unless contraindicated by medical risk in the opinion of the treating physician Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2. a.) Arm 2 (Dose Expansion Phase): Subjects enrolling in Arm 2 must have an ECOG PS of ≤ 3. Key Exclusion Criteria: Subjects who have other malignancy which may interfere with the diagnosis and/or treatment of metastatic UM. Subject has thrombocytopenia (platelets < 50 × 109/L) or another major bleeding disorder/diathesis. Note: Subjects with platelets < 50 × 109/L may be permitted to enroll only in Arm 2 of the Dose Expansion Phase at the discretion of the Investigator and the Sponsor. Subject has active brain metastases and/or leptomeningeal disease. Subjects with known CNS metastases are only permitted under the following conditions; exceptions may be made on a case-by-case basis with the approval of the Sponsor: Brain metastases must have been stable for approximately 2 months since completion of most recent CNS-directed intervention. Subject may be on corticosteroids so long as the dose is stable for approximately 14 days or decreasing at the time of study entry. Anti-epileptic therapy is allowed so long as medications are not otherwise excluded and seizures have been controlled for approximately 4 weeks since last anti-epileptic medication adjustment. Dose Escalation Phase: Subjects with known CNS metastases that meet the above conditions are permitted to enroll in dose escalation. Arm 1 (Dose Expansion Phase): Subjects with known or suspected CNS metastases are excluded from Arm 1. Arm 2 (Dose Expansion Phase): Subjects with CNS metastases that meet the above conditions are permitted to enroll in Arm 2. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections; subjects with a sustained viral response to HCV treatment or immunity to prior HBV infection will be permitted. Subject has known positive HIV antibody results or acquired immunodeficiency syndrome (AIDS)-related illness; subjects with CD4+ T-cell counts greater than or equal to 350 cells/µL will be permitted, as will subjects who have not had an AIDS-related illness within the past 12 months Subjects with an active infection cannot be enrolled until any required antibiotic and/or antifungal therapy has been completed and/or infection is determined to be controlled Subjects who have an uncontrolled intercurrent illness. Known and possible risk for QT prolongation. Subject is on medications that are strong CYP3A inhibitors, are strong CYP3A inducers, or are sensitive CYP3A substrates with narrow TIs Subject is on medications with narrow TIs that are sensitive P-gp or BCRP substrates and are administered orally such as digoxin Subjects who require clinically significant or increasing doses of systemic steroid therapy or any other systemic immunosuppressive medication. The use of a stable dose of systemic steroids and/or immunosuppressive medication is permitted with Sponsor approval. Local or targeted steroid and immunosuppressive therapies (e.g. inhaled or topical steroids) are acceptable. Appropriate steroid replacement to manage endocrine toxicities resulting from prior systemic anticancer therapy is permitted. See exclusion criterion 3 for exceptions regarding steroid therapy for subjects with CNS metastases. See exclusion criterion 13 for exclusions regarding medications that are strong CYP3A inhibitors, strong CYP3A inducers, or sensitive CYP3A substrates with narrow TIs. Subjects have undergone any prior treatment with a BRG1/BRM inhibitor.

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
Intervention Model: Single Group Assignment
Interventional Model Description: Open label single arm dose escalation and two-arm expansion study in patients with metastatic UM
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FHD-286 dose escalation and expansion<br>Up to approximately 125 patients will be enrolled in dose escalation and expansion | Drug: FHD-286<br>* FHD-286 as a single agent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) | Dose escalation and expansion | Up to 31 months | 
| Incidence of adverse events (AEs), serious adverse events (SAEs) including changes in safety laboratory parameters and AEs leading to discontinuation | Dose escalation and expansion | Up to 31 months | 
| Incidence of dose limiting toxicities (DLTs) during cycle 1 (28 days) | Dose escalation | Cycle 1 (cycle length = 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the percentage of subjects with evidence of a complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1. | Up to 30 months | 
| Duration of Response (DOR) | DOR is defined as the time from first documented evidence of CR or PR until the earliest date of documented radiological progression per RECIST 1.1. or death due to any cause among subjects who achieved a CR or PR | Up to 30 months | 
| Time to Response (TTR) | TTR is defined as the period of time from the date of first study drug administration until the first objective documentation of a CR or PR per RECIST 1.1. | Up to 30 months | 
| Time to Progression (TTP) | TTP is defined as the time from the date of first study drug administration until the start of disease progression per RECIST Version 1.1. | Up to 30 months | 
| Progression Free Survival (PFS) | PFS defined as the time from first dose of study treatment until the first date of either objective disease progression per RECIST 1.1. or death due to any cause | Up to 54 months | 
| Overall Survival (OS) | OS is defined as the time from first dose of study treatment to the date of death, irrespective of the cause of death | Up to 54 months | 
| PK parameter: Area under the plasma concentration time curve (AUC) | Characterization of the PK profile of FHD-286 | Cycle 1 (28 days) | 
| Plasma concentration vs. time profiles | Plasma concentration of FHD-286 at the scheduled timepoints | Cycle 1 (28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UM, metastatic uveal melanoma, advanced uveal melanoma, phase 1, FHD-286, Foghorn