A Phase 1/2 Study of FS118 in Patients With Advanced Malignancies

Study Overview
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Brief Summary
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This study will be conducted in adult participants diagnosed with advanced tumors to characterize the safety, tolerability, pharmacokinetics (PK), and activity of FS118. This is a Phase 1/2, multi-center, open-label, multiple-dose, first-in-human study, designed to systematically assess safety and tolerability, to identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) for FS118 in participants with advanced tumors and to determine the efficacy of FS118 in participants with squamous cell carcinoma of the head and neck (SCCHN) as monotherapy and in combination with paclitaxel. In addition to safety, pharmacokinetics, pharmacodynamics, immunogenicity and efficacy will also be assessed.

Official Title
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A Phase 1/2, Open-Label, Study to Evaluate the Safety and Anti-Tumor Activity of FS118, a LAG-3/PD-L1 Bispecific Antibody, as a Monotherapy and in Combination With Paclitaxel, in Patients With Advanced Malignancies

Conditions
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Advanced Cancer, Metastatic Cancer, Squamous Cell Carcinoma of Head and Neck

Intervention / Treatment
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* Drug: FS118
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants: Age ≥18 years; Participants with histologically confirmed, locally advanced, unresectable, or metastatic solid tumors that progressed while on or after PD-1/PD-L1 containing therapy; Measurable disease; Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1; Life expectancy estimated to be at least 3 months; Highly effective contraception; Willing and able to provide written informed consent. Expansion cohort only: Histologically and/or cytologically confirmed recurrent/metastatic (R/M) SCCHN that is not amenable to curative therapy by surgery or radiation; Only 1 prior anti-PD-1 or anti-PD-L1 therapy and documented PD-L1 scoring ≥1% by combined positive score or tumor proportion score as part of their treatment; An anti-PD-1 or anti-PD-L1 treatment regimen must be the last prior therapy before study enrollment, following no more than 2 prior systemic regimens for R/M SCCHN; Acquired resistance to an anti-PD-1- or anti-PD-L1-containing therapy; The participant agrees to undergo a pre-treatment and on-treatment core or excisional biopsy and the biopsy procedure is not judged to be high risk by the Investigator. Exclusion Criteria: All participants: Participant is deemed at high risk of fatal outcome in case of COVID-19; Participants with a history of COVID-19 and have not provided a negative test for SARS CoV-2 infection within 28 days of the planned first dose date with FS118; Prior therapy: Received systemic anti-cancer therapy within 28 days or 5 half-lives, of the first dose of study drug, or prior treatment with a LAG-3 inhibitor; Participants with active or documented history of autoimmune disease; History of uncontrolled intercurrent illness; Known infections; Uncontrolled CNS metastases, primary CNS tumors, or solid tumors with CNS metastases as only measurable disease; Prior history of or active interstitial lung disease or pneumonitis, encephalitis, seizures, severe immune related adverse events with prior PD-1/PD-L1 containing treatments; Significant cardiac abnormalities; Significant laboratory abnormalities; Intolerance to the investigational product or its excipients, or any condition that would significantly impair and/or prohibit the participants's participation in the study, as per the Investigator's judgment. Expansion cohort only: Participant has nasopharynx or thyroid primary tumor site; History of severe immune-related toxicity during the prior treatment with checkpoint inhibitors.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FS118 weekly<br>The initial cohorts will enroll sequentially as single-participant cohorts. If no DLT or ≥Grade 2 study drug related adverse event is observed, then dosing will proceed in a 3+3 design followed by an expansion cohort of participants with SCCHN and an expansion SCCHN cohort in combination with Paclitaxel. | Drug: FS118<br>* Dosing of participants will occur intravenously (IV) weekly in 3-week treatment cycles until iCPD (i.e., immune confirmed progressive disease), unacceptable toxicity, or discontinuation.<br>Drug: Paclitaxel<br>* Dosing on Days 1, 8 and 15 of each 28 day cycle in combination with FS118 given on days 1, 8, 15 and 22 of each 28 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation: Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | Incidence, severity and duration of adverse events will be assessed by CTCAEv4.03 | 12 months | 
| Dose escalation: Serum Concentration vs time profile of FS118 | Blood samples for serum PK analysis will be obtained (concentrations measured in mcg/mL) | 7 months | 
| Dose escalation: Maximum Serum Concentration of FS118 | Blood samples for serum PK analysis will be obtained (Cmax measured in mcg/mL) | 7 months | 
| Dose escalation: Time to reach maximum serum concentration (Tmax) of FS118 | Blood samples for serum PK analysis will be obtained (Tmax measured in hours) | 7 months | 
| Dose escalation: Trough serum concentration (Ctrough) of FS118 prior to the next dose | Blood samples for serum PK analysis will be obtained (Ctrough measured in mcg/mL) | 7 months | 
| Dose escalation: Area under the serum FS118 concentration vs time Curve (AUC) | Blood samples for serum PK analysis will be obtained (AUC measured in d.mcg/mL) | 7 months | 
| Dose escalation: Systemic Clearance (CL) of FS118 | Blood samples for serum PK analysis will be obtained (CL measured in mL/day) | 7 months | 
| Expansion cohort: Disease control rate as assessed by RECIST 1.1 in evaluable participants with PD-L1 and LAG-3 positive SCCHN | Assessed by RECIST 1.1 | 24 weeks | 
| Expansion cohort (FS118 + paclitaxel): Incidence of Treatment Emergent Adverse Events (safety and Tolerability) Incidence, severity and duration of adverse events | Assessed by CTCAE v 5.0 | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation: Disease Response as assessed by RECIST 1.1 and iRECIST | Assessed by RECIST 1.1 and iRECIST | 7 months | 
| Dose escalation and expansion cohort of FS118 + paclitaxel | Incidence of FS118 immunogenicity will include ADA detection and analysis (incidence measured in titre) | 7 months | 
| Expansion cohort: Disease Response as assessed by RECIST 1.1 and iRECIST in all SCCHN participants | Assessed by RECIST 1.1 and iRECIST | 24 months | 
| Expansion cohort: Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) | Incidence, severity and duration of adverse events will be assessed by CTCAEv4.03 | 12 months | 
| Expansion cohort: Maximum Serum Concentration of FS118 | Blood samples for serum PK analysis will be obtained (Cmax measured in mcg/mL) | 7 months | 
| Expansion cohort: Time to reach maximum serum concentration (Tmax) of FS118 | Blood samples for serum PK analysis will be obtained (Tmax measured in hours) | 7 months | 
| Expansion cohort: Trough serum concentration (Ctrough) of FS118 prior to the next dose | Blood samples for serum PK analysis will be obtained (Ctrough measured in mcg/mL) | 7 months | 
| Expansion cohort: Area under the serum FS118 concentration vs time Curve (AUC) | Blood samples for serum PK analysis will be obtained (AUC measured in d.mcg/mL) | 7 months | 
| Expansion cohort: Systemic Clearance (CL) of FS118 | Blood samples for serum PK analysis will be obtained (CL measured in mL/day) | 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bispecific antibody, FS118, Immuno-oncology, check-point inhibitor, dose escalation, cohort expansion, PK, PD, biomarker, LAG-3, PD-L1, SCCHN, F-star