A Study of Ficlatuzumab in Combination With Cetuximab in Participants With Recurrent or Metastatic (R/M) HPV Negative Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy and safety of ficlatuzumab plus cetuximab compared to placebo plus cetuximab in participants with recurrent/metastatic (R/M) HPV-negative Head and Neck Cancer. The primary hypothesis is that ficlatuzumab combined with cetuximab is superior to cetuximab alone in terms of progression-free survival and/or overall survival.

Detailed Description
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This multicenter, randomized, double-blind, placebo-controlled Phase 3 study is designed to compare the efficacy and safety of two dose levels of ficlatuzumab combined with cetuximab (Arm 1 or Arm 2) to a control arm of placebo plus cetuximab (Arm 3) in participants with R/M human papilloma virus (HPV)-negative HNSCC. Eligible participants must have failed prior therapy with an anti-PD-1 [programmed cell death protein 1] or PD-L1 [programmed death ligand 1] immune checkpoint inhibitor (ICI) and with platinum-based chemotherapy, administered in combination or sequentially. Failure of prior treatment may be due to progression of disease or intolerance to treatment. It is anticipated that the study will enroll approximately 410 participants across 3 arms.

Official Title
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A Multicenter, Randomized, Double Blind, Placebo - Controlled, Phase 3 Study of Ficlatuzumab in Combination With Cetuximab in Participants With Recurrent or Metastatic (R/M) HPV -Negative Head and Neck Squamous Cell Carcinoma. (FIERCE-HN)

Conditions
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Metastatic Head-and-neck Squamous-cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Biological: Ficlatuzumab
* Biological: Cetuximab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female and ≥ 18 years of age Histologically and/or cytologically confirmed primary diagnosis of R/M HNSCC Participants with oropharyngeal cancer will be required to have proof of HPV-negative status submitted on the basis of a pathology report At least 1 measurable lesion by contrast CT or MRI scan according to RECIST v.1.1. Such lesions must not have been previously irradiated; if the measurable lesion(s) has been irradiated, clear progression must be documented Participants must have failed prior therapy with an anti-PD-1/PD-L1 ICI and with platinum-based chemotherapy administered in combination or sequentially, in either the locally advanced or R/M setting. Failure of prior treatment may be due to progression of disease or intolerance to treatment Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with a life expectancy of at least 12 weeks For women of childbearing potential (WOCBP), documentation of negative serum pregnancy test within 30 days of randomization For WOCBP and male participants whose sexual partners are of childbearing potential, agreement to use an effective method of contraception during the study and for at least 60 days after the last dose of study treatment. Birth control methods which may be considered highly effective include methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Ability to give written informed consent and comply with protocol requirements Patients with feeding tubes are eligible for the study. Archived tissue sample must be submitted to the Sponsor-designated laboratory within 60 days of randomization for c-Met/HGF analysis Exclusion Criteria: History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agent or cetuximab Known untreated and uncontrolled brain metastases or leptomeningeal carcinomatosis Note: Participants with locally treated brain metastases are eligible provided 2 weeks have elapsed since local therapy. Participants are allowed to continue steroid taper during the start of study treatment. Prior treatment with any other investigational drug or biologic agent before a washout has been completed (must be completed prior to randomization): 2 weeks (14 days) or 5 half-lives, whichever is shorter, for chemotherapeutic agents, small molecules, and checkpoint inhibitors 3 weeks (21 days) or 5 half-lives, whichever is shorter, for antibody-drug conjugates 4 weeks (28 days) for cell therapies Any unresolved and significant toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0) Grade > 2 from previous anticancer therapy (including radiation therapy), other than alopecia Significant cardiovascular disease, including: Cardiac failure New York Heart Association class III or IV; Myocardial infarction, severe or unstable angina within 6 months prior to randomization; History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) Any other medical condition or psychiatric condition that, in the opinion of the Investigator, might interfere with the participant's involvement in the study or interfere with the interpretation of study results History of prior malignancy within 2 years prior to randomization (except for adequately treated non-melanoma skin cancer, carcinoma in situ of the breast or cervix, superficial bladder cancer, or early-stage prostate cancer, without evidence of recurrence; participants may or may not be on maintenance therapy) Female participants who are pregnant or breastfeeding A full list of inclusion and exclusion criteria can be found in the protocol.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (Investigational Arm: ficlatuzumab plus cetuximab)<br>Intravenous (IV) ficlatuzumab dose A on Day 1 (D1) and D15 of each 28-day cycle IV cetuximab on D1 and D15 of each 28-day cycle | Biological: Ficlatuzumab<br>* Ficlatuzumab (AV-299) is a humanized hepatocyte growth factor (HGF) inhibitory immunoglobulin G1 (IgG1) monoclonal antibody (mAb).<br>* Other names: AV-299;Biological: Cetuximab<br>* Cetuximab is an epidermal growth factor receptor (EGFR) antagonist.<br>* Other names: Erbitux;|
| Experimental: Arm 2 (Investigational Arm: ficlatuzumab plus cetuximab)<br>IV ficlatuzumab dose B on D1 and D15 of each 28-day cycle IV cetuximab on D1 and D15 of each 28-day cycle | Biological: Ficlatuzumab<br>* Ficlatuzumab (AV-299) is a humanized hepatocyte growth factor (HGF) inhibitory immunoglobulin G1 (IgG1) monoclonal antibody (mAb).<br>* Other names: AV-299;Biological: Cetuximab<br>* Cetuximab is an epidermal growth factor receptor (EGFR) antagonist.<br>* Other names: Erbitux;|
| Placebo Comparator: Arm 3 (Comparator Arm: placebo plus cetuximab)<br>IV placebo (saline, ficlatuzumab-matched) on D1 and D15 of each 28-day cycle IV cetuximab on D1 and D15 of each 28-day cycle | Biological: Cetuximab<br>* Cetuximab is an epidermal growth factor receptor (EGFR) antagonist.<br>* Other names: Erbitux;Other: Placebo<br>* Placebo for this study will be normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the efficacy by overall survival of ficlatuzumab plus cetuximab vs placebo plus cetuximab in participants with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) | Overall survival (OS), defined as the time from the date of randomization to the date of death for any cause | From Randomization until death from any cause (Approximately 44 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate additional endpoints of efficacy for ficlatuzumab plus cetuximab vs placebo plus cetuximab in participants with R/M HNSCC | Progression-free survival (PFS), defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause, whichever occurs first | From Randomization until disease progression or death (Approximately 44 months) | 
| To evaluate additional endpoints of efficacy for ficlatuzumab plus cetuximab vs placebo plus cetuximab in participants with R/M HNSCC | Objective response rate (ORR), defined as the percentage of participants who have a complete response (CR) or a partial response (PR) per RECIST v1.1 | From Cycle 1 Day 1 until last response assessment (response assessments are every 8 weeks for the first year, every 12 weeks for years 2 and 3 and then every 6 months) | 
| To evaluate additional endpoints of efficacy for ficlatuzumab plus cetuximab vs placebo plus cetuximab in participants with R/M HNSCC | Duration of response (DOR), defined as the time from first documented evidence of a confirmed CR or PR per RECIST v1.1 | From Cycle 1 Day 1 until last response assessment (response assessments are every 8 weeks for the first year, every 12 weeks for years 2 and 3 and then every 6 months) | 
| To compare the safety and tolerability of ficlatuzumab plus cetuximab vs placebo plus cetuximab in participants with R/M HNSCC | Number of times participants experience Adverse Events (AE) or abnormal laboratory values. | From Screening until 30 days after last dose | 
| To evaluate the pharmacokinetics (Pk) of ficlatuzumab and cetuximab | Serum samples will be assessed for concentrations of ficlatuzumab and cetuximab | From Baseline (Cycle 1 Day 1 pre-dose) until End of Treatment (Approximately 44 months) | 
| To assess the immunogenicity of ficlatuzumab via antidrug antibodies (ADAs) | Serum samples will be assessed for the presence of ADA to ficlatuzumab. | From Baseline (Cycle 1 Day 1 pre-dose) until End of Treatment (Approximately 44 months) | 
| To assess the immunogenicity of ficlatuzumab via neutralizing antibodies (nAB) | Serum samples that test positive for the presence of ADA to ficlatuzumab will be further tested for the presence of nAB. | From Baseline (Cycle 1 Day 1 pre-dose) until End of Treatment (Approximately 44 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent, Metastatic, HPV-negative, Head and Neck, Squamous Cell Carcinoma