Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Ficlatuzumab and Cetuximab in Recurrent or Metastatic HPV-Negative Head and Neck Squamous Cell Carcinoma
- Trial ID
- 2023-505606-42-00
- Protocol
- AV-299-23-301
- Sponsor
- Aveo Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** by overall survival (OS) of **ficlatuzumab** plus **cetuximab** versus placebo plus cetuximab in participants with recurrent or metastatic (R/M) human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). This is clinically relevant as it aims to determine whether the combination therapy can extend the survival of patients with this aggressive cancer type, which is known for its poor prognosis and limited treatment options.
Secondary objectives include:
- Evaluating progression-free survival (PFS) for ficlatuzumab plus cetuximab versus placebo plus cetuximab.
- Assessing the objective response rate (ORR) for the combination therapy compared to placebo.
- Evaluating the disease control rate (DCR) for ficlatuzumab plus cetuximab versus placebo plus cetuximab.
- Determining the duration of response (DOR) for the combination therapy compared to placebo.
- Comparing the safety and tolerability of ficlatuzumab plus cetuximab versus placebo plus cetuximab.
- Evaluating the pharmacokinetics (PK) of ficlatuzumab.
- Assessing the immunogenicity of ficlatuzumab.
- Evaluating the quality of life (QOL) of participants receiving ficlatuzumab plus cetuximab versus placebo plus cetuximab.
Participants
The clinical trial involves a total of **206 participants** diagnosed with **recurrent or metastatic (R/M) human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including a confirmed primary diagnosis of R/M HNSCC, inoperable and incurable tumor status, and failure of prior therapy with an anti-PD-1/PD-L1 immune checkpoint inhibitor and platinum-based chemotherapy. The trial population is characterized by a requirement for measurable lesions as per RECIST v.1.1 criteria and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating a relatively stable general health status. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with protocol requirements, including the use of effective contraception for those of childbearing potential. The trial does not exclude participants with feeding tubes, and archived tissue samples are required for c-Met analysis. The study does not provide specific information on the lifestyle habits of the participants.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase 3 study to evaluate the efficacy of **ficlatuzumab** in combination with **cetuximab** in participants with recurrent or metastatic HPV-negative **head and neck squamous cell carcinoma** (HNSCC). The primary objective is to compare overall survival between the treatment group receiving ficlatuzumab plus cetuximab and the control group receiving placebo plus cetuximab. The trial is expected to commence recruitment on February 1, 2024, and conclude by April 29, 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, laboratory values, and previous treatment history. Eligible participants will be randomized to receive either the investigational treatment or placebo. The study involves intravenous administration of the investigational products, with ficlatuzumab provided as a concentrate for injection and cetuximab as a solution for infusion. The placebo will be a 0.9% sodium chloride injection.
Throughout the trial, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of progression-free survival, objective response rate, and disease control rate. The presence of anti-drug antibodies and any adverse events will also be evaluated. The end-of-study visit will mark the completion of the participant's involvement, which is anticipated to last up to 48 weeks, depending on the treatment arm and individual response.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. The trial will adhere to strict ethical guidelines, ensuring that all participants provide informed consent and that their health and safety are prioritized throughout the study duration.
Treatment
The clinical trial involves the administration of **Erbitux**, a **cetuximab**-based solution for infusion, which is provided in a concentration of 5 mg/mL. This pharmaceutical form is specifically designed for **intravenous infusion**. The maximum daily dose is set at 500 mg/m², with a total maximum dose of 12,000 mg/m² over a treatment period of 28 days. The administration schedule is determined by the study protocol, and participant compliance is monitored throughout the trial. Erbitux is classified as a chemical medicinal product and is manufactured by Merck Europe B.V.
**Ficlatuzumab** is another investigational product used in this study, provided as a concentrate for injection. It is administered via **intravenous infusion**. The dosing regimen includes a maximum daily dose of 20 mg/kg, with a total maximum dose of 480 mg/kg over a 28-day treatment period. An alternative dosing regimen involves a maximum daily dose of 10 mg/kg, with a total maximum dose of 240 mg/kg over a 48-day treatment period. Ficlatuzumab is a biologic product developed by AVEO Pharma Ltd, and its administration is closely monitored to ensure adherence to the dosing schedule.
The study also includes a placebo control, which is a 0.9% Sodium Chloride injection for intravenous administration. This placebo is provided by the study site and reimbursed by the sponsor. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The administration of the placebo follows the same route and schedule as the active treatments to ensure consistency across the study arms.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **overall survival (OS)**, defined as the time from the date of randomization to the date of death from any cause. Secondary endpoints include **progression-free survival (PFS)**, which is the time from randomization to the first documented progressive disease or death, and **objective response rate (ORR)**, defined as the percentage of participants achieving a complete or partial response. Additionally, the **disease control rate (DCR)**, **duration of response (DOR)**, and the incidence and severity of adverse events will be evaluated. The trial will also assess the concentrations of ficlatuzumab in serum samples and the presence of anti-drug antibodies (ADA) and neutralizing antibodies (nAB) to ficlatuzumab.
Patient-reported outcomes will be measured using the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-Head and Neck Module 35 (H&N35) and the EuroQol-5 dimensions-3 level (EQ-5D-3L) to evaluate changes from baseline and time to clinically meaningful deterioration in scores. Efficacy assessments will be conducted at specified intervals throughout the study, with data collection and analysis performed according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), as assessed by the Investigator. The trial is designed to provide comprehensive data on the efficacy of ficlatuzumab in combination with cetuximab compared to placebo plus cetuximab in participants with recurrent or metastatic HPV-negative head and neck squamous cell carcinoma.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female and ≥ 18 years of age
- 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 daysof randomization for c-Met analysis a. If a tissue sample is not available, the reason should be clearly documented, and a fresh biopsy may be required prior to enrollment after discussion with the Medical Monitor
- Histologically and/or cytologically confirmed primary diagnosis of R/M HNSCC a. Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx
- Participants with oropharyngeal cancer will be required to have proof of p16 negative status submitted on the basis of a pathology report. Equivocal/uncertain test status will not be allowed on trial. a. If p16 status is not known, it is recommended that sites use archived tissue for p16 analysis in participants with oropharyngeal cancer. A report of this analysis must be submitted to confirm eligibility for the study. Note: Per CAP guidelines, p16 positivity is declared when there is at least 70% nuclear and cytoplasmic expression of p16 with at least moderate to strong intensity (Lewis 2018).
- At least 1 measurable lesion by contrast computed tomography (CT) or magnetic resonance imaging (MRI) scan according to Response Evaluation Criteria in Solid Tumors Version 1.1 (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 (if treatment failure was due to intolerance, the patient must have experienced documented progression of disease since the cessation of prior therapy)
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 with a life expectancy of at least 12 weeks
- Clinical laboratory values meeting the following criteria prior to randomization: a. Serum creatinine clearance > 30 mL/min, using Cockcroft and Gault formula b. Total bilirubin ≤ 1.5 × upper limit of normal (ULN;< 3 × ULN for Gilbert’s disease) c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN, or AST and ALT ≤ 5 × ULN if there are liver metastases d. Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN and prothrombin time/international normalized ratio (PT/INR) ≤ 1.5 × ULN if not on anticoagulation therapy. Participants receiving anticoagulation therapy with an agent such as warfarin, low–molecular weight heparin, or a direct oral anticoagulant (DOAC) may be allowed to participate if the participant is on a stable (≥ 2 weeks) dose of anticoagulant and coagulation test results are in the therapeutic range established prior to initiation of study treatment e. Hematologic function: i. Absolute neutrophil count (ANC) ≥ 1200 cells/μL ii. Hemoglobin (Hgb) ≥ 9 g/dL or 5.6 mmol/L. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dL is acceptable) iii. Platelet count ≥ 75,000/μL
- For 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 5 months after the last dose of study treatment. Birth control methods that may be considered highly effective include methods that achieve a failure rate of less than 1% per year when used consistently and correctly.
- The patient’s tumor is considered inoperable and incurable in the opinion of the Investigator.
Exclusion Criteria
- Participants who have received >2 prior lines of anticancer therapy or prior treatment with cetuximab/alternative EGFR inhibitors for the treatment of R/M HNSCC a. Cetuximab/EGFR inhibitors in the adjuvant setting are not allowed b. Cetuximab/EGFR inhibitors for the treatment of locally advanced HNSCC is allowed as long as disease recurrence was at least 6 months after the completion of cetuximab/EGFR treatment. c. Participants who progressed within 6 months after treatment with a platinum-based therapy for HNSCC will be considered to have received 1 prior line of treatment for R/M HNSCC.
- 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)
- Major surgery within 2 weeks prior to randomization. This is defined as any surgery involving general anesthesia and ≥ 48 hours of hospital convalescence, or surgery requiring ≥ 2 weeks for recovery. Participants must be fully recovered from surgery. Surgical procedures for placement of an IV shunt are not excluded
- Serious and/or symptomatic active infection within 14 days prior to first dose of study drug. Participants who have asymptomatic or mild infection and are currently taking a short course of antibiotics (eg, urinary tract infection, bronchitis) may be allowed after discussion with the Medical Monitor
- Participants on immune-suppressive therapy for organ transplant or participants with a history of genetic or acquired immune suppression disease such as HIV, except: a. Participants with HIV are eligible who have cluster of differentiation 4 (CD4+) T-cell counts > 350 cells/μL without a history of AIDS-defining opportunistic infections; have been on established antiretroviral therapy that does not include a cytochrome P450 3A4 inducer for at least 4 weeks; and have an HIV viral load less than 400 copies/mL
- Radiographic evidence (historical or at Screening) of ILD or idiopathic pulmonary fibrosis
- Female participants who are pregnant or breastfeeding
- Participants with nasopharyngeal cancer or paranasal sinus cancer
- History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agent or cetuximab
- Known or suspected untreated and uncontrolled brain metastases or leptomeningeal carcinomatosis Note: Participants with a history of brain metastases or with suspected brain metastases at Screening must have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry. Participants with locally treated brain metastases are eligible provided 2 weeks have elapsed since local therapy. Any neurologic symptoms that developed either because of brain metastases or their treatment must have resolved or be either stable without the use of steroids or stable on a steroid dose of ≤ 10 mg/day of prednisone or its equivalent. Participants are allowed to continue steroid taper during the start of study treatment.
- Prior treatment with any other investigational drug or biologic agentor, or radiation therapy before a washout has been completed (must be completed prior to randomization): a. 2 weeks (14 days) or 5 half-lives, whichever is shorter, for chemotherapeutic agents, small molecules, and checkpoint inhibitors b. 3 weeks (21 days) or 5 half-lives, whichever is shorter, for antibody-drug conjugates c. 4 weeks (28 days) for cell therapiesd. d. 2 weeks (14 days) for radiation therapy
- 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
- Active tumor-related bleeding within the last 30 days that is clinically significant in the opinion of the investigator
- Significant cardiovascular disease, including: a. Echocardiogram (ECHO) showing left ventricular ejection fraction of less than 45% b. Cardiac failure New York Heart Association class III or IV c. Myocardial infarction, severe or unstable angina within 6 months prior to randomization d. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) e. Significant thrombotic or embolic events within 3 months prior to randomization (significant thrombotic or embolic events include, but are not limited to, stroke or transient ischemic attack). Participants with catheter-related thrombosis, asymptomatic deep vein thrombosis, or asymptomatic pulmonary embolism are not excluded f. Any uncontrolled or severe cardiovascular disease, such as uncontrolled high blood pressure, in the opinion of the investigator
- 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
- Treatment with any live or attenuated vaccine within 30 days prior to the first dose of study therapy.
- Participants who are positive for hepatitis B virus (HBV) or hepatitis C virus (HCV) with indication of acute or chronic hepatitis, as follows: a. Participants who are positive for hepatitis B surface antigen (HBsAg; indicative of chronic HBV or recent acute HBV) are not eligible. b. Participants who are negative for HBsAg and positive for hepatitis B core antibody should undergo assessment of HBV DNA by polymerase chain reaction (PCR); detectable hepatitis B virus DNA suggests occult hepatitis B and warrants exclusion c. Participants who are positive for HCV virus antibody (HCVAb) should undergo assessment of HCV RNA by PCR; detectable HCV RNA suggests chronic HCV and warrants exclusion.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 01 Feb 2024 | 12 |
 Bulgaria | Not Recruiting | 01 Feb 2024 | 4 |
 Czechia | Recruiting | 01 Feb 2024 | 16 |
 France | Recruiting | 01 Feb 2024 | 28 |
 Germany | Recruiting | 01 Feb 2024 | 20 |
 Hungary | Recruiting | 01 Feb 2024 | 20 |
 Italy | Recruiting | 01 Feb 2024 | 40 |
 The Netherlands | Recruiting | 01 Feb 2024 | — |
 Poland | Recruiting | 01 Feb 2024 | 8 |
 Romania | Recruiting | 01 Feb 2024 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Erbitux 5 mg/mL solution for infusion | Test | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 500 | 28 | PRD327539 |
Ficlatuzumab | Test | CONCENTRATE FOR INJECTION | INTRAVENOUS INFUSION | 10 | 48 | PRD10914052 |
Ficlatuzumab | Test | CONCENTRATE FOR INJECTION | INTRAVENOUS INFUSION | 20 | 28 | PRD10914059 |
The corresponding placebo for this study is 0.9% Sodium Chloride injection for intravenous administration and this will be provided by the study site (and reimbursed by the Sponsor). | Placebo | N/A | — | — | — | N/A |