A phase 3 study to look at the effects of 2 treatments used together (ficlatuzumab and cetuximab) on the overall survival of adults with a certain type of head and neck cancer (called HPV-negative) that has come back or spread to another part of the body.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Aveo Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Oct 2024 → ongoing

Decision date (initial)

2024-04-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AVEO Pharmaceuticals, Inc.

External identifiers

EU CT number

2023-505606-42-00

WHO UTN

U1111-1292-3222

ClinicalTrials.gov

NCT06064877

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Efficacy, Therapy, Pharmacodynamic, Pharmacokinetic

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)

Secondary objectives 8

1. 4. To evaluate the duration of response (DOR) for ficlatuzumab plus cetuximab versus placebo plus cetuximab in participants with R/M HPV-negative HNSCC
2. 5. To compare the safety and tolerability of ficlatuzumab plus cetuximab versus placebo plus cetuximab in participants with R/M HPV-negative HNSCC
3. 6. To evaluate the pharmacokinetics (PK) of ficlatuzumab
4. 7. To assess the immunogenicity of ficlatuzumab
5. 3. To evaluate the disease control rate (DCR) for ficlatuzumab plus cetuximab versus placebo plus cetuximab in participants with R/M HPV-negative HNSCC
6. 1. To evaluate progression-free survival (PFS) for ficlatuzumab plus cetuximab versus placebo plus cetuximab in participants with R/M HPV-negative HNSCC
7. 2. To evaluate objective response rate (ORR) for ficlatuzumab plus cetuximab versus placebo plus cetuximab in participants with R/M HPV-negative HNSCC
8. 8. To evaluate quality of life of ficlatuzumab plus cetuximab versus placebo plus cetuximab in participants with R/M HPV-negative HNSCC

Conditions and MedDRA coding

Head and Neck Squamous Cell Carcinoma (HNSCC)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

Yes

IPD plan description

The coded Personal health information collected during this study may also be added to research databases and used in the future by the Sponsor and other companies and people working for or with the Sponsor to: • Develop a better understanding of the safety and effectiveness of the study drug; • Study other therapies for patients; • Develop a better understanding of diseases included in the study; and • Improve the efficiency, design and methods of future studies.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Male or female and ≥ 18 years of age
2. 11. Ability to give written informed consent and comply with protocol requirements
3. 12. Patients with feeding tubes are eligible for the study.
4. 13. 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
5. 2. Histologically and/or cytologically confirmed primary diagnosis of R/M HNSCC a. Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx
6. 3. 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).
7. 4. 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
8. 5. 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)
9. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 with a life expectancy of at least 12 weeks
10. 8. 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
11. 9. For WOCBP, documentation of negative serum pregnancy test within 30 days of randomization
12. 10. 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.
13. 6. The patient’s tumor is considered inoperable and incurable in the opinion of the Investigator.

Exclusion criteria 17

1. 1. 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.
2. 10. 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)
3. 11. 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
4. 12. 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
5. 15. 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
6. 16. Radiographic evidence (historical or at Screening) of ILD or idiopathic pulmonary fibrosis
7. 17. Female participants who are pregnant or breastfeeding
8. 2. Participants with nasopharyngeal cancer or paranasal sinus cancer
9. 3. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agent or cetuximab
10. 4. 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.
11. 5. 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
12. 6. 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
13. 7. Active tumor-related bleeding within the last 30 days that is clinically significant in the opinion of the investigator
14. 8. 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
15. 9. 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
16. 13. Treatment with any live or attenuated vaccine within 30 days prior to the first dose of study therapy.
17. 14. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (OS), defined as the time from the date of randomization to the date of death for any cause

Secondary endpoints 8

1. 1. PFS defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) as assessed by the investigator, or death from any cause, whichever occurs first
2. 2. ORR defined as the percentage of participants who have a complete response (CR) or a partial response (PR) per RECIST v1.1 as assessed by the investigator
3. 3. DCR defined as the percentage of participants who have achieved a CR, PR, or stable disease (SD) for at least 8 weeks per RECIST v1.1 (as assessed by the investigator)
4. 4. Duration of response (DOR), defined for participants who have a confirmed CR or PR as the time from the date of first documented response (which is subsequently confirmed) per RECIST v1.1, as assessed by the investigator, until date of documented PD or death due to any cause, whichever occurs first
5. 5. Incidence and severity of adverse events (AEs); Incidence and severity of laboratory abnormalities
6. 6. Concentrations of ficlatuzumab in serum samples
7. 7. The presence of antidrug antibodies (ADA) to ficlatuzumab based on seroconversion status, and the evaluation of the potential impact of ADA on PK, efficacy, and safety • The presence of neutralizing antibodies, when ADA is positive, and the evaluation of the potential interference of ADA on ficlatuzumab-HGF binding
8. 8. Change from baseline in the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-Head and Neck Module 35 (H&N35) • Time to clinically meaningful deterioration in scores on the EORTC H&N35 • Change from baseline in overall health status per the EuroQol-5 dimensions-3 level (EQ-5D-3L)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Aveo Pharmaceuticals Inc.

Sponsor organisation

Aveo Pharmaceuticals Inc.

Address

1 Marina Park Drive Floor 12th

City

Boston

Postcode

02210-1832

Country

United States

Scientific contact point

Organisation

Aveo Pharmaceuticals Inc.

Contact name

AVEO Clinical Trials Medical

Public contact point

Organisation

Aveo Pharmaceuticals Inc.

Contact name

AVEO Clinical Trials Medical

Third parties 12

Locations

11 EU/EEA countries · 50 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 146 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications