Trial: A Study of Ficlatuzumab in Combination …

Trial Details

Sponsor: AVEO Pharmaceuticals, Inc. (industry)

Phase: 3

Start date: Jan. 11, 2024

Planned enrollment: 410

Trial ID: NCT06064877

More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: Ficlatuzumab (AV-299)

Overview

Ficlatuzumab (AV-299) is a humanized IgG1 monoclonal antibody that binds and neutralizes hepatocyte growth factor (HGF), the sole ligand of the MET receptor. It is being developed primarily for oncology indications where HGF/MET signaling contributes to tumor growth and drug resistance. A randomized, phase 2 signal-finding study in pan‑refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) supports ongoing phase 3 evaluation of ficlatuzumab plus cetuximab in HPV‑negative disease; the combination also has FDA Fast Track designation for relapsed/recurrent HNSCC. (ascopubs.org, aveooncology.com)

Mechanism of action

Target: HGF ligand. Ficlatuzumab prevents HGF–MET binding and downstream signaling (e.g., ERK/AKT), with pharmacodynamic evidence of reduced tumor p‑MET in treated patients. As an IgG1, it may also engage immune effector functions. (aacrjournals.org, ascopubs.org)
Dosing used in trials: most commonly 20 mg/kg IV every 2 weeks (RP2D) as monotherapy or in combinations. (aacrjournals.org)

Efficacy

Head and neck squamous cell carcinoma (HNSCC) - Randomized phase 2 (NCT03422536) in pan‑refractory R/M HNSCC compared ficlatuzumab alone vs ficlatuzumab+cetuximab. The monotherapy arm was stopped for futility (median PFS 1.8 months; ORR 4%). The combination met its prespecified PFS benchmark vs historical control: median PFS 3.7 months; ORR 19% (6/32; 2 CR, 4 PR). Activity was concentrated in HPV‑negative patients (HPV‑negative ORR 38% [6/16] and median PFS 4.1 months vs 0% ORR and 2.3 months in HPV‑positive). (ascopubs.org)
- Phase 3 (FIERCE‑HN; NCT06064877) is an ongoing, double‑blind, placebo‑controlled trial in HPV‑negative R/M HNSCC comparing two ficlatuzumab doses plus cetuximab vs placebo plus cetuximab; primary endpoint OS. Status: recruiting (first patient enrolled January 16, 2024). No efficacy results reported yet. (aveooncology.com, ichgcp.net, redjournal.org)

Non–small cell lung cancer (NSCLC) - Randomized phase 2 in Asian patients with pulmonary adenocarcinoma: ficlatuzumab+gefitinib did not improve ORR, PFS, or OS vs gefitinib alone in the overall population. Exploratory analyses suggested potential benefit in proteomic biomarker–defined VeriStrat‑poor subgroups. (jto.org, pubmed.ncbi.nlm.nih.gov)
- Phase 1b combination with gefitinib showed tolerability and preliminary activity (objective responses in 5/12 at 20 mg/kg cohort), informing dose selection. (pmc.ncbi.nlm.nih.gov)

Acute myeloid leukemia (AML) - Phase Ib (CyFi‑1) of ficlatuzumab plus intermediate‑dose cytarabine in high‑risk relapsed/refractory AML reported an overall response rate of 53% (all complete remissions) among 17 evaluable patients, with on‑target MET pathway suppression in correlative studies. (aacrjournals.org)
- A planned randomized phase 2 (CyFi‑2) was initiated in 2019 but was subsequently halted before enrollment due to COVID‑19–related feasibility issues; AML development was discontinued. (biodesix.com, biospace.com, ashpublications.org)

Pancreatic ductal adenocarcinoma (PDAC) - Phase Ib study adding ficlatuzumab to gemcitabine+nab‑paclitaxel in previously untreated metastatic PDAC showed partial responses in 29% and median PFS/OS of 11.0/16.2 months, respectively; higher p‑MET levels correlated with response. Toxicities included hypoalbuminemia and edema. These are single‑arm, early‑phase data. (pmc.ncbi.nlm.nih.gov, pubmed.ncbi.nlm.nih.gov)

Safety

Across studies, class‑consistent adverse events include: - Hypoalbuminemia and peripheral edema (noted with ficlatuzumab alone and in combinations; grade ≥3 hypoalbuminemia up to ~16–21% in PDAC combination; edema grade ≥3 up to ~8%). (aacrjournals.org, pmc.ncbi.nlm.nih.gov) - Dermatologic toxicity (acneiform rash) largely attributable to concomitant EGFR inhibition when combined with cetuximab/gefitinib. (ascopubs.org, jto.org) - Pneumonitis has been observed infrequently, including one fatal case in the phase 2 HNSCC monotherapy arm. (ascopubs.org) - In AML combination therapy, the most frequent treatment‑related AE was febrile neutropenia, consistent with cytarabine‑based regimens. (aacrjournals.org)

No new safety signals beyond the known class effects (edema, hypoalbuminemia, rare pneumonitis) have predominated in published trials; dosing at 20 mg/kg Q2W has been generally feasible with supportive care or dose modifications as needed. (aacrjournals.org, ascopubs.org)

Regulatory and development status

FDA Fast Track designation (September 20, 2021) for ficlatuzumab in relapsed or recurrent HNSCC. (aveooncology.com, onclive.com)
Pivotal phase 3 FIERCE‑HN in HPV‑negative R/M HNSCC is ongoing; no phase 3 results available as of September 2, 2025. (aveooncology.com, redjournal.org)

HealthScout AI Analysis

Goal: Evaluate whether adding ficlatuzumab to cetuximab improves outcomes versus cetuximab with placebo in recurrent/metastatic HPV-negative HNSCC after failure of prior PD-1/PD-L1 inhibitor and platinum therapy, with a primary focus on overall survival and key secondary efficacy and safety endpoints.

Patients: Adults ≥18 years with histologically/cytologically confirmed recurrent or metastatic HPV-negative HNSCC (p16-negative if oropharyngeal), at least one measurable RECIST v1.1 lesion, ECOG 0–1, and prior exposure to and failure/intolerance of both an anti–PD-1/PD-L1 agent and platinum-based chemotherapy in any sequence or setting. Patients must have inoperable/incurable disease and provide archived tumor (or fresh biopsy if needed) for c-MET analysis. Key exclusions include >2 prior systemic lines in the R/M setting, prior cetuximab or other EGFR inhibitor in R/M disease, uncontrolled or untreated CNS metastases, unresolved >Grade 2 toxicities, significant cardiovascular disease, active hepatitis B/C with acute or chronic hepatitis, interstitial lung disease, and pregnancy/breastfeeding.

Design: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial with approximately 410 participants allocated to two ficlatuzumab dose cohorts plus cetuximab or placebo plus cetuximab. Stratification and blinding apply across all three arms. Imaging assessments occur every 8 weeks in year 1, every 12 weeks in years 2–3, then every 6 months.

Treatments: Arm 1: Ficlatuzumab dose A IV on Days 1 and 15 of 28-day cycles plus cetuximab IV on Days 1 and 15. Arm 2: Ficlatuzumab dose B IV on the same schedule plus cetuximab. Arm 3: Placebo IV on Days 1 and 15 plus cetuximab. Ficlatuzumab is a humanized IgG1 monoclonal antibody that neutralizes hepatocyte growth factor (HGF), blocking HGF–MET signaling implicated in tumor growth, invasion, and resistance. The recommended phase 2 dose has commonly been 20 mg/kg IV every 2 weeks. In a randomized phase 2 study in pan-refractory R/M HNSCC, ficlatuzumab plus cetuximab showed higher activity than ficlatuzumab alone, with responses enriched in HPV-negative disease, supporting this phase 3 evaluation. Cetuximab is an EGFR inhibitor with established activity in HNSCC and a known dermatologic toxicity profile.

Outcomes: Primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate, disease control rate, duration of response, safety/tolerability (AEs and labs), pharmacokinetics of ficlatuzumab, immunogenicity (antidrug and neutralizing antibodies), and quality of life (change from baseline and time to deterioration).

Burden on patient: Moderate. Patients receive IV therapy every 2 weeks, requiring recurrent infusion visits and associated travel. Imaging is relatively frequent (every 8 weeks in year 1, then spaced to every 12 weeks in years 2–3 and every 6 months thereafter), consistent with many phase 3 oncology trials. Archival tumor submission is required and a fresh biopsy may be needed if tissue is unavailable, adding procedural burden. Safety labs and AE monitoring are routine; pharmacokinetic and immunogenicity sampling add extra blood draws but are scheduled alongside treatment visits. Overall, treatment and assessment intensity exceeds standard post–platinum/ICI care mainly due to biweekly infusions and added PK/ADA sampling, but remains typical for a double-blind phase 3 biologic combination study.

Eligibility

Show Criteria

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 p16 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

* Patient's tumor must be considered inoperable and incurable

* 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 5 months 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 analysis (if a tissue sample is not available, a fresh biopsy may be required prior to enrollment)

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

* 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 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 or radiation therapy before a washout has been completed (must be completed prior to randomization):

1. 2 weeks (14 days) or 5 half-lives, whichever is shorter, for chemotherapeutic agents, small molecules, and checkpoint inhibitors

2. 3 weeks (21 days) or 5 half-lives, whichever is shorter, for antibody-drug conjugates

3. 4 weeks (28 days) for cell therapies

4. 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

* 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)

* Participants who are positive for HBV or HCV with indication of acute or chronic hepatitis (as defined in protocol)

* Radiographic evidence (historical or at screening) of interstitial lung disease or idiopathic pulmonary fibrosis

* Female participants who are pregnant or breastfeeding

Trial Details

Show Summary from Sponsor

More details:

Investigational Drug AI Analysis

Show for: Ficlatuzumab (AV-299)

Overview

Mechanism of action

Efficacy

Safety

Regulatory and development status

Further reading

HealthScout AI Analysis

Eligibility

Show Criteria

Sites (110)

St George Hospital

St. Vincent's Hospital

Princess Alexandra Hospital

St. John of God Murdoch Hospital

Vitaz-Sint-Niklaas Moerland

CHU Universite Catholique de Louvain

CHU Liège

University Hospital

Tom Baker Cancer Centre (Alberta Health Services)

Cross Cancer Institute

The Ottawa Hospital Cancer Centre

Princess Margaret Cancer Center - University Health Network

McGill University Health Centre (MUHC)

Fakultni nemocnice Bulovka

Fakultni Nemocnice Olomouc

Fakultni Nemocnice Kralovske Vinohrady

Masaryk Memorial Cancer Institute

Fakultni nemocnice Brno

Institut Gustave Roussy

Institut Curie

Assistance Publique Hopitaux de Marseille (APHM)-Hôpital La Timone

Centre Léon Bérard

Pôle Santé Léonard de Vinci

Clinique Pasteur - Lanroze- Centre Finistérien de Radiothérapie et d'Oncologie

Hôpital Privé des Côtes d'Armor

Charite-Universitaetsmedizin Berlin - Campus Virchow-Klinikum (CVK) - Medizinische Klinik mit Schwerpunkt Haematologie, Onkologie und Tumorimmunologie

UNIVERSITÄTSKLINIKUM FREIBURG, Klinik für Innere Medizin I, Schwerpunkt Hämatologie, Onkologie und Stammzelltransplantation

Ludwig-Maximilians University

Josa Andras Oktatokorhaz

Petz Aladar Country Teaching Hospital

Orszagos Onkologiai Intezet

Szent Lázár Megyei Kórház

University of Pecs - Oncology

Universita degli Studi di Pavia - Fondazione IRCCS Policlinico San Matteo

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

IRCCS Ospedale San Raffaele Milano

Fondazione IRCCS - Istituto Nazionale Tumori - Oncologia

Azienda Ospedaliera Universitaria Maggiore Della Carita Novara

Istituto Oncologico Veneto

IRCCS - ICS Maugeri

IRCCS Istituto Scienze Neurologiche

AOU Careggi

IRCCS Istituto Clinico Humanitas - Cancer center

Antoni van Leeuwenhoek

Radboud University Medical Center

Centrum Onkologii im. prof. F. Lukaszczyka w Bydgoszczy

National Research Institute of Oncology

Centrul radioterapie Amethyst Cluj-Napoca

Medisprof Cancer Center

Institute for Oncology Vojvodina

Institute of Oncology and Radiology of Serbia

University Clinical Center Kragujevac

Severance Hospital, Yonsei University Health System

The Catholic University of Korea, Eunpyeong St. Mary's Hospital

Seoul National University Hospital

Korea University Anam Hospital

Keimyung University Dongsan Hospital

Ajou University Hospital

Samsung Medical Center

Hospital Clinico Universitario de Valencia (CHUV)

Hospital Universitario Vinalopo

Institut Catala d'Oncologia - Hospital Duran i Reynals

UOMI Cancer Center-Clinica Tres Torres

Institut Catala d'Oncologia (ICO) - Hospitalet