Ficlatuzumab + Cetuximab for Head and Neck Cancer

(FIERCE-HN Trial)

Recruiting at 129 trial locations

Overseen By Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AVEO Pharmaceuticals, Inc.

Must be taking: Cetuximab

Disqualifiers: Severe allergies, Brain metastases, Cardiovascular disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 44 months

410 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, ficlatuzumab and cetuximab (also known as Erbitux), to determine its effectiveness for people with a specific type of head and neck cancer that has recurred or spread and is HPV-negative. The main goal is to see if this combination can help patients live longer or prevent their cancer from worsening compared to cetuximab with a placebo. Individuals who have this type of cancer, have tried other unsuccessful treatments, and have tumors that cannot be removed might be suitable for this study. As a Phase 3 trial, it represents the final step before FDA approval, offering patients early access to potentially effective treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there is a 'washout period' (time without taking certain medications) required for prior treatments, which includes 2 weeks for chemotherapeutic agents and radiation therapy, and 3 weeks for antibody-drug conjugates.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of ficlatuzumab and cetuximab is generally well-tolerated by patients. In earlier studies, this drug pair produced promising results, even for patients who no longer responded to cetuximab alone. Most patients underwent the treatment without serious side effects. While some side effects occurred, they were neither common nor severe. This suggests the combination is relatively safe. However, as with any treatment, individual experiences may vary, so discussing potential risks with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ficlatuzumab combined with cetuximab for head and neck cancer because it offers a new approach compared to standard treatments like chemotherapy, radiation, and cetuximab alone. Ficlatuzumab targets the hepatocyte growth factor (HGF) pathway, which plays a role in cancer cell growth and survival, potentially enhancing the effects of cetuximab, which targets the epidermal growth factor receptor (EGFR). By combining these mechanisms, the treatment aims to more effectively inhibit cancer progression and improve outcomes. This dual-target approach could offer a significant advantage over current therapies, potentially leading to better results for patients.

What evidence suggests that ficlatuzumab plus cetuximab could be an effective treatment for head and neck cancer?

Research has shown that using ficlatuzumab with cetuximab may help treat head and neck cancer that has recurred or spread. In this trial, participants in the investigational arms will receive ficlatuzumab plus cetuximab. A study found that patients who received this combination experienced a longer time before their cancer progressed. Previous patients treated with these drugs together also achieved positive results, prompting further research. This combination blocks specific pathways that tumors use to grow, offering hope for individuals with HPV-negative head and neck cancer. ^{1 4 5 6 7}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with recurrent or metastatic HPV-negative head and neck squamous cell carcinoma who've had prior unsuccessful treatment with anti-PD-1/PD-L1 therapy and platinum-based chemo. They should be reasonably healthy (ECOG status of 0 or 1) and not pregnant, willing to use contraception, and have a measurable lesion that hasn't been treated by radiation unless it's clearly growing.

Inclusion Criteria

You are capable of providing written consent and following the protocol guidelines.

You possess a feeding tube, thus making you eligible for the study.

My diagnosis of head and neck cancer is confirmed by lab tests.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ficlatuzumab or placebo in combination with cetuximab every 28-day cycle

44 months

Visits on Day 1 and Day 15 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Ficlatuzumab

Trial Overview The study tests if ficlatuzumab combined with cetuximab improves survival compared to placebo plus cetuximab in patients whose cancer has returned or spread. It aims to see which combination is better at stopping the cancer from progressing.

How Is the Trial Designed?

Group I: Arm 2 (Investigational Arm: ficlatuzumab plus cetuximab) Experimental Treatment 2 Interventions

IV ficlatuzumab dose B on D1 and D15 of each 28-day cycle IV cetuximab on D1 and D15 of each 28-day cycle

Group II: Arm 1 (Investigational Arm: ficlatuzumab plus cetuximab) Experimental Treatment 2 Interventions

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

Group III: Arm 3 (Comparator Arm: placebo plus cetuximab) Placebo Group 2 Interventions

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

Cetuximab is already approved in United States, European Union for the following indications:

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Who Is Running the Clinical Trial?

AVEO Pharmaceuticals, Inc.

Lead Sponsor

Trials

46

Recruited

4,000+

Published Research Related to This Trial

Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor, which plays a crucial role in the growth of various cancers.

It received accelerated approval from the US FDA in February 2004 for treating metastatic colorectal cancer based on positive tumor response rates observed in Phase II clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab. Goldberg, RM.[2020]

In a study of 8 patients with recurrent/advanced colorectal cancer, 6 patients showed a positive response to cetuximab, a targeted therapy that binds to epidermal growth factor receptors (EGFR), indicating its efficacy even in later lines of treatment.

Patients receiving cetuximab in combination with CPT-11 had significantly better progression-free survival (7.3 months) and time to treatment failure (9.3 months) compared to those on cetuximab monotherapy (3.0 months and 4.5 months, respectively), highlighting the potential benefits of combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy of cetuximab for metastatic colorectal cancer]. Katsumoto, Y., Aritake, N., Endoh, A.[2018]

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

Cetuximab treatment in a 62-year-old patient with colorectal carcinoma led to persistent corneal erosions and accelerated eyelash growth, highlighting significant ocular side effects of this medication.

Topical application of EGF (epidermal growth factor) successfully healed the corneal erosions within 7 to 19 days, suggesting that EGF eyedrops may be an effective treatment for patients experiencing these side effects while continuing cetuximab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persisting corneal erosion under cetuximab (Erbitux) treatment (epidermal growth factor receptor antibody). Foerster, CG., Cursiefen, C., Kruse, FE.[2022]

In a study analyzing 3,086 reports of adverse events from cetuximab therapy for head and neck cancer, 89% of the events were classified as serious, with mucosal inflammation being the most common issue.

The study identified that receiving cetuximab treatment outside the US and using it alongside other medications significantly increased the risk of serious adverse outcomes, highlighting the need for careful monitoring in these situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events secondary to cetuximab therapy in head & neck cancer therapy and risk factors for serious outcomes. Stanbouly, D., Philipone, E., Morlandt, AB., et al.[2022]

Adding the EGFR inhibitor cetuximab to radiotherapy for locally advanced squamous cell carcinoma of the head and neck significantly improves clinical outcomes without increasing the toxicity associated with radiotherapy.

Current chemoradiotherapy regimens, which are often platinum-based, have reached a limit in tolerable toxicity, highlighting the need for more effective and tolerable treatment options like cetuximab combined with radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab combined with radiotherapy: an alternative to chemoradiotherapy for patients with locally advanced squamous cell carcinomas of the head and neck? Bernier, J., Schneider, D.[2015]

In a study of 32 head and neck squamous cell carcinoma (HNSCC) cell lines, researchers identified YAP1 amplification as a key factor associated with resistance to the EGFR-targeting antibody cetuximab, suggesting it could serve as a novel biomarker for treatment response.

The study demonstrated that higher levels of YAP1 not only correlated with cetuximab resistance but also that reducing YAP1 expression through RNA knockdown increased sensitivity to the drug, highlighting its potential role in guiding therapy decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer. Jerhammar, F., Johansson, AC., Ceder, R., et al.[2021]

Cetuximab, a monoclonal antibody targeting the EGFR, has been approved for first-line treatment of KRAS mutation-negative metastatic colorectal cancer (mCRC) in combination with FOLFIRI, showing significant improvements in progression-free survival and overall survival.

The combination of cetuximab with FOLFIRI also resulted in higher objective response rates compared to FOLFIRI alone, making it a valuable treatment option for patients with EGFR-expressing, KRAS wild-type mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. Lyseng-Williamson, KA.[2021]

The ERBITAX regimen (paclitaxel and cetuximab) demonstrated a response rate of 37.7% in 531 patients with recurrent/metastatic squamous cell carcinoma of the head and neck who were ineligible for cisplatin-based chemotherapy, indicating its efficacy as a first-line treatment.

Patients who received immunotherapy after ERBITAX treatment had significantly improved overall survival (OS) of 29.8 months compared to 13.8 months for those receiving other treatments, suggesting a beneficial sequential treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck. Rubió-Casadevall, J., Cirauqui Cirauqui, B., Martinez Trufero, J., et al.[2023]

The combination of cetuximab and ficlatuzumab was well-tolerated in a Phase I study with 13 patients, establishing a recommended Phase II dose without any dose-limiting toxicities.

This treatment showed promising activity in patients with cetuximab-resistant advanced head and neck squamous cell carcinoma, with a median progression-free survival of 5.4 months and an overall response rate of 17%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer. Bauman, JE., Ohr, J., Gooding, WE., et al.[2021]

Cétuximab, a monoclonal antibody targeting EGFR, has been shown to improve overall survival in patients with locally advanced head and neck cancer when used alongside radiotherapy, and is now reimbursed in Belgium under specific conditions.

In metastatic head and neck cancer, adding cétuximab to platinum-based chemotherapy has demonstrated improved overall survival compared to chemotherapy alone, marking a significant advancement in treatment options, although it is not yet available to Belgian patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Monoclonal antibodies for the treatment of head and neck cancer]. Sautois, B., Martin, M., Demez, P., et al.[2018]

Monoclonal antibodies like cetuximab work by promoting receptor endocytosis and activating the immune system to reduce tumor growth in head and neck squamous cell carcinoma (HNSCC).

Different strategies for targeting EGFR, including tyrosine kinase inhibitors and antisense approaches, have unique mechanisms of action, which could lead to more effective treatments and better patient selection for EGFR inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma. Cassell, A., Grandis, JR.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06064877

NCT06064877 | A Study of Ficlatuzumab in Combination ... The purpose of this study is to compare the efficacy and safety of ficlatuzumab plus cetuximab compared to placebo plus cetuximab in participants with ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02277197

Ficlatuzumab and Cetuximab in Recurrent/Metastatic Head ... This is a phase 1b, single arm, open-labeled study of ficlatuzumab and cetuximab in recurrent/metastatic HNSCC with biomarker correlatives.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36977289/

Randomized Phase II Trial of Ficlatuzumab With or Without ... The ficlatuzumab-cetuximab arm met significance criteria for PFS and warrants phase III development. HPV-negative HNSCC merits consideration ...

4. yalemedicine.org yalemedicine.org/clinical-trials/av-299-23-301-a-multicenter-randomized-double-blind-placebo-controlled-phase-3-study-of-ficlatu

Controlled, Phase 3 Study of Ficlatuzumab in Combination ... The purpose of this study is to compare the efficacy and safety of ficlatuzumab plus cetuximab compared to placebo plus cetuximab in ...

5. targetedonc.com targetedonc.com/view/ficlatuzumab-with-cetuximab-achieves-pfs-benefit-in-recurrent-metastatic-hnscc

Ficlatuzumab With Cetuximab Achieves PFS Benefit in ... Treatment with ficlatuzumab (AV-299) plus cetuximab (Erbitux) demonstrated a statistical progression-free survival (PFS) result in patients with pan-refractory ...

6. aveooncology.com aveooncology.com/aveo-oncology-enrolls-first-patient-in-pivotal-fierce-hnclinical-trial-to-evaluate-ficlatuzumab-in-combination-witherbitux-cetuximab/

AVEO Oncology Enrolls First Patient in Pivotal FIERCE-HN ... A global, multicenter, randomized, double-blind, placebo-controlled, phase 3 clinical trial evaluating ficlatuzumab in combination with ERBITUX® (cetuximab).

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7352434/

Phase I Study of Ficlatuzumab and Cetuximab in ... This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC. Keywords: HNSCC, cetuximab, ficlatuzumab, EGFR, HGF, ...