Monalizumab + Cetuximab for Head and Neck Cancer

(INTERLINK-1 Trial)

Recruiting at 139 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Anticancer treatments

Disqualifiers: Autoimmune disorders, Prior cetuximab, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: Unknown

Duration: 17.5 months

370 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot have any concurrent anticancer treatment, except for hormonal therapy for non-cancer-related conditions.

What data supports the effectiveness of the drug combination Monalizumab and Cetuximab for head and neck cancer?

Cetuximab, a part of the treatment, is an FDA-approved drug for head and neck squamous cell carcinoma (HNSCC) and has shown effectiveness in treating this type of cancer by targeting the epidermal growth factor receptor (EGFR), which is important for cancer growth. ^{1 2 3 4 5}

Is the combination of Monalizumab and Cetuximab safe for humans?

Cetuximab, used for colorectal and head and neck cancer, is generally safe but can cause skin rashes, infusion reactions, and mild gastrointestinal issues. It is usually well tolerated, with common side effects being mild skin problems. ^{1 4 6 7 8}

What makes the drug combination of Monalizumab and Cetuximab unique for treating head and neck cancer?

The combination of Monalizumab and Cetuximab is unique because it targets the epidermal growth factor receptor (EGFR) with Cetuximab, a monoclonal antibody, while Monalizumab may enhance the immune response against cancer cells. This dual approach could potentially improve treatment outcomes compared to using Cetuximab alone, which has been shown to improve survival when added to chemotherapy. ^{1 2 5 9 10}

What is the purpose of this trial?

This is a randomized, double-blind, multicenter, global Phase 3 study to assess the efficacy and safety of monalizumab and cetuximab, compared to placebo and cetuximab, in Participants with recurrent or metastatic head and neck cancer.

Research Team

Roger B Cohen, MD

Principal Investigator

Abramson Cancer Center, Perelman Center for Advanced Medicine

Jérôme Fayette, MD, PhD

Principal Investigator

Centre Leon Berard

Dario Ruscica, MD

Principal Investigator

AstraZeneca, Cambridge, UK

Eligibility Criteria

This trial is for adults over 18 with recurrent or metastatic head and neck cancer who have had prior treatments fail, including a PD-(L)1 inhibitor. They should not have used cetuximab unless it was part of curative therapy without progression for at least 6 months. Participants must be in good physical condition (WHO/ECOG status of 0 or 1) and cannot have autoimmune or inflammatory disorders.

Inclusion Criteria

I am fully active or able to carry out light work.

My cancer has returned or spread and cannot be cured with treatment.

Has measurable disease per RECIST 1.1

Exclusion Criteria

I am not on any cancer treatments, except hormone therapy for other conditions.

My cancer is in the head or neck but not specified in the study details.

I had cetuximab for early-stage cancer without worsening for 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive monalizumab and cetuximab or placebo and cetuximab until disease progression or unacceptable toxicity

17.5 months

Bi-weekly visits for monalizumab/placebo and weekly visits for cetuximab

Follow-up

Participants are monitored for survival after progression is confirmed

4-6 months

Treatment Details

Interventions

• Cetuximab
• Monalizumab

Trial Overview The study compares the effectiveness and safety of Monalizumab plus Cetuximab against a placebo combined with Cetuximab in patients with advanced head and neck cancer. It's randomized, meaning participants are randomly assigned to groups, double-blind so neither researchers nor participants know who gets which treatment, and conducted globally across multiple centers.

Participant Groups

Group I: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 Experimental Treatment 2 Interventions

Participants will receive intravenous (IV) monalizumab 750 mg every two weeks (Q2W) and IV cetuximab 400 mg/m\^2 initial dose followed by 250 mg/m\^2 every one week (Q1W) until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

Group II: Placebo Q2W + Cetuximab 400 mg/m^2 Active Control 2 Interventions

Participants will receieve IV placebo matched to monalizumab Q2W and IV cetuximab 400 mg/m\^2 initial dose followed by 250 mg/m\^2 Q1W until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

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?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Innate Pharma

Industry Sponsor

Trials

29

Recruited

3,100+

Findings from Research

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]

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]

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]

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]

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]

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, an EGFR-inhibiting antibody used for treating certain cancers, is generally considered safe and well-tolerated, but this case highlights the potential for severe complications following its use, particularly in complex surgical situations.

The patient experienced a rare and fatal combination of complications after surgery, raising concerns about the safety of cetuximab in the context of surgical procedures, and emphasizing the need for careful monitoring and documentation of adverse effects in clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after oesophagectomy with possible contribution of neoadjuvant therapy including an EGFR-antibody to a fatal outcome. Knauer, M., Haid, A., Ammann, K., et al.[2021]

HLX07, a re-engineered version of cetuximab, maintains similar binding affinity to EGFR but demonstrates improved bioactivity and reduced toxicity in preclinical studies, suggesting it may be a more effective treatment option.

In a preliminary phase 1 study, HLX07 showed a lower incidence of severe skin rashes compared to cetuximab, indicating a potential for better tolerability in patients undergoing EGFR-targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Distinguishing features of a novel humanized anti-EGFR monoclonal antibody based on cetuximab with superior antitumor efficacy. Lin, PH., Tseng, CL., Cheng, YC., et al.[2022]

In a study involving 201 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, the two-drug regimen of cetuximab plus cisplatin (CetCis) demonstrated noninferior progression-free survival (PFS) compared to the three-drug regimen that included paclitaxel (CetCisPac), with median PFS of 6 months versus 7 months, respectively.

The CetCis regimen also showed a lower rate of grade 4 toxicities (14% compared to 33% in the CetCisPac group), indicating a potentially safer treatment option without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Bossi, P., Miceli, R., Locati, LD., et al.[2023]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Cetuximab. [2020]

2. Switzerland 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. [2023]

3. England pubmed.ncbi.nlm.nih.gov

YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer. [2021]

4. Japan pubmed.ncbi.nlm.nih.gov

[The efficacy of cetuximab for metastatic colorectal cancer]. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma. [2021]

6. England pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Complications after oesophagectomy with possible contribution of neoadjuvant therapy including an EGFR-antibody to a fatal outcome. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Distinguishing features of a novel humanized anti-EGFR monoclonal antibody based on cetuximab with superior antitumor efficacy. [2022]

9. England pubmed.ncbi.nlm.nih.gov

A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. [2023]

10. Belgium pubmed.ncbi.nlm.nih.gov

[Monoclonal antibodies for the treatment of head and neck cancer]. [2018]