Monalizumab + Cetuximab for Head and Neck Cancer

(INTERLINK-1 Trial)

Not currently recruiting at 169 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for individuals with head and neck cancer that has returned or spread after previous treatments. It compares a combination of two medicines, monalizumab (an experimental treatment) and cetuximab (a type of targeted therapy), against a placebo with cetuximab to determine which is more effective. Eligible participants have squamous cell carcinoma in areas like the mouth or throat that has not responded to past treatments and cannot be cured with surgery. Participants must have previously tried certain cancer therapies and have a type of cancer that doctors can measure. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking cancer treatment advancements.

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.

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

Research shows that patients generally tolerate the combination of monalizumab and cetuximab well. Previous studies found that the side effects of this combination resemble those of cetuximab alone, aligning with expectations from cetuximab treatment. Additionally, earlier studies with both monalizumab and cetuximab indicated that patients managed the treatment without major issues. This suggests the treatment is likely safe for most people, though individual experiences may vary. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for head and neck cancer?

Researchers are excited about Monalizumab combined with Cetuximab for treating head and neck cancer because it targets the immune system in a novel way. While standard treatments like surgery, radiation, and chemotherapy focus on attacking cancer cells directly, Monalizumab enhances the body's natural immune response by inhibiting a receptor called NKG2A found on immune cells. This could potentially improve the effectiveness of Cetuximab, which is already used to block a protein that helps cancer cells grow. By combining these mechanisms, the treatment aims to offer a more comprehensive attack on the cancer, potentially leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

This trial will compare the combination of monalizumab and cetuximab with cetuximab alone for patients with recurring or spreading head and neck cancer. Research has shown that using monalizumab with cetuximab does not significantly improve survival rates compared to cetuximab alone. The side effects of the combination align with those expected from these drugs. While further research is underway, current evidence does not strongly support that this treatment extends patients' lives with this type of cancer. ^{2 4 5 6 7}

Who Is on the Research Team?

Dario Ruscica, MD

Principal Investigator

AstraZeneca, Cambridge, UK

Roger B Cohen, MD

Principal Investigator

Abramson Cancer Center, Perelman Center for Advanced Medicine

Jérôme Fayette, MD, PhD

Principal Investigator

Centre Leon Berard

Are You a Good Fit for This Trial?

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.

Has measurable disease per RECIST 1.1

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

Exclusion Criteria

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

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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 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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04590963

Study Details | NCT04590963 | Assessment of Efficacy and ... 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 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40300079/

INTERLINK-1: A Phase III, Randomized, Placebo- ... Monalizumab plus cetuximab did not improve OS compared with placebo plus cetuximab. The safety profile of the combination was consistent ...

3. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D7310C00001/

Assessment of Efficacy and Safety of Monalizumab Plus ... This is a randomized, double-blind, multicenter, global Phase 3 study to assess the efficacy and safety of monalizumab and cetuximab, compared to placebo ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02643550

NCT02643550 | Study of Monalizumab and Cetuximab in ... The objective of this study is to evaluate in a 3 +3 design, the safety of escalating doses of Monalizumab given IV in combination with cetuximab in patients ...

5. targetedonc.com targetedonc.com/view/study-of-monalizumab-and-cetuximab-in-recurrent-metastatic-scchn-discontinued

Study of Monalizumab and Cetuximab in Recurrent ... In the phase 3 INTERLINK-1 study (NCT04590963), the combination of monalizumab and cetuximab (Erbitux) did not improve overall survival (OS) ...

6. aacrjournals.org aacrjournals.org/clincancerres/article/31/13/2617/763087/INTERLINK-1-A-Phase-III-Randomized-Placebo

INTERLINK-1: A Phase III, Randomized, Placebo-Controlled ... Additionally, the safety profile of monalizumab plus cetuximab was consistent with safety observations for cetuximab monotherapy. Introduction.

7. innate-pharma.com innate-pharma.com/sites/default/files/asco2020_monacetux.pdf

Combination of monalizumab and cetuximab in patients with ... In a Phase 1 study, the combination of monalizumab and cetuximab was well tolerated. In an initial expansion cohort (cohort 1) of 40 patients (pts) who had ...