AZD2936 for Head and Neck Cancer

(MERIDIAN Trial)

Overseen by Lillian Siu, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University Health Network, Toronto

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Metastasis, Autoimmune disorders, Infections, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests AZD2936, a new drug, in patients with high-risk head and neck cancer who still have cancer DNA in their blood. The drug aims to clear out any leftover cancer cells by targeting the cancer DNA found in the blood.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, you cannot use any concurrent anticancer treatment or immunosuppressive medication within 14 days before starting the study. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug AZD2936 for head and neck cancer?

Cetuximab, a component of AZD2936, 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 AZD2936 (Cetuximab) safe for humans?

Cetuximab has been used in treating various cancers, including head and neck cancer, and is generally considered safe, but it can cause side effects like skin reactions and other toxicities. In some studies, it was shown to be effective without increasing radiotherapy-related side effects, but serious skin reactions have been reported in head and neck cancer patients. ^{1 2 6 7 8}

What makes the drug AZD2936 unique for head and neck cancer?

AZD2936 is unique because it combines cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor (EGFR) important in cancer growth, with monalizumab, potentially enhancing the immune response against cancer cells. This combination may offer a novel approach compared to standard treatments that typically focus on single-agent therapies. ^{1 2 3 4 5}

Research Team

Lillian Siu, MD

Principal Investigator

Princess Margaret Cancer Centre

Eligibility Criteria

This trial is for adults with advanced head and neck squamous cell carcinoma (LA-HNSCC) who have detectable cancer DNA in their blood after initial treatment. They must be able to perform daily activities with ease or with some limitation (ECOG 0-1), weigh at least 35 kg, and have a life expectancy of over 12 weeks.

Inclusion Criteria

My head or neck cancer is either high-risk HPV positive or negative.

I am 18 years old or older.

I weigh at least 35 kilograms.

Exclusion Criteria

I have or had an autoimmune or inflammatory disorder.

My cancer has spread to distant parts of my body.

Participation in another clinical study with an investigational product administered in the last 28 days prior to randomization or concurrent enrollment in another clinical study

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Definitive Treatment

Participants undergo definitive treatment which may include surgery followed by radiation or chemoradiation, or definitive radiation or chemoradiation according to standard of care.

Varies

Baseline ctDNA sample collection and CT staging before treatment

Post Definitive Treatment

ctDNA analysis performed at approximately week 5 and week 10 to classify patients as MRD positive or negative.

10 weeks

ctDNA analysis at week 5 and week 10

Randomized Interventional Treatment

MRD positive patients are randomized to receive AZD2936 or observation. Treatment continues until completion of 6 cycles, intolerable toxicity, or patient decision.

Varies

ctDNA analysis at week 10

Follow-up for MRD Positive

Follow-up for MRD positive patients with ctDNA samples analyzed at week 2 and week 10. Plasma samples collected every 6 months for 3 years.

3 years

Plasma samples every 6 months, CT/MRI at week 2

Observational Follow-up for MRD Negative

Observational follow-up for MRD negative patients with ctDNA sample collection at first follow-up and at progression if applicable.

3 years

Treatment Details

Interventions

• Cetuximab (Monoclonal Antibodies)
• Monalizumab (Monoclonal Antibodies)

Trial Overview The study tests AZD2936's ability to clear molecular residual disease (MRD), which is cancer DNA found in the blood post-treatment, in patients with high-risk LA-HNSCC. It's an open-label phase II trial where around 200 participants will receive this experimental therapy.

Participant Groups

Group I: MRD positive Cohort - Arm A (treatment) Experimental Treatment 1 Intervention

Dose formulation- AZD2936 is supplied as a liquid drug product in a 20R vial containing 750 mg (nominal) of active AZD2936. The solution contains 50 mg/mL AZD2936 in 20 mM L-histidine/L- histidine-hydrochloride, 240 mM sucrose, 0.04% (w/v) poloxamer 188, at pH 6.0. Unit dose strength(s)- 750 mg/vial (50 mg/mL) Dosage levels- 750mg administered Q3W Route of administration- IV infusion over 1 hour

Group II: MRD negative Cohort Active Control 1 Intervention

Observation

Group III: MRD positive Cohort - Arm B (observation) Active Control 1 Intervention

Observation

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Dr. Brad Wouters

University Health Network, Toronto

Chief Medical Officer since 2020

MD from University of Toronto

Dr. Kevin Smith

University Health Network, Toronto

Chief Executive Officer since 2018

Professor at McMaster University and University of Toronto

NeoGenomics Laboratories, Inc.

Collaborator

NeoGenomics Laboratories

Collaborator

Trials

1

Recruited

200+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

AstraZeneca

Industry 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

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]

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 study of 99 head-and-neck cancer patients receiving simultaneous integrated boost intensity-modulated radiotherapy with cetuximab, 34% experienced severe dermatitis (Grade 3/4), significantly higher than the 3% in a control group treated with cisplatin.

There was a clear link between the radiation dose to the skin and the severity of dermatitis in patients receiving cetuximab, indicating that higher radiation exposure increases the risk of severe skin reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Grade 3/4 dermatitis in head and neck cancer patients treated with concurrent cetuximab and IMRT. Studer, G., Brown, M., Salgueiro, EB., et al.[2015]

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]

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]

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. England pubmed.ncbi.nlm.nih.gov

Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol. [2020]

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

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

6. United States pubmed.ncbi.nlm.nih.gov

Grade 3/4 dermatitis in head and neck cancer patients treated with concurrent cetuximab and IMRT. [2015]

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

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

8. England 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? [2015]