Assessment of Efficacy and Safety of Monalizumab Plus Cetuximab Compared to Placebo Plus Cetuximab in Recurrent or Metastatic Head and Neck Cancer (INTERLINK-1)

A Phase 3 Randomized, Double-blind, Multicenter, Global Study of Monalizumab or Placebo in Combination With Cetuximab in Participants With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With an Immune Checkpoint Inhibitor

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Squamous Cell Carcinoma of the Head and Neck
• Intervention / Treatment: Drug: Monalizumab; Drug: Cetuximab; Other: Placebo

Detailed Description

Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) who had prior immune checkpoint inhibitor and platinum-based chemotherapy treatment will be randomized in a 2:1 ratio to monalizumab and cetuximab or placebo and cetuximab. Efficacy and safety assessments will be performed periodically from the time of enrollment and throughout the study. Participants in all arms will continue therapy until progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. All Participants will be followed for survival after progression is confirmed.

• Study Type: Interventional
• Enrollment (Actual): 370
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1012AAR
    • Research Site
  • Caba, Argentina, 1426
    • Research Site
  • Caba, Argentina, C1426ANZ
    • Research Site
• Australia
  • Camperdown, Australia, 2050
    • Research Site
  • Elizabeth Vale, Australia, 5112
    • Research Site
  • Heidelberg, Australia, 3084
    • Research Site
  • Melbourne, Australia, 3000
    • Research Site
• Austria
  • Linz, Austria, 4010
    • Research Site
• Belgium
  • Bruxelles, Belgium, 1200
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Namur, Belgium, 5000
    • Research Site
  • Roeselare, Belgium, 8800
    • Research Site
• Brazil
  • Belo Horizonte, Brazil, 30110-022
    • Research Site
  • Porto Alegre, Brazil, 90560-030
    • Research Site
  • Rio de Janeiro, Brazil, 22271-110
    • Research Site
  • Sao Paulo, Brazil, 01321-001
    • Research Site
  • Sao Paulo, Brazil, 01327-001
    • Research Site
  • Sao Paulo, Brazil, 01509-900
    • Research Site
  • Sao Paulo, Brazil, 04543-000
    • Research Site
• Bulgaria
  • Panagyurishte, Bulgaria, 4500
    • Research Site
  • Plovdiv, Bulgaria, 4004
    • Research Site
  • Sofia, Bulgaria, 1527
    • Research Site
• Canada
  • British Columbia
    • Victoria, British Columbia, Canada, V8R 6V5
      • Research Site
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Research Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Research Site
• France
  • Avignon, France, 84918
    • Research Site
  • Bordeaux, France, 33000
    • Research Site
  • Clermont Ferrand cedex 01, France, 63011
    • Research Site
  • Dijon, France, 21079
    • Research Site
  • Lyon Cedex 08, France, 69373
    • Research Site
  • Marseille, France, 13005
    • Research Site
  • Montpellier Cedex 05, France, 34298
    • Research Site
  • Strasbourg, France, 67033
    • Research Site
• Germany
  • Berlin, Germany, 12203
    • Research Site
  • Essen, Germany, 45122
    • Research Site
  • Freiburg, Germany, 79106
    • Research Site
  • Hannover, Germany, 30625
    • Research Site
  • Leipzig, Germany, 04103
    • Research Site
  • Ulm, Germany, 89081
    • Research Site
  • Würzburg, Germany, 97070
    • Research Site
• Greece
  • Athens, Greece, 11528
    • Research Site
  • Chaidari, Greece, 124 62
    • Research Site
  • Thessaloniki, Greece, 54645
    • Research Site
• Italy
  • Brescia, Italy, 25123
    • Research Site
  • Candiolo, Italy, 10060
    • Research Site
  • Firenze, Italy, 50134
    • Research Site
  • Milano, Italy, 20132
    • Research Site
  • Milano, Italy, 20133
    • Research Site
  • Modena, Italy, 41124
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Padova, Italy, 35128
    • Research Site
• Japan
  • Chuo-ku, Japan, 104-0045
    • Research Site
  • Fukuoka-shi, Japan, 811-1395
    • Research Site
  • Hiroshima-shi, Japan, 734-8551
    • Research Site
  • Isehara-shi, Japan, 259-1193
    • Research Site
  • Kashiwa, Japan, 277-8577
    • Research Site
  • Kobe-shi, Japan, 650-0017
    • Research Site
  • Koto-ku, Japan, 135-8550
    • Research Site
  • Okayama, Japan, 700-8558
    • Research Site
  • Osakasayama, Japan, 589-8511
    • Research Site
  • Sunto-gun, Japan, 411-8777
    • Research Site
  • Yokohama-shi, Japan, 241-8515
    • Research Site
  • Yokohama-shi, Japan, 236-0004
    • Research Site
• Korea, Republic of
  • Busan, Korea, Republic of, 49267
    • Research Site
  • Cheongju-si, Korea, Republic of, 28644
    • Research Site
  • Goyang-si, Korea, Republic of, 10408
    • Research Site
  • Seongnam-si, Korea, Republic of, 13620
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
  • Seoul, Korea, Republic of, 138-736
    • Research Site
  • Seoul, Korea, Republic of, 110-744
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Research Site
  • Maastricht, Netherlands, 6229 HX
    • Research Site
  • Nijmegen, Netherlands, 6525 GA
    • Research Site
• Philippines
  • Manila, Philippines, 1000
    • Research Site
  • Pasig City, Philippines, 1605
    • Research Site
  • Quezon City, Philippines, 1112
    • Research Site
• Poland
  • Białystok, Poland, 15-027
    • Research Site
  • Bydgoszcz, Poland, 85-796
    • Research Site
  • Poznan, Poland, 61-866
    • Research Site
• Portugal
  • Coimbra, Portugal, 3000-075
    • Research Site
  • Porto, Portugal, 4099-001
    • Research Site
  • Porto, Portugal, 4200-319
    • Research Site
  • Vila Nova de Gaia, Portugal, 4434-502
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Research Site
  • Moscow region, Russian Federation, 143081
    • Research Site
  • Obninsk, Russian Federation, 249036
    • Research Site
  • Saint Petersburg, Russian Federation, 195271
    • Research Site
  • Saint-Petersburg, Russian Federation, 197758
    • Research Site
  • Saint-Petersburg, Russian Federation, 197022
    • Research Site
  • St.Petersburg, Russian Federation, 191014
    • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
  • Madrid, Spain, 28007
    • Research Site
  • Valencia, Spain, 46014
    • Research Site
• Switzerland
  • Basel, Switzerland, 4031
    • Research Site
  • Bern, Switzerland, 3010
    • Research Site
  • Lausanne, Switzerland, CH-1011
    • Research Site
• Taiwan
  • Changhua, Taiwan, 500
    • Research Site
  • Taichung, Taiwan, 40705
    • Research Site
  • Taichung, Taiwan, 40447
    • Research Site
  • Tainan City, Taiwan, 704
    • Research Site
  • Taipei, Taiwan, 235
    • Research Site
  • Taipei, Taiwan, 112
    • Research Site
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Research Site
  • Sutton, United Kingdom, SM2 5PT
    • Research Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Research Site
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Research Site
  • New York
    • New York, New York, United States, 10029
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Research Site
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
    • Philadelphia, Pennsylvania, United States, 19111
      • Research Site
    • Pittsburgh, Pennsylvania, United States, 15232
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75246
      • Research Site
    • Houston, Texas, United States, 77090
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Are aged 18 years and over
• Recurrent or metastatic squamous cell carcinoma of the SCCHN, oral cavity, oropharynx, hypopharynx, or larynx which has progressed on or after previous systemic cancer therapy and is not amenable to curative therapy
• Received prior treatment using a programmed cell death ligand-1 (PD-L1) inhibitor
• Prior platinum failure
• Received 1 or 2 prior systemic regimens for recurrent or metastatic SCCHN
• Has measurable disease per RECIST 1.1
• A fresh or recently acquired tumor tissue for the purpose of biomarker testing
• World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

Exclusion Criteria:

• Head and neck cancer of any primary anatomic location in the head and neck not specified in the inclusion criteria, including participants with SCCHN of unknown primary or non-squamous histologies
• Had prior cetuximab therapy (unless it was administered in curative locally advanced setting with radiotherapy and no disease progression for at least 6 months following the last cetuximab dose)
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis
• Any concurrent anticancer treatment, except for hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2; 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.	Drug: Monalizumab; Participants will receive IV infusion of monalizumab as stated in arm description.; Other Names: IPH2201; Drug: Cetuximab; Participants will receive IV infusion of cetuximab as stated in arm description.; Other Names: Erbitux
Active Comparator: Placebo Q2W + Cetuximab 400 mg/m^2; 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.	Drug: Cetuximab; Participants will receive IV infusion of cetuximab as stated in arm description.; Other Names: Erbitux; Other: Placebo; Participants will receive IV infusion of placebo as stated in arm description.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) in Human Papillomavirus (HPV)-Unrelated Analysis Set	The OS is defined as time from the date of randomization until death due to any cause regardless of whether the participant withdraws from randomized therapy or receives another anti-cancer therapy (i.e. date of death or censoring - date of randomization + 1). The OS was analyzed using Kaplan-Meier technique. Statistical analysis was performed using P-value from a stratified log-rank test and hazard ratio (HR) and confidence intervals (CIs) from a stratified Cox proportional hazards model. Analyses were stratified on World Health Organization/ Eastern Cooperative Oncology Group performance status (WHO/ECOG PS) (0 or 1) and number of prior lines of therapy in recurrent or metastatic (R/M) setting (1 or 2).	Baseline (-28 to -1) through 17.5 months (maximum observed duration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival in Full Analysis Set (FAS)	The OS is defined as time from the date of randomization until death due to any cause regardless of whether the participant withdraws from randomized therapy or receives another anti-cancer therapy (i.e. date of death or censoring - date of randomization + 1). The OS was analyzed using Kaplan-Meier technique. Statistical analysis was performed using P-value from a stratified log-rank test and HR and CIs from a stratified Cox proportional hazards model. Analyses were stratified on HPV status (OPC HPV positive or HPV-unrelated), WHO/ECOG PS (0 or 1) and number of prior lines of therapy in R/M setting (1 or 2).	Baseline (-28 to -1) through 17.5 months (maximum observed duration)
Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by Investigator Assessment in HPV-unrelated Analysis Set	PFS per RECIST 1.1 as assessed by the investigator is defined as time from randomization until date of RECIST 1.1-defined radiological progressive disease (PD) or death regardless of whether participant withdraws from therapy or received subsequent anticancer therapy prior to progression. PD: at least 20% increase in sum of diameters of target lesions (TLs), taking as reference the smallest sum on study (nadir) and sum must demonstrate an absolute increase of at least 5 mm from nadir or unequivocal progression of existing non-TLs (NTLs) or appearance of new lesions. PFS was analyzed using Kaplan-Meier technique. Statistical analysis was performed using P-value from stratified log-rank test and HR and CIs from a stratified Cox proportional hazards model. Analyses were stratified on WHO/ECOG PS (0/1) and no. of prior lines of therapy in R/M setting.	Baseline (-28 to -1) through 17.5 months (maximum observed duration)
Progression-Free Survival Per RECIST 1.1 by Investigator Assessment in FAS	PFS per RECIST 1.1 as assessed by the investigator is defined as time from randomization until date of RECIST 1.1-defined radiological progressive disease (PD) or death regardless of whether participant withdraws from therapy or received subsequent anticancer therapy prior to progression. PD: at least 20% increase in sum of diameters of target lesions (TLs), taking as reference the smallest sum on study (nadir) and sum must demonstrate an absolute increase of at least 5 mm from nadir or unequivocal progression of existing NTLs or appearance of new lesions. PFS was analyzed using Kaplan-Meier technique. Statistical analysis was performed using P-value from a stratified log-rank test and HR and CIs from a stratified Cox proportional hazards model. Analyses were stratified on HPV status, WHO/ECOG PS (0/1) and no. of prior lines of therapy in R/M setting.	Baseline (-28 to -1) through 17.5 months (maximum observed duration)
Percentage of Participants With Objective Response (OR) Per RECIST 1.1 in HPV-unrelated Analysis Set	The OR is defined as the percentage of participants with at least one confirmed investigator-assessed response of complete response (CR) or partial response (PR) as assessed by RECIST 1.1 guidelines. The CR is defined as disappearance of all TLs and NTLs, any pathological lymph nodes (target and non-target) must have reduction in short axis < 10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the sum of the diameters (SoD) of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. Percentage of participants with OR is reported. Participants who had measurable disease at baseline per the site investigator were analyzed for this outcome.	Baseline (-28 to -1) through 17.5 months (maximum observed duration)
Percentage of Participants With OR Per RECIST 1.1 in FAS	The OR is defined as the percentage of participants with at least one confirmed investigator-assessed response of CR or PR as assessed by RECIST 1.1 guidelines. The CR is defined as disappearance of all TLs and NTLs, any pathological lymph nodes (target and non-target) must have reduction in short axis < 10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. Percentage of participants with OR is reported. Participants who had measurable disease at baseline per the site investigator were analyzed for this outcome.	Baseline (-28 to -1) through 17.5 months (maximum observed duration)
Duration of Response (DoR) Per RECIST 1.1 in HPV-unrelated Analysis Set	The DoR is defined as the time from the date of first documented confirmed response until date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1). The CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The PR is defined as at least a 30% decrease in the SoDs of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest previous SoDs (nadir) and the sum must demonstrate an absolute increase of at least 5 mm from nadir or unequivocal progression of existing NTLs or appearance of new lesions. The DoR was analyzed using Kaplan-Meier technique.	Baseline (-28 to -1) through 17.5 months (maximum observed duration)
Duration of Response Per RECIST 1.1 in FAS	The DoR is defined as the time from the date of first documented confirmed response until date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1). The CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The PR is defined as at least a 30% decrease in the SoDs of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest previous SoDs (nadir) and the sum must demonstrate an absolute increase of at least 5 mm from nadir or unequivocal progression of existing NTLs or appearance of new lesions. The DoR was analyzed using Kaplan-Meier technique.	Baseline (-28 to -1) through 17.5 months (maximum observed duration)
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs included events from the first dose of study drug, up to 90 days after the last dose of study drug received or up to the start date of any subsequent anticancer therapy following discontinuation of study drug, or the final safety DCO date of 01Sep2022, whichever occurred first.	Day 1 through 21.4 months (maximum observed duration)
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs	Participants with abnormal laboratory parameters reported as TEAEs are reported. Laboratory analysis included hematology and clinical chemistry. TEAEs included events from the first dose of study drug, up to 90 days after the last dose of study drug received or up to the start date of any subsequent anticancer therapy following discontinuation of study drug, or the final safety DCO date of 01Sep2022, whichever occurred first.	Day 1 through 21.4 months (maximum observed duration)
Number of Participants With Abnormal Vital Signs Reported as TEAEs	Participants with abnormal vital signs (heart rate, blood pressure, temperature, and respiratory rate) reported as TEAEs are reported. TEAEs included events from the first dose of study drug, up to 90 days after the last dose of study drug received or up to the start date of any subsequent anticancer therapy following discontinuation of study drug, or the final safety DCO date of 01Sep2022, whichever occurred first.	Day 1 through 21.4 months (maximum observed duration)
Number of Participants With Electrocardiograms (ECGs) Reported as TEAEs	Participants with Abnormal ECGs reported as TEAEs are reported. TEAEs included events from the first dose of study drug, up to 90 days after the last dose of study drug received or up to the start date of any subsequent anticancer therapy following discontinuation of study drug, or the final safety DCO date of 01Sep2022, whichever occurred first.	Day 1 through 21.4 months (maximum observed duration)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Innate Pharma
• Investigators: Principal Investigator: Roger B Cohen, MD, Abramson Cancer Center, Perelman Center for Advanced Medicine; Principal Investigator: Jérôme FAYETTE, MD, Centre Leon Berard; Study Director: Dario Ruscica, MD, AstraZeneca, Cambridge, UK

Publications and helpful links

Helpful Links

• Redacted Statistical Analysis Plan
• Redacted Study Protocol
• Redacted CSR synopsis

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2020
• Primary Completion (Actual): May 11, 2022
• Study Completion (Estimated): June 28, 2024

Study Registration Dates

• First Submitted: September 23, 2020
• First Submitted That Met QC Criteria: October 12, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: head and neck cancer; Squamous Cell Carcinoma of the Head and Neck; cetuximab; Erbitux; oropharynx; pharynx; larynx; hypopharynx; oral cavity; monalizumab; natural killer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: D7310C00001; 2019-004770-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of the timelines, please refer to the disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No