Phase II Study of MEDI4736, Tremelimumab, and MEDI4736 in Combination w/ Tremelimumab Squamous Cell Carcinoma of the Head and Neck

A Phase II, Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 Monotherapy, Tremelimumab Monotherapy, and MEDI4736 in Combination With Tremelimumab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

The purpose of this study is to determine the efficacy and safety of investigational medical products (MEDI4736 monotherapy, tremelimumab monotherapy, and MEDI4736 + tremelimumab combination therapy) in the treatment of patients with recurrent or metastatic carcinoma of the head and neck who have progressed during or after treatment with a platinum containing regimen for recurrent/metastatic disease.

Study Overview

• Status: Completed
• Conditions: Recurrent/Metastatic Squamous Cell Carcinoma of Head & Neck
• Intervention / Treatment: Drug: MEDI4736 + Tremelimumab; Drug: MEDI4736; Drug: Tremelimumab

Detailed Description

This is a randomized, open-label, multi-center, global, Phase II study to determine the efficacy and safety of MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy and tremelimumab monotherapy in the treatment of patients with recurrent or metastatic PD-L1-negative squamous cell carcinoma of the head and neck (SCCHN) who have progressed during or after treatment with only 1 systemic palliative regimen for recurrent or metastatic disease, that must have contained a platinum agent.

Patients will be randomized in a stratified manner according to prognostic factors, including human papillomavirus (HPV) status and smoking status to achieve a balance between treatments for each of the factors. Patients will be randomized in a 1:1:2 fashion to receive MEDI4736 monotherapy, tremelimumab monotherapy, or MEDI4736 + tremelimumab combination.

All treatments will be administered beginning on Day 0 for 12 months or until confirmed progression of disease; unless, in the Investigator's opinion, the patient continues to receive benefit from the treatment), initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. Patients with confirmed progression of disease who, in the Investigator's opinion, continue to receive benefit from their assigned investigational product and who meet the criteria for treatment in the setting of progression of disease may continue to receive their assigned investigational product treatment for a maximum of 12 months after consultation with the Sponsor and at the Investigator's discretion. The monotherapy arms (tremelimumab and MEDI4736) should be discontinued if there is confirmed progression of disease following a previous response in target lesions (complete response or partial response).

Tumor assessments will be performed using computed tomography or magnetic resonance imaging. Efficacy for all patients will be assessed by objective tumor assessments every 8 weeks (q8w) for the first 48 weeks (relative to the date of the first infusion) then q12w in patients who have disease control after 12 months until confirmed objective disease progression.

Following completion or discontinuation of treatment, patients will enter a follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 267
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Research Site
  • Darlinghurst, Australia, 2010
    • Research Site
  • Tweed Heads, Australia, 2485
    • Research Site
• Belgium
  • Brussels, Belgium, 1090
    • Research Site
  • Charleroi, Belgium, 6000
    • Research Site
  • Kortrijk, Belgium, 8500
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Namur, Belgium, 5000
    • Research Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Research Site
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 6Z8
      • Research Site
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • Research Site
    • Ottawa, Ontario, Canada, K1H 8L6
      • Research Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Research Site
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Research Site
• Czechia
  • Olomouc, Czechia, 775 20
    • Research Site
  • Zlin, Czechia, 762 75
    • Research Site
• France
  • Angers, France, 49933
    • Research Site
  • Bordeaux, France, 33604
    • Research Site
  • Brest, France, 29229
    • Research Site
  • Dijon, France, 21079
    • Research Site
  • Le Mans, France, 72000
    • Research Site
  • Lille cedex, France, 59020
    • Research Site
  • Lorient cedex, France, 56322
    • Research Site
  • Lyon Cedex 08, France, 69373
    • Research Site
  • Montpellier, France, 34298
    • Research Site
  • Nice, France, 6189
    • Research Site
  • Rouen, France, 76038
    • Research Site
  • Saint Brieuc, France, 22015
    • Research Site
  • St Grégoire, France, 35768
    • Research Site
  • Strasbourg Cedex, France, 67085
    • Research Site
  • Toulouse Cedex 9, France, 31059
    • Research Site
  • Villejuif Cedex, France, 94805
    • Research Site
• Georgia
  • Batumi, Georgia, 6010
    • Research Site
  • Batumi, Georgia, 6400
    • Research Site
  • Tbilisi, Georgia, 0144
    • Research Site
  • Tbilisi, Georgia, 0179
    • Research Site
  • Tbilisi, Georgia, 0177
    • Research Site
• Germany
  • Berlin, Germany, 12203
    • Research Site
  • Halle, Germany, 06120
    • Research Site
  • Hannover, Germany, 30625
    • Research Site
  • Heidelberg, Germany, 69120
    • Research Site
  • Leipzig, Germany, 04103
    • Research Site
  • München, Germany, 81377
    • Research Site
• Hungary
  • Budapest, Hungary, 1083
    • Research Site
  • Budapest, Hungary, 1122
    • Research Site
  • Budapest, Hungary, 1077
    • Research Site
  • Gyula, Hungary, 5700
    • Research Site
  • Györ, Hungary, 9024
    • Research Site
  • Kecskemét, Hungary, 6000
    • Research Site
  • Miskolc, Hungary, 3526
    • Research Site
  • Zalaegerszeg, Hungary, 8900
    • Research Site
• Israel
  • Haifa, Israel, 31096
    • Research Site
  • Petach-Tikva, Israel, 4941492
    • Research Site
  • Tel Hashomer, Israel, 52621
    • Research Site
• Korea, Republic of
  • Daegu, Korea, Republic of, 42601
    • Research Site
  • Goyang-si, Korea, Republic of, 10408
    • Research Site
  • Suwon, Korea, Republic of, 16247
    • Research Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Research Site
  • Kuching, Malaysia, 93586
    • Research Site
• Spain
  • Barakaldo, Spain, 48903
    • Research Site
  • Barcelona, Spain, 08035
    • Research Site
  • Barcelona, Spain, 08036
    • Research Site
  • Barcelona, Spain, 08907
    • Research Site
  • Gerona, Spain, 17007
    • Research Site
  • Granada, Spain, 18014
    • Research Site
  • Jaén, Spain, 23007
    • Research Site
  • Madrid, Spain, 28046
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Madrid, Spain, 28050
    • Research Site
  • Malaga, Spain, 29010
    • Research Site
  • Marbella (Málaga), Spain, 29600
    • Research Site
  • Valencia, Spain, 46026
    • Research Site
  • Valencia, Spain, 46014
    • Research Site
  • Zaragoza, Spain, 50009
    • Research Site
• Taiwan
  • Taipei, Taiwan, 10449
    • Research Site
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Research Site
  • Birmingham, United Kingdom, B15 2TH
    • Research Site
  • Glasgow, United Kingdom, G12 0YN
    • Research Site
  • London, United Kingdom, E1 1BB
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
  • Wirral, United Kingdom, CH63 4JY
    • Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Research Site
  • Arizona
    • Yuma, Arizona, United States, 85364
      • Research Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Research Site
  • California
    • Downey, California, United States, 90241
      • Research Site
    • Duarte, California, United States, 91010-3012
      • Research Site
    • La Jolla, California, United States, 92093
      • Research Site
    • Long Beach, California, United States, 90813
      • Research Site
    • Los Angeles, California, United States, 90095
      • Research Site
    • Los Angeles, California, United States, 90033
      • Research Site
    • San Francisco, California, United States, 94115
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
  • Florida
    • Tampa, Florida, United States, 33612
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Research Site
    • Augusta, Georgia, United States, 30912
      • Research Site
    • Macon, Georgia, United States, 31201
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Research Site
    • Evanston, Illinois, United States, 60201
      • Research Site
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0001
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21204
      • Research Site
    • Baltimore, Maryland, United States, 21201
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Research Site
    • Detroit, Michigan, United States, 48201
      • Research Site
    • Southfield, Michigan, United States, 48075
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0001
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Research Site
  • New York
    • Bronx, New York, United States, 10467
      • Research Site
    • New York, New York, United States, 10032
      • Research Site
    • Stony Brook, New York, United States, 11794
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Research Site
    • Winston-Salem, North Carolina, United States, 27157
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Research Site
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • Research Site
    • Pittsburgh, Pennsylvania, United States, 15232
      • Research Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Research Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • Research Site
    • Nashville, Tennessee, United States, 37232
      • Research Site
  • Texas
    • Arlington, Texas, United States, 76012
      • Research Site
    • Austin, Texas, United States, 78701
      • Research Site
    • Dallas, Texas, United States, 75230
      • Research Site
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 96 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥18 years;
• Written informed consent obtained from the patient/legal representative;
• Histologically confirmed recurrent or metastatic SCCHN; tumor progression or recurrence during or after treatment with only 1 systemic palliative regimen for recurrent or metastatic disease that must have contained a platinum agent; Patients who have only received chemo-radiation with curative intent for treatment of their locally advanced disease or recurrent disease are not eligible. Patients who received concurrent chemo-radiation as part of treatment of their recurrent disease are also not eligible.
• Written consent to provide newly acquired tumor tissue (preferred) or archival tissue for the purpose of establishing PD-L1 status.
• Confirmed PD-L1-negative SCCHN by Ventana SP263;
• WHO/ECOG performance status of 0 or 1;
• At least 1 measurable lesion at baseline;
• No prior exposure to immune-mediated therapy;
• Adequate organ and marrow function; Evidence of post-menopausal status or negative urinary or serum pregnancy test.

Exclusion Criteria:

• Histologically confirmed squamous cell carcinoma of any other primary anatomic location in the head and neck;
• Received more than 1 regimen for recurrent or metastatic disease
• Any concurrent chemotherapy, Investigational Product, biologic, or hormonal therapy for cancer treatment;
• Receipt of any investigational anticancer therapy within 28 days or 5 half-lives;
• Receipt of last dose of an approved (marketed) anticancer therapy (chemotherapy, targeted therapy, biologic therapy, mAbs, etc) within 21 days prior to the first dose of study treatment;
• Major surgical procedure within 28 days prior to the first dose of Investigational Product;
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criterion;
• Current or prior use of immunosuppressive medication within 14 days before the first dose of their assigned Investigational Product;
• History of allogeneic organ transplantation;
• Active or prior documented autoimmune or inflammatory disorders;
• Uncontrolled intercurrent illness;
• another primary malignancy
• Patients with history of brain metastases, spinal cord compression, or a history of leptomeningeal carcinomatosis;
• History of active primary immunodeficiency;
• Known history of previous tuberculosis;
• Active infection including hepatitis B, hepatitis C or human immunodeficiency virus (HIV);
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of Investigational Product;
• Pregnant or breast-feeding female patients;
• Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction
• Known allergy or hypersensitivity to Investigational Product.
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of patient safety or study results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MEDI4736; MEDI4736 monotherapy	Drug: MEDI4736; MEDI4736 monotherapy
Experimental: Tremelimumab; Tremelimumab monotherapy	Drug: Tremelimumab; Tremelimumab monotherapy
Experimental: MEDI4736 + Tremelimumab; MEDI4736 + Tremelimumab combination therapy	Drug: MEDI4736 + Tremelimumab; MEDI4736 + Tremelimumab combination therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate at 6 Months	Objective response rate, primary analysis, based on BICR assessments according to RECIST v1.1. The number (%) of patients with a response excludes unconfirmed responses	After 6 months
Objective Response Rate at 12 Months	Objective response rate (per RECIST 1.1 as assessed by blinded independent central review [BICR]) is defined as the number (%) of patients with a confirmed complete response or confirmed partial response and will be based on all treated patients who are PD-L1-positive with measurable disease at baseline per BICR. Response Evaluation Criteria in Solid Tumors [RECIST] 1.1. criteria are: Complete response [CR] = disappearance of all target lesions since baseline; and partial response [PR] = at least a 30% decrease in the sum of the diameters of target lesions.	After 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Objective Response	The best response a patient has had during their time in the study	After 12 months
Duration of Response - Participants Remaining in Response	Participants remaining in response - based on BICR assessments according to RECIST v1.1. An ongoing response was defined as a patient who had documented objective response and was still alive and progression-free at the time of the data cut-off.	After 12 months
Time to Response	Time to response in patients with objective response based on BICR assessments according to RECIST 1.1	After 12 months
Time to Onset of Response From First Dose	Time to onset of response in patients with objective response based on BICR assessments according to RECIST 1.1	After 12 months
Disease Control Rate (DCR)	Disease control rate (DCR) at 6 months based on BICR assessments according to RECIST v1.1. DCR at 6 months was evaluated using 2 different approaches to the length of stable disease (SD). -Method 1: Patients who had a best objective response of complete response (CR) or partial response (PR) within 24 weeks or had demonstrated SD for a minimum interval of 24 weeks following randomization. -Method 2: Patients who had a best objective response of CR or PR in the first 24 weeks or who had demonstrated SD for a minimum interval of 16 weeks following randomization.	After 6 months
Disease Control Rate (DCR)	Disease control rate (DCR) at 12 months based on BICR assessments according to RECIST v1.1. DCR at 6 months was evaluated using 2 different approaches to the length of stable disease (SD). -Method 1: Patients who had a best objective response of complete response (CR) or partial response (PR) within 24 weeks or had demonstrated SD for a minimum interval of 24 weeks following randomization. -Method 2: Patients who had a best objective response of CR or PR in the first 24 weeks or who had demonstrated SD for a minimum interval of 16 weeks following randomization.	After 12 months
Progression-free Survival (PFS)	Progression status at 6 months based on BICR assessments according to RECIST v1.1 at time of Progression Free Survival (PFS) analysis. Progression was defined as the time from the data of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to progression. -Target Lesions, Non Target Lesions and New Lesions are not necessarily mutually exclusive categories. -Progression death refers to death in the absence of RECIST 1.1 progression.	After 6 months
Progression-free Survival (PFS)	Progression status at 12 months based on BICR assessments according to RECIST v1.1 at time of Progression Free Survival (PFS) analysis. Progression was defined as the time from the data of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to progression. -Target Lesions, Non Target Lesions and New Lesions are not necessarily mutually exclusive categories. -Progression death refers to death in the absence of RECIST 1.1 progression.	After 12 months
Overall Survival	Survival status at time of overall survival analysis. 'Still in survival follow-up' includes patients known to be alive at data cut-off. 'Terminated prior to death' includes patients with unknown survival status or patients who were lost to follow-up.	After 12 months
Quality of Life	Improvement in quality of life was assessed using European Organisation for Research and Treatment of Cancer (EORTC) questionnaires: -The impact of treatment on Health-Related Quality of Life, functioning, and symptoms was evaluated using the EORTC QLQ-C30 v3. -Head and neck cancer-specific symptoms were evaluated using the EORTC QLQ-H&N35. The symptom and QoL/function improvement rate was defined as the number (%) of patients with 2 consecutive assessments at least 14 days apart that showed a clinically meaningful improvement (a decrease from baseline score ≥10 or EORTC QLQ-C30 scales) in that symptom/function from baseline. For QLQ-H&N35A a minimum clinically meaningful change was defined as a change in the score from baseline of >10 for scales/items	After 12 months
Duration of Response	Duration of objective response in patients with objective response based on BICR assessments according to RECIST v1.1. Duration of response was the time from the first documentation of Complete response/Partial response (which was subsequently confirmed) until the date of progression, death, or the last evaluable RECIST assessment for patients that did not progress. An ongoing response was defined as a patient who had documented objective response and was still alive and progression-free at the time of the data cut-off (per RECIST v1.1 as assessed by BICR).	After 12 months

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: PRA Health Sciences
• Investigators: Study Director: Magdalena Wrona, Medical Scientist AstraZeneca Magdalena.Wrona@astrazeneca.com; Principal Investigator: Lillian Siu, MD, Princess Margaret Hospital in Toronto, Ontario

Publications and helpful links

General Publications

• Siu LL, Even C, Mesia R, Remenar E, Daste A, Delord JP, Krauss J, Saba NF, Nabell L, Ready NE, Brana I, Kotecki N, Zandberg DP, Gilbert J, Mehanna H, Bonomi M, Jarkowski A, Melillo G, Armstrong JM, Wildsmith S, Fayette J. Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial. JAMA Oncol. 2019 Feb 1;5(2):195-203. doi: 10.1001/jamaoncol.2018.4628.

Helpful Links

• Redacted Protocol

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2015
• Primary Completion (Actual): September 26, 2016
• Study Completion (Actual): July 6, 2020

Study Registration Dates

• First Submitted: December 12, 2014
• First Submitted That Met QC Criteria: December 17, 2014
• First Posted (Estimate): December 18, 2014

Study Record Updates

• Last Update Posted (Actual): September 29, 2020
• Last Update Submitted That Met QC Criteria: September 11, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Head and neck cancer; SCCHN
• 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; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Durvalumab; Tremelimumab; Antibodies, Monoclonal
• Other Study ID Numbers: D4193C00003

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 request 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 our timelines, please rerefer to our 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 device product: No