Phase III Open Label Study of MEDI 4736 With/Without Tremelimumab Versus Standard of Care (SOC) in Recurrent/Metastatic Head and Neck Cancer

Study Overview
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Brief Summary
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This is a randomized, open-label, multi-center, 3-arm, global Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination or MEDI4736 monotherapy versus SoC (EXTREME regimen) in the treatment of patients with SCCHN who have not received prior systemic chemotherapy for recurrent or metastatic disease.

Detailed Description
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Patients will be randomized in a 2:1:1 ratio to MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, or SoC. Patients in all arms will continue therapy until progression. Tumor assessments will be performed on computed tomography scans or magnetic resonance imaging scans, preferably with intravenous (IV) contrast. Efficacy for all patients will be assessed by objective tumor assessments every 6 weeks for the first 24 weeks, then every 8 weeks thereafter until treatment discontinuation due to progression or toxicity. All patients will be followed every 3 months for survival after progression is confirmed.

Official Title
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A Phase III Randomized, Open-label, Multi-center, Global Study of MEDI4736 Alone or in Combination With Tremelimumab Versus Standard of Care in the Treatment of First-line Recurrent or Metastatic Squamous Cell Head and Neck Cancer Patients

Conditions
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Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Biological: MEDI4736
* Biological: Tremelimumab
* Biological: MEDI4736+Tremelimumab
* Biological: Cetuximab
* Drug: 5-fluorouracil (5FU)
* Drug: Cisplatin
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years at the time of screening Documented evidence of recurrent or metastatic SCCHN (oral cavity, oropharynx, hypopharynx, or larynx). A fresh tumor biopsy for the purpose of screening or an available archival tumor sample. Tumor lesions used for fresh biopsies should not be the same lesions used as RECIST target lesions, unless there are no other lesions suitable for biopsy. No prior systemic chemotherapy for recurrent or metastatic disease World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment No prior exposure to immune-mediated therapy, Exclusion Criteria: Histologically or cytologically confirmed head and neck cancer of any other primary anatomic location in the head and neck not specified in the inclusion criteria including patients with SCCHN of unknown primary or non-squamous histologies (eg, nasopharynx or salivary gland) Tumor progression or recurrence within 6 months of last dose of platinum therapy in the primary treatment setting Receipt of any radiotherapy or hormonal therapy for cancer treatment within 30 days prior to first dose of study treatment Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy<br>MEDI4736 monotherapy. | Biological: MEDI4736<br>* Anti-PD-L1 antibody<br>|
| Experimental: Combination Therapy<br>MEDI4736+Tremelimumab combination therapy | Biological: Tremelimumab<br>* Anti-CTLA-4 Antibody<br>Biological: MEDI4736+Tremelimumab<br> <br> |
| Active Comparator: Standard of Care<br>Standard of Care treatment | Biological: Cetuximab<br>* Monoclonal Antibody<br>Drug: 5-fluorouracil (5FU)<br>* Chemotherapy Agent<br>Drug: Cisplatin<br>* Chemotherapy agent<br>Drug: Carboplatin<br>* Chemotherapy Agent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Status in the PD-L1 TC/IC High Subgroup - Durvalumab Versus Standard of Care (SOC) | Number of participants with Overall Survival (OS) | From date of randomization until time of final analysis, an average of approximately 4 years | 
| Overall Survival (OS) Median Duration in the PD-L1 TC/IC High Subgroup | Time from the date of randomization until death due to any cause (i.e., date of death or censoring - date of randomization + 1) | From date of randomization until time of final analysis, an average of approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Status in the PD-L1 TC/IC High Subgroup - Durvalumab + Tremelimumab Versus Standard of Care (SOC) | Number of participants with Overall Survival (OS) | From date of randomization until time of final analysis, an average of approximately 4 years | 
| Percentage of Patients Alive at 12, 18 and 24 Months in the PD-L1 TC/IC High Subgroup | Percentage of patients alive | 12, 18 and 24 months after randomization | 
| Progression Free Survival (PFS) in the PD-L1 TC/IC High Subgroup | Time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined using Response Evaluation Criteria in Solid Tumours criteria (RECIST v1.1), as ≥20% increase in the sum of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years | 
| Objective Response Rate (ORR) in the PD-L1 TC/IC High Subgroup | Number (%) of patients with at least 1 visit response of complete response (CR) or partial response (PR). Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions (TL) and assessed by MRI or CT: CR: Disappearance of all TLs since baseline; PR: >= 30% decrease in the sum of diameters of TLs; Overall Response (OR = CR + PR) | Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years | 
| Duration of Response (DoR) in the PD-L1 TC/IC High Subgroup | Time from the date of first documented response until the first date of documented progression or death in the absence of disease progression | Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years | 
| Overall Survival (OS) Status in the All-comers (Full Analysis Set) | Number of participants with Overall Survival (OS) | From date of randomization until time of final analysis, an average of approximately 4 years | 
| Overall Survival (OS) Median Duration in the All-comers (Full Analysis Set) | Time from the date of randomization until death due to any cause (i.e., date of death or censoring - date of randomization + 1) | From date of randomization until time of final analysis, an average of approximately 4 years | 
| Percentage of Patients Alive at 12, 18 and 24 Months in the All-comers (Full Analysis Set) | Percentage of patients alive | 12, 18 and 24 months after randomization | 
| Progression Free Survival (PFS) in the All-comers (Full Analysis Set) | Time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined using Response Evaluation Criteria in Solid Tumours criteria (RECIST v1.1), as ≥20% increase in the sum of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years | 
| Objective Response Rate (ORR) in the All-comers (Full Analysis Set) | Number (%) of patients with at least 1 visit response of complete response (CR) or partial response (PR). Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions (TL) and assessed by MRI or CT: CR: Disappearance of all TLs since baseline; PR: >= 30% decrease in the sum of diameters of TLs; Overall Response (OR = CR + PR) | Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years | 
| Duration of Response (DoR) in the All-comers (Full Analysis Set) | Time from the date of first documented response until the first date of documented progression or death in the absence of disease progression | Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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programmed cell death ligand 1 (PD-L1), MEDI4736, Cytotoxic T-lymphocyte-associated antigen 4 {CTLA-4}, PFS, SCCHN