Study of MEDI4736 Monotherapy and in Combination With Tremelimumab Versus Standard of Care Therapy in Patients With Head and Neck Cancer

Study Overview
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Brief Summary
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This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination therapy and MEDI4736 monotherapy versus SoC therapy in the target patient population.

Detailed Description
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This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination therapy and MEDI4736 monotherapy versus SoC therapy in the target patient population. The main objectives of the study are to: assess the efficacy of MEDI4736 + tremelimumab combination therapy versus SoC in patients with squamous cell carcinoma of the head and neck (SCCHN), in terms of overall survival (OS), regardless of PDL-1 status assess the efficacy of MEDI4736 monotherapy versus SOC in patients with SCCHN, in terms of OS, regardless of PDL-1 status Patients will undergo a screening assessment on their tumor tissue sample to determine PD-L1 expression per a pre-specified cut-off level. Patients with ≥25% of tumor cells with membrane staining will be considered PD-L1 positive while those with 0% to 24% of tumor cells with membrane staining will be considered PD-L1 negative. Based on the underlying PD-L1 status, patients will be randomized in a 1:1:1 ratio to receive treatment with MEDI4736 monotherapy, MEDI4736 + tremelimumab combination therapy, or SoC therapy. Patients who discontinue treatment in 1 treatment group may not switch to treatment in a different group. Stratification factors include PD-L1 status, human papillomavirus status, (in patients with oropharyngeal cancer only), and smoking status. Tumor assessments will be performed every 8 weeks until objective tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

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

Conditions
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Recurrent or Metastatic PD-L1-positive or -Negative Squamous Cell Carcinoma of the Head and Neck SCCHN

Intervention / Treatment
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* Drug: MEDI4736
* Drug: MEDI4736 + Tremelimumab
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Age ≥18 years; - Written informed consent obtained from the patient/legal representative; - Histologically or cytologically confirmed recurrent or metastatic SCCHN; - Tumor progression or recurrence during or after only one palliative systemic treatment regimen for recurrent or metastatic disease that must have contained a platinum agent OR progression within 6 months of the last dose of platinum given as part of multimodality therapy with curative intent; - Confirmed PD-L1-positive or -negative SCCHN by the Ventana PD-L1 SP263 IHC assay; - WHO/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; At least 1 measurable lesion, - Not previously irradiated; - No prior exposure to immune-mediated therapy; - Adequate organ and marrow function; Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Exclusion Criteria: - Histologically or cytologically confirmed squamous cell carcinoma of any other primary anatomic location in the head and neck; - Received more than 1 palliative systemic 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; - Patients with a history of brain metastases, spinal cord compression, or leptomeningeal carcinomatosis; - Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction; - History of active primary immunodeficiency; - Active 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; - Known allergy or hypersensitivity to Investigational Product

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 96 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: MEDI4736<br>MEDI4736 monotherapy | Drug: MEDI4736<br>* MEDI4736 Monotherapy<br>|
| Experimental: MEDI4736 + Tremelimumab<br>MEDI4736 + tremelimumab combination therapy | Drug: MEDI4736 + Tremelimumab<br>* MEDI4736 + Tremelimumab combination therapy<br>|
| Active Comparator: Standard of Care<br>Standard of Care | Drug: Standard of Care<br>* Standard of Care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from the date of randomization until death due to any cause. OS was analyzed for the full analysis set, regardless of programmed death-ligand 1 (PD-L1) status. | September 2015 to September 2018 (36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in PD-L1 Negative Participants | OS is defined as the time from the date of randomization until death due to any cause. PD-L1 negative was defined as <25% of tumor cells with membrane staining for PD-L1 at any intensity. | September 2015 to September 2018 (36 months) | 
| Overall Survival (OS) in PD-L1 Positive Participants | OS is defined as the time from the date of randomization until death due to any cause. PD-L1 positive was defined as ≥25% of tumor cells with membrane staining for PD-L1 at any intensity. | September 2015 to September 2018 (36 months) | 
| Progression Free Survival (PFS) | PFS was defined as the time from the date of randomization until the date of objective disease progression or death based on investigator assessments, according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). Objective disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | September 2015 to September 2018 (36 months) | 
| Objective Response Rate (ORR) | The percentage of participants who experienced an objective response (complete response [CR] or partial response [PR]), based on investigator assessments according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters. | Assessed at randomization and every 8 weeks thereafter | 
| Duration of Response (DoR) | Median DoR, in months, based on investigator assessments, according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A complete response was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A partial response was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters. | September 2015 to September 2018 (36 months) | 
| Disease Control Rate (DCR) | 6 Months: The percentage of participants who had a best objective response of complete response (CR) or partial response (PR) in the first 6 months or had demonstrated stable disease (SD) for a minimum interval of 24 weeks following randomization. 12 Months: The percentage of participants who had a best objective response of CR or PR within 12 months or had demonstrated SD for a minimum interval of 48 weeks following randomization. Objective response was based on investigator assessments, according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters. | Baseline up to 6 months; baseline up to 12 months | 
| Percentage of Participants Alive and Progression Free (APF) | APF is defined as the percentage of participants who are alive and progression free at 6 months and 12 months after randomization. Estimates of progression free survival were based on investigator assessments according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). Objective disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Baseline up to 6 months; baseline up to 12 months | 
| Percentage of Participants Alive | Percentage of participants alive at 12, 18 and 24 months using a Kaplan Meier estimate. | 12, 18 and 24 months | 
| Progression Free Survival (PFS) in PD-L1 Negative Participants | Number of participants with confirmed objective disease progression (PD) at the time of the participant's last evaluable response evaluation criteria in solid tumors 1.1 (RECIST1.1) assessment. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PD-L1 negative was defined as <25% of tumor cells with membrane staining for PD-L1 at any intensity. | September 2015 to September 2018 (36 months) | 
| Objective Response Rate (ORR) in PD-L1 Negative Participants | The percentage of PD-L1 negative participants who experienced an objective response (complete response [CR] or partial response [PR]), based on investigator assessments according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters. PD-L1 negative was defined as <25% of tumor cells with membrane staining for PD-L1 at any intensity. | September 2015 to September 2018 (36 months) | 
| Time to Deterioration in European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire, Version 3 (EORTC QLQ-C30) | The EORTC QLQ-C30 consists of 30 questions that can be combined to produce functional scales (e.g. physical), symptom scales (e.g. fatigue), and a global measure of health status. Each of the scales are measured from 0 to 100. Deterioration was defined as a 10-point decrease from baseline in a functioning or global health status/ quality of life score or a 10-point increase from baseline in a symptom score. | September 2015 to September 2018 (36 months) | 
| Time to Deterioration for European Organisation for Research and Treatment of Cancer 35-item Head and Neck Quality of Life Questionnaire (EORTC QLQ-H&N35) | The EORTC QLQ-H&N35 comprises of 35 questions to assess head and neck cancer symptoms (e.g. pain, swallowing). Deterioration was defined as a 10-point increase from baseline in the symptom score. | September 2015 to September 2018 (36 months) | 
| Number of Participants Reporting One or More Adverse Events (AE) | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. Inclusive of AEs and serious AEs. | First dose to last dose + 90 days or data cut off (up to 36 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Head and Neck cancer; MEDI4736; Tremelimumab