Study To Compare Avelumab In Combination With Standard of Care Chemoradiotherapy (SoC CRT) Versus SoC CRT for Definitive Treatment In Patients With Locally Advanced Squamous Cell Carcinoma Of The Head And Neck (JAVELIN HEAD AND NECK 100)

Study Overview
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Brief Summary
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This is a phase 3 randomized, placebo controlled study to evaluate the safety and anti-tumor activity of Avelumab in combination with standard of care chemoradiation (SoC CRT) versus SoC CRT alone in front-line treatment of patients with locally advanced head and neck cancer.

Official Title
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A RANDOMIZED DOUBLE-BLIND PHASE 3 STUDY OF AVELUMAB IN COMBINATION WITH STANDARD OF CARE CHEMORADIOTHERAPY (CISPLATIN PLUS DEFINITIVE RADIATION THERAPY) VERSUS STANDARD OF CARE CHEMORADIOTHERAPY IN THE FRONT-LINE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Conditions
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Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Avelumab
* Other: Chemoradiation


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Histological diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx HPV negative disease, Stage III, IVa, IVb; non-oropharyngeal HPV positive disease Stage III, IVa, IVb, HPV positive oropharyngeal disease T4 or N2c or N3 No prior therapy for advanced stage SCCHN; eligible for definitive CRT with curative intent. Available tumor samples for submission or willing to undergo further tumor biopsies: Age ≥18 years (≥19 in Korea;20 years in Japan and Taiwan). ECOG Performance Status 0 or 1 Adequate bone marrow function Adequate renal function Adequate liver function Pregnancy test (for patients of childbearing potential) negative at screening EXCLUSION CRITERIA Prior immunotherapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti CTLA 4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways. Major surgery 4 weeks prior to randomization. Prior malignancy requiring tumor-directed therapy within the last 2 years prior to enrollment, or concurrent malignancy associated with clinical instability. Exceptions for disease within the 2 years are superficial esophageal cancer (TIS or T1a) fully resected by endoscopy, prostate cancer (Gleason score 6) either curatively treated or deemed to not require treatment, ductal IS carcinoma of the breast that has completed curative treatment, adequately treated basal cell or squamous cell skin cancer. Active autoimmune disease Any of the following in the 6 months prior to randomization: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism. Active infection requiring systemic therapy. Use of immunosuppressive medication at time of randomization Prior organ transplantation including allogenic stem-cell transplantation. Diagnosis of prior immunodeficiency or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Vaccination within 4 weeks prior to randomization. Current use of or anticipated need for treatment with other anti-cancer drugs. Pregnant female patients, breastfeeding female patients, and male patients able to father children and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in the protocol for the duration of the study and for at least 6 months after the last dose of cisplatin and 60 days after the last dose of avelumab/placebo (whichever is later).

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avelumab + SOC Chemoradiation Therapy<br>Avelumab 10 mg/kg IV: Day 1 of the Lead-in Phase; Days 8, 25, and 39 of the CRT Phase; and Q2W for 12 months during the Maintenance Phase Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase Intensity Modulated Radiation Therapy (IMRT) 70 Gy/35 fractions/7 weeks; 1 fraction per day, 5 fractions/week for 7 weeks during the CRT Phase | Drug: Avelumab<br>* Avelumab + SOC Chemoradiation<br>|
| Placebo Comparator: Placebo + SOC CRT<br>Placebo IV matching avelumab: Days 1 of the Lead-in Phase; Days 8, 25, and 39 of the CRT Phase; Q2W for 12 months during the Maintenance Phase Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase IMRT 70 Gy/35 fractions/7 weeks; 1 fraction per day, 5 fractions/week for 7 weeks during the CRT Phase | Other: Chemoradiation<br>* Cisplatin + Radiation Therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) as Assessed by Investigator | PFS was defined as the time (in months) from the date of randomization to the first documentation of objective progressive disease (PD) per modified RECIST v1.1 as assessed by Investigator or death (due to any cause), whichever occurred first. Analysis was performed using Kaplan Meier method. PD refers to any of following: 1) Locoregional PD confirmed by pathology to verify radiographic changes represent true tumor progression and not radiation effects or non-malignant contrast enhancement. 2) Locoregional clinically detectable progression confirmed by pathology. 3) Surgical removal (salvage) of primary tumor with tumor present on final pathology. 4) Salvage neck dissection greater than (>) 20 weeks after completion of CRT with tumor present on final pathology. 5) Metastatic PD. PFS data was censored on date of last adequate tumor assessment for participants with no PFS event. | From randomization until documented PD or death, censored date, whichever occurred first (up to 37 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan Meier method. | From randomization to the date of death or censored date, whichever occurred first (up to 37 months) | 
| Pathologic Complete Response (pCR) Rate in Participants With Salvage Surgery at the Primary Site | pCR was defined as the absence of histologically identifiable residual cancer in any resected specimen. The pCR rate at primary site was estimated by dividing the number of participants with pCR recorded at any visit from randomization until PD per modified RECIST v1.1 or death due to any cause by the number of participants randomized who had salvage surgery at the primary site. | From randomization until PD or death (up to 37 months) | 
| Time to Locoregional Failure Per Modified RECIST v1.1 as Assessed by Investigator | Locoregional failure was defined as the time from the date of randomization to the date of the first documentation of locoregional recurrence or death due to any cause per modified RECIST v1.1 as assessed by Investigator, whichever occurred first. Analysis was performed using Kaplan Meier method. | From the date of randomization to the date of the first documentation of locoregional recurrence or death, whichever occurred first (up to 37 months) | 
| Objective Response Rate (ORR) Per Modified RECIST v1.1 as Assessed by Investigator | Objective response (OR) was defined as a complete response (CR) or partial response (PR) per RECIST v1.1 recorded from randomization until disease progression per modified RECIST v1.1 or death due to any cause. A participant was considered to have achieved an OR if the participant had a CR or PR which did not need to be confirmed at a subsequent assessment. CR for target disease: complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis less than [<] 10 millimeter [mm]). CR for non-target disease: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (<10 mm short axis) . PR: Greater than or equal to (>=) 30% decrease under baseline of the sum of diameters of all target measurable lesions. The ORR was estimated by dividing the number of participants with OR (CR or PR) by the number of participants randomized. | From randomization until disease progression or death, whichever occurred first (up to 37 months) | 
| Time to Distant Metastatic Failure Per Modified RECIST v1.1 as Assessed by Investigator | Time to distant metastatic failure or distant metastasis (DM) was defined as the time from the date of randomization to the date of the first documentation of distant metastatic or death due to any cause, whichever occurred first. Distant metastatic disease was defined as new tumor identified at a site distant from the head and neck anatomic region or draining lymph nodes. Analysis was performed using Kaplan Meier method. | From the date of randomization to the date of the first documentation of distant metastatic or death (up to 37 months) | 
| Duration of Response (DOR) Per Modified RECIST v1.1 as Assessed by Investigator | DOR:time from first documentation of objective tumor response (CR/PR) to first documentation of PD/death due to any cause, whichever occurred first.PR:>=30% decrease under baseline of sum of diameters of all target measurable lesions. CR for target disease:complete disappearance of all target lesions with exception of nodal disease.CR for non-target disease: disappearance of all non-target lesions and normalization of tumor marker levels. PD is any of following:1)Locoregional PD confirmed by pathology to verify radiographic changes denote true tumor progression and not radiation effects or non-malignant contrast enhancement.2)Locoregional clinically detectable progression confirmed by pathology.3)Surgical removal of primary tumor with tumor present on final pathology.4)Salvage neck dissection >20 weeks after completion of CRT with tumor present on final pathology.5)Metastatic PD. DOR data was censored on date of last adequate tumor assessment for participants with no overall response. | From the first documentation of objective tumor response to the first documentation of PD or death or censored date, whichever occurred first (up to 37 months) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. TEAE was defined as event with onset dates occurring during the on-treatment period. | Baseline up to 44 months | 
| Number of Participants With Shift From Baseline in Clinical Laboratory Parameters | Grade 1 and 3 ranges are: Anemia:Hb:<LLN-10.0,<8.0 g/dL;LC decreased (dec):<LLN-800/mm^3,500-200/mm^3;LC increased (inc):grade 3:>20,000/mm^3:NC dec:<LLN-1500/mm^3;<1000-500/mm^3;PC dec:<LLN-75,000/mm^3;<50,000-25,000/mm^3;WBC dec:<LLN-3000/mm^3;<2000-1000/mm^3;ALT inc:>ULN-3.0*ULN;>5.0-20.0*ULN;ALP & GGT inc:>ULN-2.5*ULN;>5.0-20.0*ULN;AST inc:>ULN-3.0*ULN;>5.0-20.0*ULN;BB inc:>ULN-1.5*ULN;>3.0-10.0*ULN;CH high:>ULN-300 mg/dL;>400-500 mg/dL;CPK inc:>ULN-2.5*ULN;>5*ULN-10*ULN;Hypercalcemia:>ULN-11.5;>12.5-13.5mg/dL;Hyperglycemia:>ULN-160; >250-500mg/dL;Hyperkalemia:>ULN-5.5;>6.0-7.0mmol/L;Hypermagnesemia:>ULN-3.0;>3.0-8.0 mg/dL;Hypernatremia:>ULN-150; >155-160 mmol/L;Hypertriglyceridemia;150-300;>500-1000 mg/dL;Hypoalbuminemia:<LLN-3;<2g/dL;Hypocalcemia:<LLN-8.0;<8.0-7.0mg/dL;Hypokalemia:<LLN-3.0;<3.0-2.5mmol/L;Hypomagnesemia;<LLN-1.2;<0.9-0.7 mg/dL;Hyponatremia:<LLN-130;<130-120mmol/L; Hypophosphatemia:<LLN-2.5;<2.0-1.0mg/dL;lipase & serum amylase inc:>ULN-1.5*ULN;>2.0-5.0*ULN. | Baseline up to 15 months | 
| Change From Baseline in Vital Sign - Systolic and Diastolic Blood Pressure | Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) measured in sitting position were reported. | Baseline, Lead-in phase: Day1; CRT Phase: Days 1, 8, 22, 25, 39, and 43; Maintenance phase: on Days 1 and 15 in Cycles 1 to 13 and EOT (3 days after the last dose of study drug) | 
| Change From Baseline in Vital Sign - Pulse Rate | Change from baseline in pulse rate in sitting position in beats per minute was reported. | Baseline, Lead-in phase: Day1; CRT Phase: Days 1, 8, 22, 25, 39, and 43; Maintenance phase: on Days 1 and 15 in Cycles 1 to 13 and EOT (3 days after the last dose of study drug) | 
| Change From Baseline in the European Quality of Life- 5 Dimension-5 Levels (EQ-5D-5L) Index Score at CRT Phase and Maintenance Phase | EQ-5D-5L is a standardized participant completed questionnaire that measures health status in terms of a single index value or utility score. EQ-5D-5L consisted of two components: a health state profile (descriptive system) and a visual analogue scale (VAS) in which participants rate their overall health status from 0 (worst imaginable) to 100 (best imaginable), where higher scores indicated better health status. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. EQ-5D-5L health status index score range between 0 to 1. Higher score indicated better health status. | Baseline, CRT Phase: Days 1 and 29; Maintenance phase: Cycle 1/Day 1, Cycle 3/Day 1, Cycle 7/Day 1, Cycle 7/Day 15, Cycle 11/Day 1, Cycle 11/Day 15, EOT (3 days after the last dose of study drug) | 
| Change From Baseline in the European Quality of Life- 5 Dimension-5 Levels (EQ-5D-5L) VAS Score at CRT Phase and Maintenance Phase | EQ-5D-5L is a standardized participant completed questionnaire that measures health status in terms of a single index value or utility score. EQ-5D-5L consisted of two components: a health state profile (descriptive system) and a visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. EQ-5D-5L health status index score range between 0 to 1. Higher score indicated worse health status. In VAS participants rate their overall health status from 0 (worst imaginable) to 100 (best imaginable), where higher scores indicated better health status. | Baseline, CRT Phase: Days 1 and 29; Maintenance phase: Cycle 1/Day 1, Cycle 3/Day 1, Cycle 7/Day 1, Cycle 7/Day 15, Cycle 11/Day 1, Cycle 11/Day 15, EOT (3 days after the last dose of study drug) | 
| Change From Baseline in National Cancer Comprehensive Network Head and Neck Symptom Index-22 Item Scores (NCCN FHNSI-22) at CRT Phase and Maintenance Phase | The NCCN FHNSI-22 questionnaire measured disease symptoms, treatment side effects and overall quality of life in participants with head and neck cancer. The questionnaire contained 22 items with 5-point Likert scales ranging from 0 to 4 as follows: 'not at all = 0', a little bit = 1, somewhat = 2, quite a bit = 3 and very much = 4. Total score ranged from 0 to 88 where, higher scores represented better symptomatology, quality of life or functioning. | Baseline, CRT Phase: Days 1 and 29; Maintenance phase: Cycle 1/Day 1, Cycle 3/Day 1, Cycle 7/Day 1, Cycle 7/Day 15, Cycle 11/Day 1, Cycle 11/Day 15, EOT (3 days after the last dose of study drug) | 
| Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) | PD-L1 biomarker expression in tumor tissue as assessed by IHC in the form of positive immune cells and tumor staining cells. | Baseline (prior to first dose) | 
| Mean Percentage (%) of Total Tumor Area Occupied by Cluster of Differentiation 8 (CD8+) Cells | Description: CD8+ cells are the type of T-lymphocytes. Mean percentage of total tumor area occupied by CD8+ Cells has been reported. Area was measured in millimeter square (mm^2). | Baseline (prior to first dose) | 
| Percentage of Participants With Positive and Negative Pathology of Neck Dissection | Percentage of participants with positive and negative pathology of neck dissection were reported. Positive pathology included live tumor cells present or 10% or greater vital tumor tissues. Negative pathology included no live tumor cells present, complete tumor regression, no evidence of vital tumor tissues, less than 10% vital tumor tissue, or not consistent with disease under study. | From randomization until PD as per investigator assessment (up to 37 months) | 
| Maximum Plasma Concentration (Cmax) of Avelumab | Maximum observed plasma concentration (Cmax) of Avelumab is reported. | Pre-dose and end of infusion on Day 1 of lead-in phase, Days 8, 25 of CRT phase, Day 1 of Cycle 1 and 2 (each cycle 28 days) | 
| Predose Plasma Concentration (Ctrough) of Avelumab | Ctrough refers to plasma concentration of Avelumab observed just before treatment administration. | Pre-dose on Day 1 of lead-in phase, Days 8, 25 of CRT phase, Day 1 of Cycle 1, 2, 5, 8, 11 (each cycle 28 days) | 
| Dose Normalized Maximum Plasma Concentration (Cmax [dn]) of Total and Free Cisplastin | Dose normalized (dn) Cmax was calculated by dividing Cmax by the exact dose of total and free Cisplastin (in mg) administered to a participant. | Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase | 
| Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) of Total and Free Cisplatin | Area under the plasma concentration time-curve from time zero to the time of last measured concentration (AUClast). AUClast (dn) was calculated by dividing AUClast by the exact dose of cisplastin (in mg) administered to a participant. | Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase | 
| Maximum Plasma Concentration (Cmax) of Total and Free Cisplatin | Maximum observed plasma concentration (Cmax) of total and free Cisplatin is reported. | Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase | 
| Time to Attain Maximum Observed Plasma Concentration (Tmax) of Total and Free Cisplatin | Time to reach maximum observed plasma concentration (Tmax) of total and free Cisplatin. | Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase | 
| Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status | ADA never-positive was defined as no positive ADA results at any time point; ADA-negative participants (titer less than< cut point) and ADA ever-positive was defined as at least one positive ADA result at any time point; ADA-positive participants (titer greater than or equal to cut point) | pre-dose on Day 1 up to 30 Days after the end of treatment | 
| Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status |  | Day 1 of lead-in phase and on Days 8 and 25 of CRT phase |