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.
Terminated
Phase 3
| Drug | Synonyms | Arms |
|---|---|---|
| Avelumab | Avelumab + SOC Chemoradiation Therapy |
| Name | Type | Description | Interventions |
|---|---|---|---|
| Avelumab + SOC Chemoradiation Therapy | Experimental | 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 |
|
| Placebo + SOC CRT | Placebo Comparator | 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 |
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).
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Progression-free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) as Assessed by Investigator |
| Time Frame: | From randomization until documented PD or death, censored date, whichever occurred first (up to 37 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Overall Survival (OS) |
| Time Frame: | From randomization to the date of death or censored date, whichever occurred first (up to 37 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Pathologic Complete Response (pCR) Rate in Participants With Salvage Surgery at the Primary Site |
| Time Frame: | From randomization until PD or death (up to 37 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Time to Locoregional Failure Per Modified RECIST v1.1 as Assessed by Investigator |
| Time Frame: | From the date of randomization to the date of the first documentation of locoregional recurrence or death, whichever occurred first (up to 37 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Objective Response Rate (ORR) Per Modified RECIST v1.1 as Assessed by Investigator |
| Time Frame: | From randomization until disease progression or death, whichever occurred first (up to 37 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Time to Distant Metastatic Failure Per Modified RECIST v1.1 as Assessed by Investigator |
| Time Frame: | From the date of randomization to the date of the first documentation of distant metastatic or death (up to 37 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Duration of Response (DOR) Per Modified RECIST v1.1 as Assessed by Investigator |
| Time Frame: | 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) |
| Safety Issue: | |
| Description: | 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. 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. 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. |
| Measure: | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 |
| Time Frame: | Baseline up to 37 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Shift From Baseline in Clinical Laboratory Parameters |
| Time Frame: | Baseline up to end of treatment (EOT) (up to 17 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Change From Baseline in Vital Sign - Systolic and Diastolic Blood Pressure |
| Time Frame: | 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) |
| Safety Issue: | |
| Description: | Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) measured in sitting position were reported. |
| Measure: | Change From Baseline in Vital Sign - Pulse Rate |
| Time Frame: | 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) |
| Safety Issue: | |
| Description: | Change from baseline in pulse rate in sitting position in beats per minute was reported. |
| Measure: | Change From Baseline in the European Quality of Life- 5 Dimension-5 Levels (EQ-5D-5L) Index Score at CRT Phase and Maintenance Phase |
| Time Frame: | 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Change From Baseline in the European Quality of Life- 5 Dimension-5 Levels (EQ-5D-5L) VAS Score at CRT Phase and Maintenance Phase |
| Time Frame: | 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| Time Frame: | 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC) |
| Time Frame: | Baseline (prior to first dose) |
| Safety Issue: | |
| Description: | PD-L1 biomarker expression in tumor tissue as assessed by IHC in the form of positive immune cells and tumor staining cells. |
| Measure: | Mean Percentage (%) of Total Tumor Area Occupied by Cluster of Differentiation 8 (CD8+) Cells |
| Time Frame: | Baseline (prior to first dose) |
| Safety Issue: | |
| Description: | 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). |
| Measure: | Percentage of Participants With Positive and Negative Pathology of Neck Dissection |
| Time Frame: | From randomization until PD as per investigator assessment (up to 37 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Maximum Plasma Concentration (Cmax) of Avelumab |
| Time Frame: | Pre-dose, end of infusion on Day 1 of lead-in phase and on Days 8, 25 of CRT phase |
| Safety Issue: | |
| Description: |
| Measure: | Predose Plasma Concentration (Ctrough) of Avelumab |
| Time Frame: | Pre-dose, end of infusion on Day 1 of lead-in phase and on Days 8, 25 of CRT phase |
| Safety Issue: | |
| Description: |
| Measure: | Dose Normalized Maximum Plasma Concentration (Cmax [dn]) of Avelumab |
| Time Frame: | Pre-dose, end of infusion on Day 1 of lead-in phase and on Days 8, 25 of CRT phase |
| Safety Issue: | |
| Description: |
| Measure: | Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Cisplatin |
| Time Frame: | Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase |
| Safety Issue: | |
| Description: |
| Measure: | Maximum Plasma Concentration (Cmax) of Cisplatin |
| Time Frame: | Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase |
| Safety Issue: | |
| Description: |
| Measure: | Clearance (CL) of Cisplatin |
| Time Frame: | Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase |
| Safety Issue: | |
| Description: |
| Measure: | Time to Attain Maximum Observed Plasma Concentration (Tmax) of Cisplatin |
| Time Frame: | Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase |
| Safety Issue: | |
| Description: |
| Measure: | Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status |
| Time Frame: | Day 1 of lead-in phase and on Days 8 and 25 of CRT phase |
| Safety Issue: | |
| Description: |
| Measure: | Number of Participants With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status |
| Time Frame: | Day 1 of lead-in phase and on Days 8 and 25 of CRT phase |
| Safety Issue: | |
| Description: |
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Terminated |
| Lead Sponsor: | Pfizer |
June 22, 2021
