Study of GSK3359609 and Pembrolizumab in Programmed Death Receptor 1-ligand 1 (PD-L1) Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of study is to evaluate if the addition of GSK3359609 to pembrolizumab as first-line treatment improves the efficacy of pembrolizumab in participants with recurrent or metastatic (R/M) head and neck squamous cell carcinoma/cancer (HNSCC).This is a randomized, double-blind, adaptive Phase II/III study comparing a combination of GSK3359609 inducible T cell co-stimulatory receptor (ICOS) agonist and pembrolizumab to pembrolizumab plus placebo in participants with programmed death receptor 1-ligand 1 (PD-L1) combined positive score (CPS) >=1 R/M HNSCC.

Official Title
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A Randomized, Double-blind, Adaptive, Phase II/III Study of GSK3359609 or Placebo in Combination With Pembrolizumab for First-Line Treatment of PD-L1 Positive Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Conditions
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Neoplasms, Head and Neck

Intervention / Treatment
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* Drug: feladilimab
* Drug: Pembrolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent Male or female, age >=18 years Histological or cytological documentation of Head and Neck Squamous Cell Carcinoma (HNSCC) that is considered incurable by local therapies Primary tumor location of the oral cavity, oropharynx, hypopharynx or larynx No prior systemic therapy administered in the recurrent or metastatic setting (except for systemic therapy given as part of multimodal treatment for locally advanced disease) Measurable disease per RECIST version 1.1 guidelines ECOG Performance PS score of 0 or 1 Adequate organ function Life expectancy of at least 12 weeks Female participants: must not be pregnant, not breastfeeding, and at least one of the following conditions apply: Not a woman of childbearing potential (WOCBP) A WOCBP who agrees to use a method of birth control from 30 days prior to randomization and for at least 120 days after the last dose of study treatment Male participants with female partners of child-bearing potential: must agree to use a highly effective contraception while receiving study treatment and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period Provide tumor tissue from excisional or core biopsy (fine needle aspirates and bone biopsies are not acceptable) acquired within 2 years prior to randomization for PD-L1 immunohistochemistry (IHC) testing by central laboratory Have PD-L1 Immunohistochemistry (IHC) CPS 1 status by central laboratory testing Have results from testing of Human Papilloma Virus (HPV) status for oropharyngeal cancer Exclusion Criteria: Prior therapy with an anti-PD-1/L1/L2 and/or anti-ICOS directed agent Systemic approved or investigational anticancer therapy within 30 days or 5 half-lives of the drug, whichever is shorter Major surgery 28 days prior to randomization Has high risk of bleeding Toxicity related to prior treatment that has not resolved to <=Grade 1 (except alopecia, hearing loss, endocrinopathy managed with replacement therapy, and peripheral neuropathy which must be<= Grade 2) Received transfusion of blood products or administration of colony stimulating factors within 14 days prior to randomization Central nervous system (CNS) metastases, with the following exception: Participants with asymptomatic CNS metastases who are clinically stable and have no requirement for steroids for at least 14 days prior to randomization Invasive malignancy or history of invasive malignancy other than disease under study within the last 3 years, except as noted below: a. Any other invasive malignancy for which the participant was definitively treated, has been disease-free for 3 years and in the opinion of the principal investigator and GSK Medical Monitor will not affect the evaluation of the effects of the study treatment on the currently targeted malignancy, may be included in this clinical study Autoimmune disease or syndrome that required systemic treatment within the past 2 years Has a diagnosis of immunodeficiency or is receiving systemic steroids (≥10 mg oral prednisone per day or equivalent) or other immunosuppressive agents within 7 days prior to randomization Receipt of any live vaccine within 30 days prior randomization Prior allogeneic/autologous bone marrow or solid organ transplantation Has current pneumonitis or history of non-infectious pneumonitis that required steroids or other immunosuppressive agents Recent history (within the past 6 months) of uncontrolled symptomatic ascites, pleural or pericardial effusions Recent history (within the past 6 months) of gastrointestinal obstruction that required surgery, acute diverticulitis, inflammatory bowel disease, or intra-abdominal abscess Recent history of allergen desensitization therapy within 4 weeks of randomization History or evidence of cardiac abnormalities within the 6 months prior to randomization Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice Active infection requiring systemic therapy Known HIV infection, or positive test for hepatitis B active infection (presence of hepatitis B surface antigen), or hepatitis C active infection History of severe hypersensitivity to monoclonal antibodies or any ingredient used in the study treatment formulations Known history of active tuberculosis Any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric disorder, or other condition that could interfere with participant's safety, obtaining informed consent, or compliance to the study procedures in the opinion of the investigator Is currently participating in (unless in follow-up phase and 4 weeks have elapsed from last dose of prior investigational agent), or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to date of randomization Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study

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
Interventional Model Description: This will be a randomized, parallel group treatment study with eligible participants receiving GSK3359609 plus pembrolizumab or placebo plus pembrolizumab.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving feladilimab and pembrolizumab<br>Participants were administered feladilimab (humanized anti-ICOS immunoglobulin G4 [IgG4] monoclonal antibody [mAb]) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an intravenous (IV) infusion once every three weeks. | Drug: feladilimab<br>* feladilimab is available as an intravenous infusion.<br>Drug: Pembrolizumab<br>* Pembrolizumab is available as an intravenous infusion.<br>|
| Active Comparator: Participants receiving placebo and pembrolizumab<br>Participants were administered placebo and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an IV infusion once every three weeks. | Drug: Pembrolizumab<br>* Pembrolizumab is available as an intravenous infusion.<br>Drug: Placebo<br>* Placebo is available as an intravenous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in the Programmed Death Receptor-ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 Population | OS was defined as the time from the date of randomization to the date of death due to any cause. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Kaplan-Meier estimate for the median OS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. | Up to approximately 16 months | 
| OS in the PD-L1 Expression High (CPS ≥20) Population | OS was defined as the time from the date of randomization to the date of death due to any cause. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Kaplan-Meier estimate for the median OS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. | Up to approximately 16 months | 
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) in the PD-L1 CPS ≥1 Population | PFS per RECIST version (v)1.1 was defined as the time from the date of randomization to the date of first documented disease progression or death due to any cause, whichever occurs first. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Kaplan-Meier estimate for the median PFS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. | Up to approximately 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS Per Immune-based RECIST (iRECIST) in the PD-L1 CPS ≥1 Population | PFS per iRECIST was defined as the interval of time from the date of randomization to the date of the first documented disease progression confirmed consecutively per iRECIST based on investigator assessment, or death due to any cause, whichever occurs first. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Kaplan-Meier estimate for the median PFS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. | Up to approximately 16 months | 
| PFS Per RECIST in the PD-L1 CPS ≥20 Population | PFS per RECIST v1.1 was defined as the time from the date of randomization to the date of first documented disease progression per RECIST v1.1. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Kaplan-Meier estimate for the median PFS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. | Up to approximately 16 months | 
| PFS Per iRECIST (iPFS) in the PD-L1 CPS ≥20 Population | PFS per iRECIST was defined as the interval of time from the date of randomization to the date of the first documented disease progression confirmed consecutively per iRECIST based on investigator assessment, or death due to any cause, whichever occurs first. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Kaplan-Meier estimate for the median PFS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. | Up to approximately 16 months | 
| Milestone OS Rate at 12 Months in the PD-L1 CPS ≥1 Population | Milestone OS rate at 12 months was estimated using the Kaplan-Meier method. Associated 95% confidence intervals are estimated using the Brookmeyer-Crowley method. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | 12 months | 
| Milestone OS Rate at 24 Months in the PD-L1 CPS ≥1 Population | Milestone OS rate at 24 months was not evaluated. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | 24 months | 
| Milestone OS Rate at 12 Months in the PD-L1 CPS ≥20 Population | Milestone OS rate at 12 months was estimated using the Kaplan-Meier method. Associated 95% confidence intervals are estimated using the Brookmeyer-Crowley method. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | 12 months | 
| Milestone OS Rate at 24 Months in the PD-L1 CPS ≥20 Population | Milestone OS rate at 24 months was not evaluated. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | 24 months | 
| Overall Response Rate (ORR) Per RECIST v1.1 in the PD-L1 CPS ≥1 Population | ORR per RECIST v1.1 was defined as the proportion of the participants who have a complete response (CR) or partial response (PR) as the best overall response per RECIST v1.1 based upon investigator assessment. As a randomized double-blind study in which primary endpoints are OS and PFS, the confirmation of CR and PR was not required. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 
| ORR Per RECIST v1.1 in the PD-L1 CPS ≥20 Population | ORR per RECIST v1.1 was defined as the proportion of the participants who have a CR or PR as the best overall response per RECIST v1.1 based upon investigator assessment. As a randomized double-blind study in which primary endpoints are OS and PFS, the confirmation of CR and PR was not required. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 
| Disease Control Rate (DCR) Per RECIST v1.1 in the PD-L1 CPS ≥1 Population | DCR per RECIST v1.1 based upon investigator assessment, was defined as the percentage of participants with a best overall response of CR or PR at any time plus stable disease (SD) meeting the minimum time of 15 weeks. A status of SD≥15 weeks will be assigned if the follow-up disease assessment has met the SD criteria at least once after the date of randomization at a minimum of 14 weeks (98 days) considering a one-week visit window. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 
| DCR Per RECIST v1.1 in the PD-L1 CPS ≥20 Population | DCR per RECIST v1.1 based upon investigator assessment, was defined as the percentage of participants with a best overall response of CR or PR at any time plus stable disease (SD) meeting the minimum time of 15 weeks. A status of SD≥15 weeks will be assigned if the follow-up disease assessment has met the SD criteria at least once after the date of randomization at a minimum of 14 weeks (98 days) considering a one-week visit window. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 
| Duration of Response (DoR) Per RECIST v1.1 in the PD-L1 CPS ≥1 Population | DoR per RECIST v1.1 is defined as the time from first documented evidence of CR or PR until first documented disease progression per RECIST v1.1 based upon investigator assessment or death due to any cause, whichever occurs first, among participants who demonstrated CR or PR as the best overall response per RECIST v1.1. Kaplan-Meier estimate for the median DoR is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 
| DoR Per RECIST v1.1 in the PD-L1 CPS ≥20 Population | DoR per RECIST v1.1 is defined as the time from first documented evidence of CR or PR until first documented disease progression per RECIST v1.1 based upon investigator assessment or death due to any cause, whichever occurs first, among participants who demonstrated CR or PR as the best overall response per RECIST v1.1. Kaplan-Meier estimate for the median DoR is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 
| Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, any other situation such as important medical events according to medical or scientific judgement. | Up to approximately 16 months | 
| Number of Participants With AEs by Severity | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Severity of each AE was reported during the study and was assigned a grade according to the National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE). AEs severity were graded on a 5-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, 3 = severe; inability to work or perform normal daily activity, 4 = life-threatening consequences and 5 = death related to AE. | Up to approximately 16 months | 
| Number of Participants With SAEs by Severity | An SAE was defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, any other situation such as important medical events according to medical or scientific judgement. Severity of each SAE was reported during the study and was assigned a grade according to the NCI-CTCAE. SAEs severity were graded on a 5-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, 3 = severe; inability to work or perform normal daily activity, 4 = life-threatening consequences and 5 = death related to AE. Data of participants experiencing SAEs of Grade ≥3 have been presented. | Up to approximately 16 months | 
| Number of Participants With Adverse Events of Special Interest (AESI) | AESI were defined as events of potential immunologic etiology, including immune-related AEs (irAEs). Such events recently reported after treatment with other immune modulatory therapy include colitis, uveitis, hepatitis, pneumonitis, diarrhea, endocrine disorders, and specific cutaneous toxicities, as well as other events that may be immune mediated. | Up to approximately 16 months | 
| Number of Participants With AESI by Severity | AESI were defined as events of potential immunologic etiology, including immune-related AEs (irAEs). Such events recently reported after treatment with other immune modulatory therapy include colitis, uveitis, hepatitis, pneumonitis, diarrhea, endocrine disorders, and specific cutaneous toxicities, as well as other events that may be immune mediated. Severity of each AESI was reported during the study and was assigned a grade according to the NCI-CTCAE. AESIs severity were graded on a 5-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, 3 = severe; inability to work or perform normal daily activity, 4 = life-threatening consequences and 5 = death related to AE. Data of participants experiencing AESIs of Grade ≥3 have been presented. | Up to approximately 16 months | 
| Number of Participants With Dose Modifications | Number of participants with dose modifications (including dose interruptions, dose delays and treatment discontinuations) were reported by each interventional component. | Up to approximately 16 months | 
| Time to Deterioration (TTD) in Pain in the PD-L1 CPS ≥1 Population | TTD in pain is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the European Organization for Research and Treatment of Cancer Item Library(EORTC IL51) pain domain, i.e. an increase from baseline of at least 8.33 observed at all subsequent non-missing visits. The EORTC Quality of Life Questionnaire 35-Item Head and Neck Module (QLQ-H&N35) is a head and neck specific module with multi-item scales. The questionnaire scores for each scale and single-item measure are averaged and transformed linearly to present a score ranging from 0-100. A high score represents a high/healthy level of functioning. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 
| TTD in Pain in the PD-L1 CPS ≥20 Population | TTD in pain is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the EORTC IL51 pain domain, i.e. an increase from baseline of at least 8.33 observed at all subsequent non-missing visits. The EORTC QLQ-H&N35 is a head and neck specific module with multi-item scales. The mouth pain, swallowing, speech problems, opening mouth, coughing, feeding tube, and trouble with social eating domains were administered and referred to as the EORTC IL51. The questionnaire scores for each scale and single-item measure are averaged and transformed linearly to present a score ranging from 0-100. A high score represents a high/healthy level of functioning. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 
| TTD in Physical Function in the PD-L1 CPS ≥1 Population | TTD in physical function is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the PF T-score, i.e. a decrease from baseline of at least 2.4 observed at all subsequent non-missing visits, as measured by the PROMIS PF 8c. The PROMIS PF 8c is an 8-item fixed length short form derived from the PROMIS Physical Function item bank. It includes a 5-point scale with three sets of response options. Scores on the PROMIS PF 8c are reported on a T score metric (mean = 50 and SD = 10), with higher scores reflecting better physical functioning. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 
| TTD in Physical Function in the PD-L1 CPS ≥20 Population | TTD in physical function is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the PF T-score, i.e. a decrease from baseline of at least 2.4 observed at all subsequent non-missing visits, as measured by the PROMIS PF 8c. The PROMIS PF 8c is an 8-item fixed length short form derived from the PROMIS Physical Function item bank. It includes a 5-point scale with three sets of response options. Scores on the PROMIS PF 8c are reported on a T score metric (mean = 50 and SD = 10), with higher scores reflecting better physical functioning. Data are presented for the PD-L1 CPS >=1 participants from mITT population. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. | Up to approximately 16 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK3359609, Pembrolizumab, Programmed death receptor 1-ligand 1, Head and neck squamous cell carcinoma/cancer, Inducible T cell co-stimulatory receptor, Keynote-A01, Head & neck, Phase III