Phase 2 Platform Study of Novel Immunotherapy Combinations as First-Line Treatment in Participants With PD-L1 Positive Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck

Study Overview
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Brief Summary
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The primary purpose of the study is to evaluate the antitumor activity and safety of novel immunotherapy combinations compared with dostarlimab in participants with Programmed death ligand 1 (PD-L1) positive Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC).

Official Title
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A Phase 2, Randomized, Open-label, Platform Study Using a Master Protocol to Evaluate Novel Immunotherapy Combinations as First-Line Treatment in Participants With Recurrent/Metastatic PD-L1 Positive Squamous Cell Carcinoma of the Head and Neck

Conditions
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Neoplasms, Head and Neck

Intervention / Treatment
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* Drug: Dostarlimab
* Drug: Belrestotug
* Drug: GSK6097608


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically or cytologically-confirmed R/M HNSCC that is considered incurable by local therapies. A) Subjects must not have had prior systemic therapy administered in the R/M setting. Chemoradiation therapy which was completed more than 6 months prior to signing consent if given as part of multimodal treatment for locally advanced disease is allowed B) The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx C) Subjects may not have a primary tumor site of nasopharynx (any histology) Has measurable (target) disease based on RECIST 1.1 as determined by the investigator. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 Provides a tumor tissue sample obtained at the time of or after the initial diagnosis of R/M HNSCC. Although a fresh tumor tissue sample obtained within 90 days of screening is highly preferred, an archival tumor specimen (≤2 years old) is acceptable. Biopsies obtained prior to the administration of any systemic therapy administered for the treatment of a participant's tumor (such as neoadjuvant/adjuvant therapy) are not acceptable. Needle or excisional biopsies or resected tissue is required. Cytological specimens such as fine needle aspirates, bone marrow samples, or cell blocks are not acceptable. Bone specimen is not acceptable. Has tumor Programmed death ligand 1 (PD-L1) expression If the primary tumor site is oropharyngeal carcinoma, the participant must have Human papillomavirus (HPV) results Exclusion Criteria: Has received prior therapy with any immune checkpoint inhibitors, including antibodies or drugs targeting Programmed death protein 1 (PD-1), PD-L1, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine based inhibitory motif domains (TIGIT), Cluster of differentiation (CD) 96, or other immune checkpoint pathways. Participants with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, esophageal, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period. Have active tumor bleeding or a high risk of bleeding (examples include but are not limited to radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates >90 degree abutment or encasement of a major vessel [carotid, jugular, bronchial artery] and/or exhibits other high-risk features such as arteriovenous fistula). Has PD within 4 months of completion of curatively intended treatment for locoregionally advanced HNSCC Participants with any carcinomatous meningitis or leptomeningeal spread and those with uncontrolled or symptomatic Central Nervous System (CNS) metastases Active autoimmune disease that has required systemic disease-modifying or immunosuppressive treatment within the last 2 years. (Stable, medically managed autoimmune endocrinopathies are acceptable if participant otherwise meets entry criteria.)

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dostarlimab Monotherapy<br> | Drug: Dostarlimab<br>* Dostarlimab will be administered.<br>|
| Experimental: Sub study 1: Dostarlimab and Belrestotug<br> | Drug: Dostarlimab<br>* Dostarlimab will be administered.<br>Drug: Belrestotug<br>* Belrestotug will be administered.<br>|
| Experimental: Sub study 2: Dostarlimab and GSK6097608<br> | Drug: Dostarlimab<br>* Dostarlimab will be administered.<br>Drug: GSK6097608<br>* GSK6097608 will be administered.<br>|
| Experimental: Sub study 3: Dosarlimab and Belrestotug and GSK6097608<br> | Drug: Dostarlimab<br>* Dostarlimab will be administered.<br>Drug: Belrestotug<br>* Belrestotug will be administered.<br>Drug: GSK6097608<br>* GSK6097608 will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (ORR) compared between Sub studies and Dostarlimab monotherapy | Confirmed ORR is defined as the percentage of participants achieving confirmed Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator assessment. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) compared between Sub studies and Dostarlimab monotherapy | OS is defined as the time from the date of randomization to the date of death due to any cause. | Up to approximately 24 months | 
| Duration of Response (DOR) compared between Sub studies and Dostarlimab monotherapy | DOR per RECIST 1.1 by investigator assessment, defined as the time from the date of first documented objective response (CR or PR) to the date of first documented Disease progression (PD) or death due to any cause, whichever comes first. | Up to approximately 24 months | 
| Progression Free Survival (PFS) compared between Sub studies and Dostarlimab monotherapy | PFS per RECIST 1.1 by investigator assessment, defined as the time from the date of randomization to the date of first documented PD or death due to any cause, whichever comes first. | Up to approximately 24 months | 
| Disease Control Rate (DCR) compared between Sub studies and Dostarlimab monotherapy | DCR is defined as the percentage of participants achieving CR or PR, or Stable disease (SD) greater than or equal to (≥) 6 months, per RECIST 1.1 by investigator assessment. | Up to approximately 24 months | 
| Rate of Circulating Tumor Deoxyribonucleic Acid (ctDNA) Molecular Response | The rate of ctDNA molecular response, is defined as the percentage of participants achieving a ≥50% decrease in ctDNA level compared to baseline, measured by plasma ctDNA assessment | Up to approximately 24 months | 
| Confirmed Objective Response Rate (ORR) compared between Sub study3 and Sub studies 1 and 2 | Confirmed ORR is defined as the percentage of participants achieving confirmed CR or PR per RECIST version 1.1 by investigator assessment. | Up to approximately 24 months | 
| Overall Survival (OS) compared between Sub study 3 and Sub studies 1 and 2 | OS is defined as the time from the date of randomization to the date of death due to any cause. | Up to approximately 24 months | 
| Duration of Response (DOR) compared between Sub study 3 and Sub studies 1 and 2 | DOR per RECIST v 1.1 by investigator assessment, defined as the time from the date of first documented objective response (CR or PR) to the date of first documented PD or death due to any cause, whichever comes first. | Up to approximately 24 months | 
| Progression Free Survival (PFS) compared between Sub study 3 and Sub studies 1 and 2 | PFS per RECIST 1.1 by investigator assessment, defined as the time from the date of randomization to the date of first documented PD or death due to any cause, whichever comes first. | Up to approximately 24 months | 
| DCR compared between sub study 3 and Sub studies 1 and 2 | DCR is defined as the percentage of participants achieving CR or PR, or Stable disease (SD) ≥ 6 months, per RECIST v1.1 by investigator assessment. | Up to approximately 24 months | 
| Number of Participants with Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAE) and Adverse Events of Special Interest (AESI) |  | Up to approximately 24 months | 
| Number of Participants with TEAEs or SAEs leading to dose modifications or study intervention discontinuation |  | Up to approximately 24 months | 
| Number of Participants with Clinically Significant Findings in Physical examination, Vital signs, Electrocardiogram (ECG), Echocardiogram (ECHO) and Laboratory test parameters |  | Up to approximately 24 months | 
| Number of Participants with Anti-Drug Antibodies (ADA) against Dostarlimab |  | Up to approximately 24 months | 
| Number of Participants with Anti-Drug Antibodies (ADA) against Belrestotug |  | Up to approximately 24 months | 
| Number of Participants with Anti-Drug Antibodies (ADA) against GSK6097608 |  | Up to approximately 24 months | 
| Maximum Concentration (Cmax) and Minimum Concentration (Cmin) of Dostarlimab |  | Up to approximately 24 months | 
| Cmax and Cmin of Belrestotug |  | Up to approximately 24 months | 
| Cmax and Cmin of GSK6097608 |  | Up to approximately 24 months | 
| Correlation of molecular response to clinical activity parameter | Correlation will be assessed by comparing clinical activity parameter (confirmed ORR), between ctDNA molecular responders and non-responders within each treatment arm. Confirmed ORR is defined as the percentage of participants achieving confirmed Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator assessment. | Up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dostarlimab, Belrestotug, GSK6097608, PD-L1, HNSCC