Study of the Safety and Effectiveness of GSK6097608 in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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This first-time-in-human (FTIH) study will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of escalating doses of GSK6097608 given as monotherapy and in combination with dostarlimab in participants with advanced solid tumors. In addition, dostarlimab will be given as monotherapy (Arm D); and in combination with belrestotug (Arm E); and with GSK6097608 + belrestotug (Arm F) in Japanese and Chinese participants. The study may assess the PK/PD cohorts for Arm E and/or Arm F in participants outside of China and Japan. Additionally, dostarlimab will be given in combination with cobolimab in Japanese participants. Drug name mentioned as belrestotug, GSK4428859A and EOS884448 are interchangeable for the same compound. In the rest of the document, the drug will be referred to as belrestotug.

Official Title
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A Phase 1 First-Time-in-Human, Open-Label Study of GSK6097608 Administered as Monotherapy and in Combination With Anticancer Agents in Participants With Advanced Solid Tumors

Conditions
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Neoplasms

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults 18 years of age or older (or >=20 years of age in Arm-A Japan, Arm-D Japan, Arm E-Japan, Arm F-Japan, and Arm G-Japan) Female participants of childbearing potential must agree to use a highly effective form of contraception Histological or cytological documentation of locally advanced, recurrent, or metastatic solid malignancy. Enrollment in PK/PD cohorts will be restricted to participants with histologically or cytologically confirmed diagnosis of 1 or more of the following: non-small-cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), endometrial cancer (EC), colorectal cancer (CRC) (including specified molecular subtypes of these) or an alternative immunogenic tumor type with medical monitor approval Disease that has progressed after standard therapy for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate, or if no further standard therapy exists Participants in a PK/PD cohort (Arms A, B, E and F) must provide fresh tumor biopsies. Biopsies are not required from participants enrolled in Arm D, Arm E, (non-PK/PD cohorts only), Arm F (non-PK/PD cohort only), Arm G or any participant enrolled in mainland China Eastern cooperative oncology group (ECOG) performance status (PS) 0 to 1 Life expectancy of at least 12 weeks Adequate organ function as determined by laboratory assessments Adequate cardiac ejection fraction as measured by echocardiogram Arm A-Japan, Arm D-Japan, Arm E-Japan, Arm F-Japan, and Arm G-Japan only: lives in Japan and is racially Japanese, defined as all biological grandparents being Japanese Arm A-China, Arm B-China, Arm D-China, Arm E-China and Arm F-China only (excluding PK/PD cohorts in Arm E and Arm F): is of Chinese descent and lives in China Arm D, Arm E, Arm F, and Arm G only: has been deemed suitable for assigned treatment based on assessment by the investigator Exclusion Criteria: Prior anti-cancer treatment including investigational agents, immune checkpoint inhibitors, chemotherapy, targeted therapy, and biological therapy: within 4 weeks or 5 half-lives of the drug, whichever is shorter Prior allogenic or autologous bone marrow transplantation or other solid organ transplantation Toxicity from previous anticancer treatment, including; greater than or equal to (>=) Grade 3 immune-mediated toxicity considered related to prior immunotherapy and that led to treatment discontinuation; or toxicity related to prior treatment that has not resolved; or history of myocarditis of any grade during a previous treatment with immunotherapy Known additional malignancy that progressed or required active treatment within the last 2 years Uncontrolled or symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis Active autoimmune disease that has required systemic disease-modifying or immunosuppressive treatment within the last 2 years Concurrent medical condition requiring the use of systemic immunosuppressive treatment Cirrhosis or current unstable liver or biliary disease per investigator assessment Active infection requiring systemic treatment, known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) Prolonged QT as measured by electrocardiogram Allergen desensitization therapy within 4 weeks of starting study intervention History of hypersensitivity to any of the study interventions or their excipients Has a history or evidence of cardiac abnormalities within the 6 months prior to enrolment Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions History of idiopathic pulmonary fibrosis; interstitial lung disease; organizing pneumonia; noninfectious pneumonitis that required steroids, or evidence of active, noninfectious pneumonitis Pregnant or lactating woman Receipt of live vaccine within 30 days of the start of study intervention Receipt of transfusion of blood products or administration of colony-stimulating factors within 14 days before the first dose of study intervention Major surgery less than 4 weeks before the first dose of study intervention Known drug or alcohol abuse

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Participants will receive treatment in different dose escalation arms of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving GSK6097608 monotherapy (Arm A)<br>Participants will be administered an intravenous (IV) infusion of GSK6097608 every 3 weeks as monotherapy in escalating doses. | Drug: GSK6097608<br>* GSK6097608 will be administered as an IV infusion.<br>|
| Experimental: Participants receiving GSK6097608 plus dostarlimab (Arm B)<br>Participants will be administered IV infusion of GSK6097608 every 3 weeks in escalating doses followed by dostarlimab. | Drug: GSK6097608<br>* GSK6097608 will be administered as an IV infusion.<br>Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>|
| Experimental: Participants receiving dostarlimab monotherapy (Arm D)<br>Participants will be administered an IV infusion of dostarlimab monotherapy (1 cohort will receive dostarlimab every 3 weeks and 1 cohort will receive dostarlimab every 6 weeks). | Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>|
| Experimental: Participants receiving dostarlimab plus belrestotug (Arm E)<br>Participants will be administered IV infusions of dostarlimab followed by belrestotug, every 3 weeks. | Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>Drug: Belrestotug<br>* Belrestotug will be administered as an IV infusion.<br>* Other names: EOS884448;|
| Experimental: Participants receiving dostarlimab plus belrestotug plus GSK6097608 (Arm F)<br>Participants will be administered an IV infusion of dostarlimab followed by belrestotug followed by GSK6097608 every 3 weeks. | Drug: GSK6097608<br>* GSK6097608 will be administered as an IV infusion.<br>Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>Drug: Belrestotug<br>* Belrestotug will be administered as an IV infusion.<br>* Other names: EOS884448;|
| Experimental: Participants receiving dostarlimab plus cobolimab (Arm G)<br>Participants will be administered an IV infusion of cobolimab followed by dostarlimab | Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>Drug: Cobolimab<br>* Cobolimab will be administered as an IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose-limiting toxicities (DLTs) |  | Up to Day 21 | 
| Number of participants with adverse events (AEs) and serious adverse events (SAEs) |  | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with clinically significant changes in laboratory parameters, vital signs, and 12-lead electrocardiogram (ECG) findings |  | Up to 2 years | 
| Number of participants with dose reductions or delay |  | Up to 2 years | 
| Number of participants withdrawn due to AEs |  | Up to 2 years | 
| Overall response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |  | Up to 2 years | 
| Arms D, E, F, G: ORR based on modified Response Evaluation Criteria in Solid Tumors (iRECIST) |  | Up to 2 years | 
| Arms D, E, F, G: Disease Control Rate (DCR) based on RECIST 1.1 |  | Up to 2 years | 
| Arms D, E, F, G: DCR based on iRECIST |  | Up to 2 years | 
| Arms D, E, F, G: Time to response (TTR) based on RECIST 1.1 |  | Up to 2 years | 
| Arms D, E, F, G: TTR based on iRECIST |  | Up to 2 years | 
| Arms D, E, F, G: Duration of response (DOR) based on RECIST 1.1 |  | Up to 2 years | 
| Arms D, E, F, G: DOR based on iRECIST |  | Up to 2 years | 
| Arms D, E, F, G: Progression-free survival (PFS) based on RECIST 1.1 |  | Up to 2 years | 
| Arms D, E, F, G: PFS based on iRECIST |  | Up to 2 years | 
| Arms A, B, F: Number of participants with positive anti-drug antibodies (ADAs) against GSK6097608 |  | Up to 2 years | 
| Arms A, B, F: Titers of ADAs against GSK6097608 |  | Up to 2 years | 
| Arms B, D, E, F, G: Number of participants with positive ADAs against dostarlimab |  | Up to 2 years | 
| Arms B, D, E, F, G: Titers of ADAs against dostarlimab |  | Up to 2 years | 
| Arms E, F: Number of participants with positive ADAs against belrestotug |  | Up to 2 years | 
| Arms E, F: Titers of ADAs against belrestotug |  | Up to 2 years | 
| Arm G: Number of participants with positive ADAs against cobolimab |  | Up to 2 years | 
| Arm G: Titers of ADAs against cobolimab |  | Up to 2 years | 
| Arms A, B, F: Maximum observed concentration (Cmax) for GSK6097608 |  | Up to 2 years | 
| Arms A, B, F: Minimum observed concentration (Cmin) for GSK6097608 |  | Up to 2 years | 
| Arms A, B, F: Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC[0-infinity]) for GSK6097608 |  | Up to 2 years | 
| Arms A, B, F: Area under the plasma concentration-time curve from time zero to time (AUC[0-t]) for GSK6097608 |  | Up to 2 years | 
| Arms A, B, F: Apparent terminal phase half-life (t1/2) for GSK6097608 |  | Up to 2 years | 
| Arms B, D, E, F, G: Cmax for dostarlimab |  | Up to 2 years | 
| Arms B, D, E, F, G: Cmin for dostarlimab |  | Up to 2 years | 
| Arms B, D, E, F, G: AUC(0-infinity) for dostarlimab |  | Up to 2 years | 
| Arms B, D, E, F, G: AUC(0-t) for dostarlimab |  | Up to 2 years | 
| Arms B, D, E, F, G: t1/2 for dostarlimab |  | Up to 2 years | 
| Arms E, F: Cmax for belrestotug |  | Up to 2 years | 
| Arms E, F: Cmin for belrestotug |  | Up to 2 years | 
| Arms E, F: AUC(0-infinity) for belrestotug |  | Up to 2 years | 
| Arms E, F: AUC(0-t) for belrestotug |  | Up to 2 years | 
| Arms E, F: t1/2 for belrestotug |  | Up to 2 years | 
| Arm G: Cmax for cobolimab |  | Up to 2 years | 
| Arm G: Cmin for cobolimab |  | Up to 2 years | 
| Arm G: AUC(0-infinity) for cobolimab |  | Up to 2 years | 
| Arm G: AUC(0-t) for cobolimab |  | Up to 2 years | 
| Arm G: t1/2 for cobolimab |  | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK6097608, dostarlimab, Dose escalation, Pharmacokinetics, Pharmacodynamics, Advanced solid tumors, First-time-in-human, GSK4428859A, EOS884448, cobolimab, belrestotug