S-531011 as Monotherapy and in Combination With an Immune Checkpoint Inhibitor in Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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The primary objective of Part A is to evaluate the safety and tolerability of S-531011 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of S-531011. The primary objective of Parts B and C is to evaluate the antitumor activity of S-531011 at the RP2D.

Official Title
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A Phase 1b/2, Multicenter, Open-label Study of S-531011 as Monotherapy and in Combination With an Immune Checkpoint Inhibitor in Participants With Locally Advanced or Metastatic Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: S-531011
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participant must be at least 18 years of age inclusive (or complies with country-specific regulatory requirements), at the time of signing the informed consent. Participants with histologically or cytologically confirmed advanced (locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors who have no standard therapies with a proven clinical benefit, or who are intolerant to or unwilling to receive these therapies for any reasons. Measurable disease by RECIST 1.1. (Part A only) Participants should have 1 of the following tumor types: malignant melanoma (MEL), head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma (RCC), urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), or triple-negative breast cancer (TNBC), esophageal cancer (EC; esophageal squamous cell carcinoma and adenocarcinoma), or gastric cancer (GC; gastric and gastroesophageal junction adenocarcinoma). (Part B only) Participants should have 1 of specific histologically or cytologically confirmed tumor types selected by the sponsor after the determination of tentative RP2D(s) in Part A-1. (Part C only) Participants should have 1 of specific histologically or cytologically confirmed tumor types selected by the sponsor after the determination of tentative RP2D(s) in Part A-2. Participants should be willing and able to provide permission to access archival formalin-fixed paraffin-embedded (FFPE) tumor tissues (as block or unstained slides) for this study. Participants should be willing and able to provide both pre-treatment and on-treatment paired tumor biopsy samples. (At selected sites only) Participants should be willing and able to provide both pre-treatment and on-treatment paired tumor biopsy samples. Fresh tissue samples are required as these will be used for the proof of mechanism analysis. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. An estimated life expectancy of at least 12 weeks. Adequate hematologic and organ function as confirmed by laboratory values. QT interval corrected with the Fridericia formula (QTcF) ≤ 480 milliseconds in 12-lead electrocardiogram (ECG) at Screening. Exclusion Criteria: Presence or history of autoimmune diseases or immune-mediated diseases that require chronic use of systemic corticosteroids (> 10 mg of prednisone equivalent per day), immunosuppressive agents, or disease-modifying agents. Presence or history of interstitial lung disease and (non-infectious) pneumonitis that required corticosteroids. Active clinically significant bacterial, viral or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks before the first dose of study intervention. Uncontrolled or clinically significant cardiovascular disease defined as New York Heart Association (NYHA) classification III or IV. A positive test for hepatitis B surface antigen (HBsAg) and/or hepatitis C virus (HCV) antibody (a confirmatory HCV RNA test if HCV antibody was positive). A positive serological test for human immunodeficiency virus (HIV) infection. Known history of any other relevant congenital or acquired immunodeficiency. Known history of an allogeneic tissue and/or solid organ transplant. Known history of severe allergy, hypersensitivity, anaphylaxis, or any serious adverse reaction to any component of study intervention or formulation components and/or any other monoclonal antibodies. Women who are pregnant or breastfeeding or trying to become pregnant. Clinical evidence of uncontrolled brain metastasis. Known additional malignancy that is progressing or has required active treatment within the past 3 years. (Parts A-2 and C only): Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137), and was discontinued from that treatment due to ≥ Grade 3 immune-related adverse event (irAE). Prior treatment with systemic anticancer drugs (including any investigational medicinal products) within 28 days or 5 half-lives (whichever is shorter) before the first dose of study intervention. Prior major surgery within 28 days before the first dose of study intervention. Prior extended field radiotherapy within 28 days before the first dose of study intervention (within 14 days for limited field radiation for palliation) or history of radiation pneumonitis. Participants who have not recovered from any previous treatment toxicities to ≤ Grade 1 or baseline (except alopecia and peripheral neuropathy) before the first dose of study intervention. Prior treatment with anti-CCR8 antibody for any indication. Receipt of hematopoietic growth factors (eg, granulocyte-colony stimulating factor [G-CSF] or erythropoietin) within 14 days before the first dose of study intervention or blood transfusions within 14 days before the first dose of study intervention. Receipt of a live, attenuated vaccine within 30 days before the first dose of study intervention.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A-1: S-531011 Monotherapy<br>Participants will receive escalating doses of S-531011 by intravenous infusion for up to approximately 12 months. | Drug: S-531011<br>* Administered by intravenous infusion<br>|
| Experimental: Part A-2: S-531011 + Pembrolizumab<br>Participants will receive escalating doses of S-531011 in combination with pembrolizumab by intravenous infusion for up to approximately 12 months. | Drug: S-531011<br>* Administered by intravenous infusion<br>Drug: Pembrolizumab<br>* Administered by intravenous infusion<br>* Other names: Keytruda®;|
| Experimental: Part B: S-531011 Monotherapy<br>Participants will receive S-531011 at the the RP2D by intravenous infusion for up to approximately 12 months. | Drug: S-531011<br>* Administered by intravenous infusion<br>|
| Experimental: Part C: S-531011 + Pembrolizumab<br>Participants will receive S-531011 at the RP2D in combination with pembrolizumab by intravenous infusion for up to approximately 12 months. | Drug: S-531011<br>* Administered by intravenous infusion<br>Drug: Pembrolizumab<br>* Administered by intravenous infusion<br>* Other names: Keytruda®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants with Treatment-emergent Adverse Events (TEAEs) |  | Approximately 12 months | 
| Parts B and C: Objective Response Rate |  | Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until the end of treatment (approximately 12 months). | 
| Parts B and C: Duration of Response |  | From first dose up to a maximum of 18 months after last dose; 2.5 years | 
| Parts B and C: Disease Control Rate |  | Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until the end of treatment (approximately 12 months). | 
| Parts B and C: Time to Response |  | Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until the end of treatment (approximately 12 months). | 
| Parts B and C: Progression-free Survival |  | From first dose up to a maximum of 18 months after last dose; 2.5 years | 
| Parts B and C: Overall Survival |  | From first dose up to a maximum of 18 months after last dose; 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Objective Response Rate |  | Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until the end of treatment (approximately 12 months). | 
| Part A: Duration of Response |  | From first dose up to a maximum of 18 months after last dose; 2.5 years | 
| Part A: Disease Control Rate |  | Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until the end of treatment (approximately 12 months). | 
| Part A: Time to Response |  | Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until the end of treatment (approximately 12 months). | 
| Part A: Progression-free Survival |  | From first dose up to a maximum of 18 months after last dose; 2.5 years | 
| All Parts: Serum concentrations of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| Part A: Maximum Serum Concentration (Cmax) of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| Part A: Time to Maximum Serum Concentration (Tmax) of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| Part A: Area Under the Concentration-time Curve from Time Zero to the Time of Last Quantifiable Concentration After Dosing (AUC0-last) of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| Part A: Area Under the Concentration-time Curve Extrapolated from Time Zero to Infinity (AUCinf) of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| Part A: Terminal elimination rate constant (λz) of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| Part A: Terminal Elimination Half-life (t1/2,z) of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| Part A: Total Clearance (CL) of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| Part A: Volume of Distribution at Steady State (Vss) of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| Part A: Mean Residence Time (MRT) of S-531011 |  | Cycle 1, Day 1: pre-infusion, end-of-infusion, and 1 and 3 hours after the end-of S-531011 infusion, and 24, 48, 72 hours after the start of S-531011 infusion (each cycle is 21 days). | 
| All Parts: Anti-S-531011 Antibody (ADA) Titer Level |  | Day 1 of Cycles 1 to 9 (each cycle is 21 days) | 
| All Parts: Changes in serum tumor markers from pretreatment to on-treatment |  | Baseline and Day 1 of each treatment cycle (each cycle is 21 days) | 
| Part B and C: Number of Participants with Treatment-emergent Adverse Events (TEAEs) |  | Approximately 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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C-C motif chemokine receptor 8 (CCR8)