S-531011 as Monotherapy and in Combination With an Immune Checkpoint Inhibitor in Advanced or Metastatic Solid Tumors (aCCeleR8-001)

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

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 with or without pembrolizumab.

The primary objective of Parts B and C is to evaluate the antitumor activity of S-531011 at the RP2D with or without pembrolizumab.

The primary objective of Parts D and E is to evaluate the antitumor activity of S-531011 at the RP2D in combination with bevacizumab with our without pembrolizumab.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: S-531011; Drug: Pembrolizumab; Drug: Bevacizumab

• Study Type: Interventional
• Enrollment (Estimated): 282
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Shionogi Clinical Trials Administrator Clinical Support Help Line; Phone Number: 800-849-9707; Email: Shionogiclintrials-admin@shionogi.co.jp

Study Locations

• Japan
  • Chiba
    • Kashiwa, Chiba, Japan
      • Recruiting
      • National Cancer Center Hospital East
  • Osaka
    • Suita, Osaka, Japan
      • Recruiting
      • The University of Osaka Hospital
  • Tokyo
    • Chuo Ku, Tokyo, Japan
      • Recruiting
      • National Cancer Center Hospital
• United States
  • California
    • Los Angeles, California, United States, 90025
      • Active, not recruiting
      • Angeles Clinic and Research Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • University of Florida Health
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Active, not recruiting
      • Henry Ford Health Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Recruiting
      • Fox Chase Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Eligibility Criteria: Key Inclusion Criteria:

1. 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.
2. Measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1.
3. (Part A only) Participants should have 1 of the following tumor types: malignant melanoma, head and neck squamous cell carcinoma, renal cell carcinoma, urothelial carcinoma, non-small cell lung cancer, or triple-negative breast cancer, esophageal cancer (esophageal squamous cell carcinoma and adenocarcinoma), or gastric cancer (gastric and gastroesophageal junction adenocarcinoma). Participants with colorectal cancer (CRC), pancreatic cancer, cervical cancer, epithelial ovarian cancer, and other types of solid tumors may also be enrolled upon discussion with and approval by the sponsor. For the backfill cohorts only, specific tumor types may be selected.
4. (Part B CRC cohorts only) Participants must have histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum, who had disease progression on or after receiving all of the following standard of care systemic therapies for advanced or metastatic disease or who were intolerant to: fluoropyrimidine, oxaliplatin, and irinotecan; anti-epidermal growth factor receptor (EGFR) therapy if rat sarcoma virus (RAS) (Kirsten RAS/neuroblastoma RAS [KRAS/NRAS]) wild-type and medically appropriate ; V-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor if BRAF V600E mutation. In addition, participants who received up to 2 additional lines of therapy for advanced or metastatic disease of the following therapies are also eligible: trifluridine/tipiracil, regorafenib, fruquintinib, other drugs approved in the country, or investigational drugs.
5. (Part C CRC cohorts only) Participants must have histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum, who had disease progression on or after receiving all of the following standard of care systemic therapies for advanced or metastatic disease or who were intolerant to: fluoropyrimidine, oxaliplatin, and irinotecan; anti-EGFR therapy if RAS (KRAS/NRAS) wild-type and medically appropriate ; BRAF inhibitor if BRAF V600E mutation. In addition, participants who received up to 2 additional lines of therapy for advanced or metastatic disease of the following therapies are also eligible: trifluridine/tipiracil, regorafenib, fruquintinib, other drugs approved in the country, or investigational drugs.
6. (Parts D and E) Participants must have histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum, who had disease progression on or after receiving all of the following standard of care systemic therapies for advanced or metastatic disease or who were intolerant to: fluoropyrimidine, oxaliplatin, and irinotecan; anti-EGFR therapy if RAS (KRAS/NRAS) wild-type and medically appropriate; BRAF inhibitor if BRAF-V600E mutation.. In addition, participants who received up to 2 additional lines of therapy for advanced or metastatic disease of the following therapies are also eligible: trifluridine/tipiracil, regorafenib, fruquintinib, other drugs approved in the country, or investigational drugs.
7. Participants should be willing and able to provide permission to access archival formalin-fixed paraffin-embedded tumor tissues (as block or unstained slides) for this study.
8. Participants should be willing and able to provide both pre-treatment and on-treatment paired tumor biopsy samples.
9. (Part A and B/CRC Cohorts only; 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 (flow cytometry) analysis.
10. Eastern Cooperative Oncology Group Performance Status of 0 or 1.
11. An estimated life expectancy of at least 12 weeks.
12. Adequate hematologic and organ function as confirmed by laboratory values.
13. QT interval corrected with the Fridericia formula ≤ 480 milliseconds in 12- lead electrocardiogram at Screening.

Key Exclusion Criteria:

1. Presence or history of autoimmune diseases or immune-mediated diseases that require chronic use of systemic corticosteroids (> 10 milligrams of prednisone equivalent per day), immunosuppressive agents, or disease-modifying agents.
2. Presence or history of interstitial lung disease and (non-infectious) pneumonitis that required corticosteroids.
3. 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.
4. Uncontrolled or clinically significant cardiovascular disease defined as New York Heart Association classification III or IV.
5. A positive test for hepatitis B surface antigen and/or hepatitis C virus (HCV) antibody (participants with positive HCV antibody are eligible if a confirmatory HCV RNA test is undetectable).
6. A positive serological test for human immunodeficiency virus infection.
7. Known history of any other relevant congenital or acquired immunodeficiency.
8. Known history of an allogeneic tissue and/or solid organ transplant.
9. 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.
10. Women who are pregnant or breastfeeding (or have discontinued breastfeeding) or trying to become pregnant.
11. (Parts D and E only) Serious non-healing wound, non-healing ulcer, or non healing bone fracture.
12. (Parts D and E only) Presence or history of severe arterial thromboembolic events (for example, cerebral infarction, transient ischemic attacks, myocardial infarction, and angina) within 6 months prior to the first dose of study intervention, and/or ≥ Grade 3 venous thromboembolic events (for example, deep vein thrombosis) within 3 months prior to the first dose of study intervention. Participants who receive a full-dose therapeutic anticoagulation should be excluded.
13. (Parts D and E only) Known coagulopathy that increases risk of bleeding, bleeding diatheses, or any other hemorrhage/bleeding event of ≥ Grade 3 within 4 weeks prior to the first dose of study intervention.
14. (Parts D and E only) Presence or history of any life-threatening vascular endothelial growth factor (VEGF)-related adverse event (AE).
15. (Parts D and E only) Proteinuria ≥ 2+ by urine dipstick test within 4 weeks prior to the first dose of study intervention.
16. Clinical evidence of uncontrolled brain metastasis.
17. Clinically uncontrollable symptomatic pleural effusion and/or ascites. (Participants who do not require fluid drainage or have no significant increase of fluid for 28 days may be eligible with approval by the sponsor.)
18. Known additional malignancy that is progressing or has required active treatment within the past 3 years.
19. (Part B, C, D and E CRC cohorts only): Colorectal cancer with mismatch repair deficient/microsatellite instability-high status.
20. (Parts A-2, C and E only): Has received prior therapy with an anti-programmed death 1, anti-programmed death ligand 1, or anti-programmed death ligand 2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (for example, cytotoxic T-lymphocyte-associated protein 4, OX-40, CD137), and was discontinued from that treatment due to ≥ Grade 3 immune-related adverse event.
21. 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.
22. Prior major surgery within 28 days before the first dose of study intervention.
23. 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.
24. 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.
25. Prior treatment with anti-CCR8 antibody for any indication.
26. Receipt of hematopoietic growth factors (for example, granulocyte-colony stimulating factor 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.
27. (Parts D and E only) Presence or history of allergic reactions or hypersensitivity to bevacizumab or any of its excipients.
28. (Parts D and E only) Presence or history of hypersensitivity to Chinese Hamster Ovary cell products or other recombinant human or humanized antibodies.
29. Receipt of a live, attenuated vaccine within 30 days before the first dose of study intervention.

Note: Additional protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A-1: S-531011 Monotherapy; Participants will receive escalating doses of S-531011 by intravenous infusion for up to approximately 12 months.	Drug: S-531011; Administered by intravenous infusion
Experimental: Part A-2: S-531011 + Pembrolizumab; Participants will receive escalating doses of S-531011 in combination with pembrolizumab by intravenous infusion for up to approximately 24 months.	Drug: S-531011; Administered by intravenous infusion; Drug: Pembrolizumab; Administered by intravenous infusion; Other Names: KEYTRUDA
Experimental: Part B: S-531011 Monotherapy; Participants will receive S-531011 at the RP2D by intravenous infusion for up to approximately 12 months.	Drug: S-531011; Administered by intravenous infusion
Experimental: Part C: S-531011 + Pembrolizumab; Participants will receive S-531011 at the RP2D in combination with pembrolizumab by intravenous infusion for up to approximately 24 months.	Drug: S-531011; Administered by intravenous infusion; Drug: Pembrolizumab; Administered by intravenous infusion; Other Names: KEYTRUDA
Experimental: Part D: S-531011 + Bevacizumab; Participants will receive S-531011 at the RP2D in combination with bevacizumab or bevacizumab biosimilar by intravenous infusion for up to approximately 24 months.	Drug: S-531011; Administered by intravenous infusion; Drug: Bevacizumab; Administered by intravenous infusion; Other Names: Avastin
Experimental: Part E: S-531011 + Bevacizumab + Pembrolizumab; Participants will receive S-531011 at the RP2D in combination with bevacizumab or bevacizumab biosimilar and pembrolizumab by intravenous infusion for up to approximately 24 months.	Drug: S-531011; Administered by intravenous infusion; Drug: Pembrolizumab; Administered by intravenous infusion; Other Names: KEYTRUDA; Drug: Bevacizumab; Administered by intravenous infusion; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Number of Participants with Treatment-emergent Adverse Events (TEAEs)	Approximately 12 months (Part A-1); Approximately 24 months (Part A-2)
Parts B, C, D, E: Objective Response Rate	Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part B]; Approximately 24 months [Parts C, D, E])
Parts B, C, D, E: Duration of Response	Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part B]; Approximately 24 months [Parts C, D, E])
Parts B, C, D, E: Disease Control Rate	Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part B]; Approximately 24 months [Parts C, D, E])
Parts B, C, D, E: Time to Response	Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part B]; Approximately 24 months [Parts C, D, E])
Parts B, C, D, E: Progression-free Survival	Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part B]; Approximately 24 months [Parts C, D, E])
Parts B, C, D, E: Overall Survival	Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part B]; Approximately 24 months [Parts C, D, E])

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 A: Duration of Response		Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part A-1]; Approximately 24 months [Part A-2])
Part A: Disease Control Rate		Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part A-1]; Approximately 24 months [Part A-2])
Part A: Time to Response		Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part A-1]; Approximately 24 months [Part A-2])
Part A: Progression-free Survival		Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part A-1]; Approximately 24 months [Part A-2])
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 (AUC0-inf) 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)
Part A: Objective Response Rate		Every 6 weeks for the first 24 weeks and every 9 weeks thereafter, until disease progression (Approximately 12 months [Part A-1]; Approximately 24 months [Part A-2])
All Parts: Serum concentrations of S-531011		Part A: Cycle 1, Days 8 and 15 (4 hours post infusion); Cycles 2-9, Day 1 (pre- and end-of-infusion); Safety Follow-up Visit. Parts B, C, D, E: Day 1 of Cycles 1-9 (pre- and end-of-infusion); Safety Follow-up Visit. (each cycle is 21 days)
All Parts: Anti-S-531011 Antibody (ADA) Titer Level	Neutralization assays will be performed only for the samples that are confirmed to have ADA.	Day 1 of Cycles 1 to 9 (each cycle is 21 days)
Parts B, C, D, E: Number of Participants with Treatment-emergent Adverse Events (TEAEs)		Approximately 12 months (Part B); Approximately 24 months (Parts C, D, E)

Collaborators and Investigators

• Sponsor: Shionogi
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line, Shionogi

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2022
• Primary Completion (Estimated): May 31, 2028
• Study Completion (Estimated): May 31, 2028

Study Registration Dates

• First Submitted: October 14, 2021
• First Submitted That Met QC Criteria: October 28, 2021
• First Posted (Actual): November 1, 2021

Study Record Updates

• Last Update Posted (Actual): March 18, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: C-C motif chemokine receptor 8 (CCR8)
• Additional Relevant MeSH Terms: Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Bevacizumab; pembrolizumab
• Other Study ID Numbers: 2023P2411; KEYNOTE-D85 (Other Identifier: Merck); MK-3475-D85 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No