Substudy 06E: Umbrella Study of Combination Therapies in Esophageal Cancer (MK-3475-06E/KEYMAKER-U06)

NCT06780111 | Recruiting Phase 1 FDA Drug

• 5 other identifiers: 3475-06EMK-3475-06E2024-514273-22-00U1111-1307-6484jRCT2041240166
• Study Type: interventional
• Target: 298
• Locations: 15 countries
• Sites: 43

Brief Summary

Researchers are looking for new ways to treat esophageal squamous cell carcinoma (ESCC). ESCC is a type of cancer that starts in certain cells that line the esophagus. The esophagus is the tube that connects the throat to the stomach. This study will look at ESCC that is either locally advanced unresectable, which means it has spread into tissue near where it started and cannot be completely removed by surgery, or metastatic, which means it has spread to other body parts. Available treatments for these types of ESCC include pembrolizumab and chemotherapy. Pembrolizumab is an immunotherapy, which is a treatment that helps the immune system fight cancer. Chemotherapy is medicine that destroys cancer cells or stops them from growing. Researchers want to learn about giving pembrolizumab and investigational agents, with or without chemotherapy to treat ESCC. Ifinatamab deruxtecan (I-DXd), is an antibody-drug conjugate (ADC). An ADC attaches to a protein on cancer cells and delivers treatment to destroy those cells. The main goal of this study is to learn about the safety of investigational agents and pembrolizumab with or without chemotherapy and if people tolerate them. Researchers also want to learn how cancer responds (gets smaller or goes away) to the study treatments.

Conditions

Esophageal Squamous Cell Carcinoma

Outcome Measures

Primary Outcomes (3)

• Percentage of Participants who Experience Dose Limiting Toxicities (DLTs) During the Safety Lead-In Phase

  Percentage of participants experiencing toxicities that are possibly, probably, or definitely related to study intervention; that meet pre-defined severity criteria; and result in a change in the given dose.

  Up to approximately 28 days

• Percentage of Participants who Experience an Adverse Event (AE)

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who experience an AE will be reported.

  Up to approximately 77 months

• Objective Response Rate (ORR)

  ORR is defined as a confirmed complete response (CR: the disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). The percentage of participants who experience CR or PR as assessed by BICR will be presented.

  Up to approximately 77 months

Secondary Outcomes (10)

• Duration of Response (DOR)

  Up to approximately 77 months

• Progression-Free Survival (PFS)

  Up to approximately 77 months

• Overall Survival (OS)

  Up to approximately 77 months

• Disease Control Rate (DCR)

  Up to approximately 77 months

• Maximum Plasma Concentration (Cmax) of I-DXd

  At designated time points up to approximately 65 months

Study Arms (5)

Pembrolizumab + Chemotherapy

ACTIVE COMPARATOR

Participants will receive 400 mg of pembrolizumab via intravenous (IV) infusion every six weeks (Q6W) on Day 1 of each 42 day cycle up to 18 cycles (up to approximately 2 years), and mFOLFOX6 chemotherapy: oxaliplatin 85 mg/m\^2 via IV infusion every 2 weeks (Q2W) until progressive disease (PD) or toxicity; leucovorin 400 mg/m2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity; 5-fluorouracil (5-FU) 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 46-48 hour IV infusion Q2W until PD or toxicity.

Biological: Pembrolizumab; Drug: Leucovorin; Drug: Levoleucovorin; Drug: 5-Fluorouracil (5-FU); Drug: Oxaliplatin

Pembrolizumab + I-DXd

EXPERIMENTAL

Participants will receive 200 mg of pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle for up to 35 cycles (up to approximately 2 years). Participants will also receive up to 12 mg/kg I-XDd Q3W via IV infusion until PD or toxicity.

Biological: Pembrolizumab; Biological: I-DXd; Drug: Rescue Medication

Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin

EXPERIMENTAL

Participants will receive 200 mg pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles (up to approximately 2 years). Participants will also receive I-DXd up to 12 mg/kg via IV infusion Q3W until PD or toxicity, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 46-48 hour IV infusion Q2W until PD or toxicity, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity.

Biological: Pembrolizumab; Biological: I-DXd; Drug: Leucovorin; Drug: Levoleucovorin; Drug: 5-Fluorouracil (5-FU); Drug: Rescue Medication

Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin + Oxaliplatin

EXPERIMENTAL

Participants will receive 200 mg of pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles (up to approximately 2 years). Participants will also receive up to 12 mg/kg I-DXd via IV infusion q3w until PD or toxicity, 5-FU 2400 mg/m\^2 continuous 46-48 hour IV infusion Q2W until PD or toxicity, 60mg/m\^2 oxaliplatin via IV infusion Q2W until PD or toxicity, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity.

Biological: Pembrolizumab; Biological: I-DXd; Drug: Leucovorin; Drug: Levoleucovorin; Drug: 5-Fluorouracil (5-FU); Drug: Oxaliplatin; Drug: Rescue Medication

Pembrolizumab + Sacituzumab tirumotecan + 5-FU IV + Leucovorin or Levoleucovorin

EXPERIMENTAL

Participants will receive 400 mg pembrolizumab via IV infusion Q6W on Day 1 of each 42 day cycle up to 18 cycles (up to approximately 2 years). Participants will also receive sacituzumab tirumotecan 4 mg/kg via IV infusion Days 1, 15, and 29 every 42 day cycle until PD or toxicity, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 46-48 hour IV infusion Q2W until PD or toxicity, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity.

Biological: Pembrolizumab; Drug: Leucovorin; Drug: Levoleucovorin; Drug: 5-Fluorouracil (5-FU); Biological: Sacituzumab tirumotecan; Drug: Rescue Medication

Interventions

Pembrolizumab BIOLOGICAL

IV infusion

Also known as: MK-3475, KEYTRUDA®

Pembrolizumab + Chemotherapy; Pembrolizumab + I-DXd; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin + Oxaliplatin; Pembrolizumab + Sacituzumab tirumotecan + 5-FU IV + Leucovorin or Levoleucovorin

Rescue Medication DRUG

Includes 5-HT3 receptor antagonist, NK-1 receptor antagonist, and corticosteroid for Arms 2, 3, and 4, and H1 receptor antagonist, H2 receptor antagonist, acetaminophen, and dexamethasone for Arm 5, administered per approved product label

Pembrolizumab + I-DXd; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin + Oxaliplatin; Pembrolizumab + Sacituzumab tirumotecan + 5-FU IV + Leucovorin or Levoleucovorin

I-DXd BIOLOGICAL

IV infusion

Also known as: Ifinatamab deruxtecan, MK-2400, DS-7300a

Pembrolizumab + I-DXd; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin + Oxaliplatin

Leucovorin DRUG

IV infusion

Pembrolizumab + Chemotherapy; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin + Oxaliplatin; Pembrolizumab + Sacituzumab tirumotecan + 5-FU IV + Leucovorin or Levoleucovorin

Levoleucovorin DRUG

IV infusion

Pembrolizumab + Chemotherapy; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin + Oxaliplatin; Pembrolizumab + Sacituzumab tirumotecan + 5-FU IV + Leucovorin or Levoleucovorin

5-Fluorouracil (5-FU) DRUG

IV Infusion

Pembrolizumab + Chemotherapy; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin + Oxaliplatin; Pembrolizumab + Sacituzumab tirumotecan + 5-FU IV + Leucovorin or Levoleucovorin

Oxaliplatin DRUG

IV infusion

Pembrolizumab + Chemotherapy; Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin + Oxaliplatin

Sacituzumab tirumotecan BIOLOGICAL

IV infusion

Also known as: MK-2870, SKB264

Pembrolizumab + Sacituzumab tirumotecan + 5-FU IV + Leucovorin or Levoleucovorin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic squamous cell carcinoma of the esophagus in first-line (1L) setting.
• Has measurable disease per RECIST 1.1 as assessed by the local site. investigator or designee/radiology assessment and verified by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
• Has AEs due to previous anticancer therapies of ≤Grade 1 or baseline (except alopecia and vitiligo). Endocrine-related AEs adequately treated with hormone replacement are acceptable.
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART).
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Has adequate organ function.

You may not qualify if:

• Has had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer.
• Has tumor invasion into organs located adjacent to the esophageal disease site (eg, aorta or respiratory tract) at an increased risk of fistula.
• Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention.
• Has clinically significant corneal disease, history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
• Has received prior therapy with an anti-programmed cell death 1 protein (PD-1), anti-programmed cell death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2) agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor.
• Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention.
• Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids.
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• Has inadequate cardiac function assessed as: - corrected QT interval by Fredericia (QTcF) value \>470 msec.
• Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
• Has peripheral neuropathy ≥ Grade 2.
• Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
• Has known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead
• Daiichi Sankyo: collaborator

Study Sites (43)

UPMC Hillman Cancer Center ( Site 1904)

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

Liga Norte Riograndense Contra o Cancer ( Site 1301)

Natal, Rio Grande do Norte, 59062-000, Brazil

RECRUITING

Hospital Nossa Senhora da Conceicao ( Site 1300)

Porto Alegre, Rio Grande do Sul, 91010-004, Brazil

RECRUITING

Clínica Puerto Montt ( Site 1406)

Port Montt, Los Lagos Region, 5500243, Chile

RECRUITING

FALP ( Site 1400)

Santiago, Region M. de Santiago, 7500921, Chile

RECRUITING

Centro de Oncología de Precisión ( Site 1402)

Santiago, Region M. de Santiago, 7560908, Chile

RECRUITING

Clínica UC San Carlos de Apoquindo ( Site 1403)

Santiago, Region M. de Santiago, 7620002, Chile

RECRUITING

Bradfordhill ( Site 1401)

Santiago, Region M. de Santiago, 8420383, Chile

RECRUITING

Bradford Hill Norte ( Site 1405)

Antofagasta, 1263521, Chile

RECRUITING

The Second Affiliated Hospital of Anhui Medical University ( Site 9511)

Hefei, Anhui, 230601, China

RECRUITING

Beijing Cancer Hospital ( Site 9500)

Beijing, Beijing Municipality, 130021, China

RECRUITING

The First Affiliated Hospital of Xiamen University ( Site 9503)

Xiamen, Fujian, 361003, China

RECRUITING

Henan Cancer Hospital ( Site 9509)

Zhengzhou, Henan, 450008, China

RECRUITING

Xuzhou Central Hospital ( Site 9512)

Xuzhou, Jiangsu, 221000, China

RECRUITING

The First Affiliated Hospital of Nanchang University ( Site 9505)

Nanchang, Jiangxi, 330006, China

RECRUITING

Masarykuv onkologicky ustav-Klinika komplexni onkologicke pece ( Site 9000)

Brno, Brno-mesto, 656 53, Czechia

RECRUITING

C.H.R.U. de Brest - Hopital Cavale Blanche ( Site 9104)

Brest, Finistere, 29609, France

RECRUITING

CHU Lille - Institut Coeur Poumon ( Site 9100)

Lille, Nord, 59037, France

RECRUITING

Pitie Salpetriere University Hospital ( Site 9102)

Paris, 75013, France

RECRUITING

Universitaetsklinikum Duesseldorf ( Site 1808)

Düsseldorf, North Rhine-Westphalia, 40225, Germany

RECRUITING

Universitätsklinikum Carl Gustav Carus - Medical Oncology ( Site 1806)

Dresden, Saxony, 01307, Germany

RECRUITING

Haematologisch-Onkologische Praxis Eppendorf Facharztzentrum Eppendorf - Hope ( Site 1807)

Hamburg, 20249, Germany

RECRUITING

Ospedale San Raffaele-Oncologia Medica ( Site 9201)

Milan, Lombardy, 20132, Italy

RECRUITING

Istituto Oncologico Veneto IRCCS ( Site 9202)

Padova, Veneto, 35128, Italy

RECRUITING

Aichi Cancer Center ( Site 9702)

Nagoya, Aichi-ken, 464-8681, Japan

RECRUITING

National Cancer Center Hospital East ( Site 9701)

Kashiwa, Chiba, 277-8577, Japan

RECRUITING

National Cancer Center Hospital ( Site 9700)

Chūō, Tokyo, 104-0045, Japan

RECRUITING

Oslo Universitetssykehus Radiumhospitalet ( Site 1501)

Oslo, 0379, Norway

RECRUITING

National University Hospital ( Site 9800)

Singapore, Central Singapore, 119074, Singapore

RECRUITING

National Cancer Center ( Site 9902)

Goyang-si, Kyonggi-do, 10408, South Korea

RECRUITING

Asan Medical Center ( Site 9901)

Seoul, 05505, South Korea

RECRUITING

Samsung Medical Center ( Site 9900)

Seoul, 06351, South Korea

RECRUITING

Kantonsspital Graubuenden ( Site 1700)

Chur, Kanton Graubünden, 7000, Switzerland

RECRUITING

Hopitaux Universitaires de Geneve HUG. ( Site 1701)

Geneva, 1211, Switzerland

RECRUITING

Kaohsiung Medical University Chung-Ho Memorial Hospital ( Site 1009)

Kaoshiung, Kaohsiung, 807, Taiwan

RECRUITING

Kaohsiung Chang Gung Memorial Hospital ( Site 1003)

Kaohsiung City, 83301, Taiwan

RECRUITING

China Medical University Hospital ( Site 1007)

Taichung, 40707, Taiwan

RECRUITING

National Cheng Kung University Hospital ( Site 1001)

Tainan, 704, Taiwan

RECRUITING

National Taiwan University Hospital ( Site 1000)

Taipei, 100225, Taiwan

RECRUITING

Taipei Veterans General Hospital ( Site 1005)

Taipei, 11217, Taiwan

RECRUITING

Chang Gung Memorial Hospital - Linkou Branch ( Site 1006)

Taoyuan, 33305, Taiwan

RECRUITING

Ramathibodi Hospital ( Site 1103)

Ratchathewi, Bangkok, 10400, Thailand

RECRUITING

Songklanagarind hospital ( Site 1101)

Hat Yai, Changwat Songkhla, 90110, Thailand

RECRUITING

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Esophageal Squamous Cell Carcinoma

Interventions

pembrolizumab; Leucovorin; Levoleucovorin; Fluorouracil; Oxaliplatin

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Esophageal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Coordination Complexes; Organic Chemicals

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Central Study Contacts

Toll Free Number

CONTACT

1-888-577-8839; Trialsites@msd.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2025
• First Posted: January 17, 2025
• Study Start: July 30, 2025
• Primary Completion (Estimated): January 4, 2032
• Study Completion (Estimated): January 4, 2032
• Last Updated: June 12, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share

Locations

NO (1); KR (3); SG (1); CH (2); TW (7); BR (2); CL (6); TH (2); CN (6); CZ (1); FR (3); IT (2); DE (3); US (1); JP (3)