A Study of Combination Therapies With or Without Pembrolizumab (MK-3475) and/or Chemotherapy in Participants With Advanced Esophageal Cancer (MK-3475-06A)

A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents With or Without Pembrolizumab (MK-3475) and/or Chemotherapy in Participants With Advanced Esophageal Cancer naïve to PD-1/PD-L1 Treatment (KEYMAKER-U06): Substudy 06A.

This is a phase I/II multicenter, open-label umbrella platform study that will evaluate the safety and efficacy of investigational agents with pembrolizumab, plus chemotherapy or lenvatinib, for the treatment of participants with advanced esophageal cancer who have failed 1 prior line of therapy and have not been previously exposed to programmed cell death 1 protein (PD-1)/ programmed cell death ligand 1 (PD-L1) based treatment.

With protocol amendment 5 (effective: 17-November-2023), enrollment in study arms "Pembrolizumab plus MK-4830 plus Chemotherapy" and "Pembrolizumab plus MK-4830 plus lenvatinib" is discontinued.

Study Overview

• Status: Recruiting
• Conditions: Esophageal Squamous Cell Carcinoma (ESCC)
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Irinotecan; Drug: Paclitaxel; Biological: Coformulation favezelimab/pembrolizumab; Drug: Lenvatinib; Biological: MK-4830

Detailed Description

The master protocol is MK-3475-U06.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Toll Free Number; Phone Number: 1-888-577-8839; Email: Trialsites@merck.com

Study Locations

• Brazil
  • Rio Grande Do Norte
    • Natal, Rio Grande Do Norte, Brazil, 59062-000
      • Recruiting
      • Liga Norte Riograndense Contra o Câncer ( Site 2303)
      • Contact: Study Coordinator; Phone Number: 55 84 991191032
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 91350-200
      • Recruiting
      • Hospital Nossa Senhora da Conceição ( Site 2301)
      • Contact: Study Coordinator; Phone Number: +5551993590437
  • Sao Paulo
    • São Paulo, Sao Paulo, Brazil, 01246-000
      • Recruiting
      • ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO ( Site 2300)
      • Contact: Study Coordinator; Phone Number: 5511993103312
• Chile
  • Region M. De Santiago
    • Santiago, Region M. De Santiago, Chile, 7500921
      • Recruiting
      • FALP-UIDO ( Site 2400)
      • Contact: Study Coordinator; Phone Number: 56224457254
    • Santiago, Region M. De Santiago, Chile, 7591047
      • Completed
      • Clínica las Condes ( Site 2403)
• France
  • Bretagne
    • Brest, Bretagne, France, 29200
      • Recruiting
      • Centre Hospitalier Régional Universitaire de Brest - Hôpital Morvan ( Site 1104)
      • Contact: Study Coordinator; Phone Number: 33298223428
  • Nord
    • Lille, Nord, France, 59037
      • Recruiting
      • Hopital Claude Huriez - CHU de Lille ( Site 1100)
      • Contact: Study Coordinator; Phone Number: +33640652949
  • Orne
    • Paris, Orne, France, 75013
      • Recruiting
      • Pitie Salpetriere University Hospital ( Site 1102)
      • Contact: Study Coordinator; Phone Number: +33142161041
• Germany
  • Berlin, Germany, 13353
    • Recruiting
    • Charité Campus Virchow-Klinikum-Klinik Hämatologie Onkologie Tumorimmunologie ( Site 2804)
    • Contact: Study Coordinator; Phone Number: +4930450657306
  • Hessen
    • Frankfurt, Hessen, Germany, 60488
      • Recruiting
      • Institut für Klinisch Onkologische Forschung-Klink für Onkologie und Hämatologie ( Site 2801)
      • Contact: Study Coordinator; Phone Number: 496976014187
  • Nordrhein-Westfalen
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40225
      • Recruiting
      • Universitaetsklinikum Duesseldorf ( Site 2802)
      • Contact: Study Coordinator; Phone Number: +492118108030
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Recruiting
      • Universitaetsklinikum Carl Gustav Carus Dresden-Medical Dept I - Medical Oncology ( Site 2806)
      • Contact: Study Coordinator; Phone Number: +493514584794
• Italy
  • Milano, Italy, 20141
    • Completed
    • Istituto Europeo di Oncologia IRCCS-Divisione di Sviluppo di Nuovi Farmaci per Terapie Innovative (
  • Padova, Italy, 35128
    • Recruiting
    • Istituto Oncologico Veneto IRCCS ( Site 1205)
    • Contact: Study Coordinator; Phone Number: 390498215910
  • Lombardia
    • Milan, Lombardia, Italy, 20133
      • Recruiting
      • Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 1200)
      • Contact: Study Coordinator; Phone Number: 390223903835
    • Milano, Lombardia, Italy, 20132
      • Recruiting
      • Ospedale San Raffaele-Oncologia Medica ( Site 1206)
      • Contact: Study Coordinator; Phone Number: +390226437624
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 464-8681
      • Recruiting
      • Aichi Cancer Center Hospital ( Site 1702)
      • Contact: Study Coordinator; Phone Number: +81-52-762-6111
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • Recruiting
      • National Cancer Center Hospital East ( Site 1701)
      • Contact: Study Coordinator; Phone Number: +81-4-7133-1111
  • Saitama
    • Ina-machi, Saitama, Japan, 362-0806
      • Recruiting
      • Saitama Prefectural Cancer Center ( Site 1703)
      • Contact: Study Coordinator; Phone Number: +81-48-722-1111
  • Shizuoka
    • Nagaizumi-cho,Sunto-gun, Shizuoka, Japan, 411-8777
      • Recruiting
      • Shizuoka Cancer Center ( Site 1704)
      • Contact: Study Coordinator; Phone Number: +81-55-989-5222
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • Recruiting
      • National Cancer Center Hospital ( Site 1700)
      • Contact: Study Coordinator; Phone Number: +81-3-3542-2511
• Korea, Republic of
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Asan Medical Center-Department of Oncology ( Site 1901)
    • Contact: Study Coordinator; Phone Number: +82230107179
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center-Division of Hematology/Oncology ( Site 1900)
    • Contact: Study Coordinator; Phone Number: +82234106518
• Norway
  • Oslo, Norway, 0310
    • Recruiting
    • Oslo universitetssykehus, Radiumhospitalet ( Site 2501)
    • Contact: Study Coordinator; Phone Number: 4723026600
• Singapore
  • South West
    • Singapore, South West, Singapore, 119074
      • Recruiting
      • National University Hospital ( Site 1800)
      • Contact: Study Coordinator; Phone Number: +65 6779 5555
• Switzerland
  • Geneve
    • Genève, Geneve, Switzerland, 1211
      • Recruiting
      • Hôpitaux Universitaires de Genève (HUG) ( Site 2702)
      • Contact: Study Coordinator; Phone Number: 41223729861
  • Grisons
    • Chur, Grisons, Switzerland, 7000
      • Recruiting
      • Kantonsspital Graubünden-Medizin ( Site 2700)
      • Contact: Study Coordinator; Phone Number: 41812566884
• Taiwan
  • Taichung, Taiwan, 404332
    • Recruiting
    • China Medical University Hospital ( Site 2007)
    • Contact: Study Coordinator; Phone Number: +886975680932
  • Taichung, Taiwan, 407
    • Recruiting
    • Taichung Veterans General Hospital-Radiation Oncology ( Site 2008)
    • Contact: Study Coordinator; Phone Number: 8864235925255613
  • Tainan, Taiwan, 704
    • Recruiting
    • National Cheng Kung University Hospital ( Site 2001)
    • Contact: Study Coordinator; Phone Number: 886623535354620
  • Taipei, Taiwan, 112
    • Recruiting
    • Taipei Veterans General Hospital ( Site 2005)
    • Contact: Study Coordinator; Phone Number: +8862287121212573
  • Taipei, Taiwan, 100225
    • Recruiting
    • National Taiwan University Hospital ( Site 2000)
    • Contact: Study Coordinator; Phone Number: +886223123456
  • Taoyuan, Taiwan, 333
    • Recruiting
    • Chang Gung Medical Foundation-Linkou Branch ( Site 2006)
    • Contact: Study Coordinator; Phone Number: +88633281200
  • Kaohsiung
    • Kaohsiung Niao Sung Dist, Kaohsiung, Taiwan, 83301
      • Recruiting
      • Chang Gung Memorial Hospital at Kaohsiung ( Site 2003)
      • Contact: Study Coordinator; Phone Number: +886975056058
• Thailand
  • Krung Thep Maha Nakhon
    • Bangkok, Krung Thep Maha Nakhon, Thailand, 10330
      • Recruiting
      • Chulalongkorn University ( Site 2104)
      • Contact: Study Coordinator; Phone Number: +ุุ6622564533
    • Bangkok, Krung Thep Maha Nakhon, Thailand, 10700
      • Recruiting
      • Faculty of Medicine Siriraj Hospital ( Site 2102)
      • Contact: Study Coordinator; Phone Number: +6624194488
  • Songkhla
    • Hatyai, Songkhla, Thailand, 90110
      • Recruiting
      • Songklanagarind hospital ( Site 2105)
      • Contact: Study Coordinator; Phone Number: +6674451469
• Turkey
  • Adana, Turkey, 01140
    • Recruiting
    • Adana Medical Park Seyhan Hastanesi-Medikal Onkoloji ( Site 1417)
    • Contact: Study Coordinator; Phone Number: 905337299897
  • Ankara, Turkey, 06230
    • Recruiting
    • Hacettepe Universite Hastaneleri-oncology hospital ( Site 1402)
    • Contact: Study Coordinator; Phone Number: 903123052910
  • Ankara, Turkey, 06800
    • Recruiting
    • Ankara City Hospital-Medical Oncology ( Site 1405)
    • Contact: Study Coordinator; Phone Number: 905555306271
  • Antalya, Turkey, 07059
    • Recruiting
    • Akdeniz Universitesi Hastanesi-Medical Oncology ( Site 1410)
    • Contact: Study Coordinator; Phone Number: +90 5421572862
  • Erzurum, Turkey, 25070
    • Recruiting
    • Atatürk Üniversitesi-onkoloji ( Site 1416)
    • Contact: Study Coordinator; Phone Number: +905072864555
  • Istanbul, Turkey, 34722
    • Recruiting
    • TC Saglik Bakanligi Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi-oncology ( Site 1403)
    • Contact: Study Coordinator; Phone Number: +905063509061
  • Istanbul
    • Üsküdar / İstanbul, Istanbul, Turkey, 34662
      • Recruiting
      • Acibadem Altunizade Hospital-Oncology ( Site 1407)
      • Contact: Study Coordinator; Phone Number: +905327950350
  • Izmir
    • Izmir, Karsiyaka, Izmir, Turkey, 009035575
      • Recruiting
      • I.E.U. Medical Point Hastanesi-Oncology ( Site 1406)
      • Contact: Study Coordinator; Phone Number: +905052642353

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of metastatic or locally advanced unresectable ESCC
• Has experienced investigator documented radiographic or clinical disease progression on one prior line of standard therapy.
• Has an evaluable baseline tumor sample (newly obtained or archival) for analysis
• Has adequately controlled blood pressure (BP) with or without antihypertensive medications
• Participants who have adverse events (AEs) due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy are eligible

Exclusion Criteria:

• Direct invasion into adjacent organs such as the aorta or trachea
• Has experienced weight loss >10% over approximately 2 months prior to first dose of study therapy
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
• Known additional malignancy that is progressing or has required active treatment within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that has undergone potentially curative therapy
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Active autoimmune disease that has required systemic treatment in past 2 years
• History of human immunodeficiency virus (HIV) infection
• History of Hepatitis B or known active Hepatitis C virus infection
• History of allogenic tissue/solid organ transplant
• Clinically significant cardiovascular disease within 12 months from first dose of study intervention
• Participants with known gastrointestinal (GI) malabsorption or any other condition that may affect the absorption of lenvatinib
• Has risk for significant GI bleeding, such as:
• Has had a serious nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to allocation/randomization
• Has significant bleeding disorders, vasculitis, or has had a significant bleeding episode from the GI tract within 12 weeks prior to allocation/randomization

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab plus chemotherapy; Participants will receive pembrolizumab intravenously plus chemotherapy (investigator's choice of irinotecan or paclitaxel) at specified doses on specified days for a total treatment duration of up to approximately 2 years.	Biological: Pembrolizumab; 200 mg administered via intravenous (IV) infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Drug: Irinotecan; 180 mg/m^2 administered via IV infusion on day 1 of every 14-day cycle.; Drug: Paclitaxel; 80-100 mg/m^2 administered via IV infusion on Days 1, 8 and 15 of every 28 day cycle
Experimental: Coformulation Favezelimab/Pembrolizumab plus Chemotherapy; Participants will receive coformulation of favezelimab/pembrolizumab administered intravenously plus chemotherapy (investigator's choice of irinotecan or paclitaxel) at specified doses on specified days for a total treatment duration of up to approximately 2 years.	Drug: Irinotecan; 180 mg/m^2 administered via IV infusion on day 1 of every 14-day cycle.; Drug: Paclitaxel; 80-100 mg/m^2 administered via IV infusion on Days 1, 8 and 15 of every 28 day cycle; Biological: Coformulation favezelimab/pembrolizumab; 800 mg favezelimab + 200 mg pembrolizumab administered via IV infusion on day 1 and then Q3W; Other Names: MK-4280A
Experimental: Pembrolizumab plus MK-4830 plus Chemotherapy; Participants will receive pembrolizumab intravenously plus MK-4830 plus chemotherapy (investigator's choice of irinotecan or paclitaxel) at specified doses on specified days for a total treatment duration of up to approximately 2 years.	Biological: Pembrolizumab; 200 mg administered via intravenous (IV) infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Drug: Irinotecan; 180 mg/m^2 administered via IV infusion on day 1 of every 14-day cycle.; Drug: Paclitaxel; 80-100 mg/m^2 administered via IV infusion on Days 1, 8 and 15 of every 28 day cycle; Biological: MK-4830; 800 mg administered via IV infusion Q3W; Other Names: anti-immunoglobulin-like transcript 4 (ILT4)
Experimental: Pembrolizumab plus MK-4830 plus lenvatinib; Participants will receive pembrolizumab intravenously plus MK-4830 plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.	Biological: Pembrolizumab; 200 mg administered via intravenous (IV) infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Drug: Lenvatinib; 20 mg administered via oral capsules each day; Other Names: MK-7902; LENVIMA®; Biological: MK-4830; 800 mg administered via IV infusion Q3W; Other Names: anti-immunoglobulin-like transcript 4 (ILT4)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing a Dose-limiting Toxicity (DLT) During Safety Lead-in Phase	A DLT is defined as any drug-related adverse event (AE) according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) Version 5.0, observed during the DLT evaluation period that results in a change to a given dose or a delay in initiating the next cycle.	Up to approximately 3 weeks
Number of Participants Experiencing an Adverse Event (AE) During Safety Lead-in Phase	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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to approximately 3 Weeks
Number of Participants Who Discontinue Study Treatment Due to an AE During Safety Lead-in Phase	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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to approximately 3 weeks
Objective Response Rate (ORR)	ORR is defined as the percentage of participants with Complete Response (CR: 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 Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.	Up to approximately 119 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Discontinue Study Treatment Due to An AE During the Efficacy Phase	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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to approximately 104 weeks
Progression-Free Survival (PFS)	PFS is defined as the time from allocation to the first documented progressive disease (PD) as assessed by RECIST 1.1 or death due to any cause, whichever occurs first. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.	Up to approximately 216 weeks
Duration of Response (DOR)	For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.	Up to approximately 216 weeks
Overall Survival (OS)	OS is defined as the time from the date of allocation to death from any cause.	Up to approximately 216 weeks
Number of Participants Experiencing at Least One Adverse Event (AE) During the Efficacy Phase	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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to approximately 216 weeks

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2022
• Primary Completion (Estimated): November 8, 2024
• Study Completion (Estimated): September 21, 2026

Study Registration Dates

• First Submitted: April 19, 2022
• First Submitted That Met QC Criteria: April 19, 2022
• First Posted (Actual): April 22, 2022

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Esophageal cancer; Programmed Cell Death 1 (PD1, PD-1); Programmed Cell Death 1 Ligand 1 (PDL-1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL-2, PD-L2)
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Topoisomerase I Inhibitors; Paclitaxel; Immunoglobulins; Pembrolizumab; Irinotecan; Lenvatinib
• Other Study ID Numbers: 3475-06A; 2021-005405-26 (EudraCT Number); 2031220197 (Registry Identifier: JRCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

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