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

Official title

A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents in Combination With Pembrolizumab (MK-3475) With or Without Chemotherapy in Participants With 1L Locally Advanced Unresectable/Metastatic Esophageal Cancer: KEYMAKER-U06 Substudy 06E

Overview

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.

Detailed description

The master protocol is MK-3475-U06.

Interventions

• Biological Pembrolizumab
  IV infusion
• Biological I-DXd
  IV infusion
• Drug Leucovorin
  IV infusion
• Drug Levoleucovorin
  IV infusion
• Drug 5-Fluorouracil (5-FU)
  IV Infusion
• Drug Oxaliplatin
  IV infusion
• Biological Sacituzumab tirumotecan
  IV infusion
• Drug Rescue Medication
  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, dexamethasone, and steroid mouthwash for Arm 5, administered per approved product label

Primary outcome measures

• Percentage of Participants who Experience Dose Limiting Toxicities (DLTs) During the Safety Lead-In Phase [Time frame: Up to approximately 28 days]
• Percentage of Participants who Experience an Adverse Event (AE) [Time frame: Up to approximately 77 months]
• Objective Response Rate (ORR) [Time frame: Up to approximately 77 months]

Secondary outcome measures (10)

• Duration of Response (DOR) [Time frame: Up to approximately 77 months]
• Progression-Free Survival (PFS) [Time frame: Up to approximately 77 months]
• Overall Survival (OS) [Time frame: Up to approximately 77 months]
• Disease Control Rate (DCR) [Time frame: Up to approximately 77 months]
• Maximum Plasma Concentration (Cmax) of I-DXd [Time frame: At designated time points up to approximately 65 months]
• Time to Maximum Plasma Concentration (Tmax) of I-DXd [Time frame: At designated time points up to approximately 65 months]
• Area Under the Concentration-Time Curve from Time 0 to Last Measurable Plasma Concentration (AUClast) of I-DXd [Time frame: At designated time points up to approximately 65 months]
• Area Under the Concentration-Time Curve from Time 0 to the End of the Dosing Period (AUCtau) of I-DXd [Time frame: At designated time points up to approximately 65 months]
• The Percentage of Participants with Antidrug Antibodies (ADA) Against I-DXd [Time frame: Up to approximately 65 months]
• The Percentage of Participants with Treatment-Emergent ADA Against I-DXd [Time frame: Up to approximately 65 months]

Eligibility criteria

Inclusion criteria

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

• 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 had AEs due to previous anticancer therapies that have recovered to ≤Grade 1 or baseline. Endocrine-related AEs that are adequately treated with hormone replacement are elegible.
• 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.

Exclusion criteria

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

• 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 by a 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.
• Has active autoimmune disease that has required systemic treatment in the past 2 years.
• Has had a history of interstitial lung disease (ILD)/pneumonitis irrespective of steroid use (except for a history of radiation pneumonitis that did not require steroids), has a current diagnosis of ILD, or has clinical or radiographic suspicion of ILD for which the diagnosis of ILD cannot be ruled out.
• Has active infection requiring systemic therapy.
• Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, including, but not limited to, any underlying pulmonary disorder.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Taiwan · 7 centers

• Kaohsiung Medical University Chung-Ho Memorial Hospital ( Site 1009) — Kaoshiung
• Kaohsiung Chang Gung Memorial Hospital ( Site 1003) — Kaohsiung City
• China Medical University Hospital ( Site 1007) — Taichung
• National Cheng Kung University Hospital ( Site 1001) — Tainan
• National Taiwan University Hospital ( Site 1000) — Taipei
• Taipei Veterans General Hospital ( Site 1005) — Taipei
• Chang Gung Memorial Hospital - Linkou Branch ( Site 1006) — Taoyuan

Chile · 6 centers

• Clínica Puerto Montt ( Site 1406) — Port Montt
• FALP ( Site 1400) — Santiago
• Centro de Oncología de Precisión ( Site 1402) — Santiago
• Clínica UC San Carlos de Apoquindo ( Site 1403) — Santiago
• Bradfordhill ( Site 1401) — Santiago
• Bradford Hill Norte ( Site 1405) — Antofagasta

China · 6 centers

• The Second Affiliated Hospital of Anhui Medical University ( Site 9511) — Hefei
• Beijing Cancer Hospital ( Site 9500) — Beijing
• The First Affiliated Hospital of Xiamen University ( Site 9503) — Xiamen
• Henan Cancer Hospital ( Site 9509) — Zhengzhou
• Xuzhou Central Hospital ( Site 9512) — Xuzhou
• The First Affiliated Hospital of Nanchang University ( Site 9505) — Nanchang

Brazil · 3 centers

• Liga Norte Riograndense Contra o Cancer ( Site 1301) — Natal
• Hospital Nossa Senhora da Conceicao ( Site 1300) — Porto Alegre
• ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO ( Site 1302) — São Paulo

France · 3 centers

• C.H.R.U. de Brest - Hopital Cavale Blanche ( Site 9104) — Brest
• CHU Lille - Institut Coeur Poumon ( Site 9100) — Lille
• Pitie Salpetriere University Hospital ( Site 9102) — Paris

Germany · 3 centers

• Universitaetsklinikum Duesseldorf ( Site 1808) — Düsseldorf
• Universitätsklinikum Carl Gustav Carus - Medical Oncology ( Site 1806) — Dresden
• Haematologisch-Onkologische Praxis Eppendorf Facharztzentrum Eppendorf - Hope ( Site 1807) — Hamburg

Japan · 3 centers

• Aichi Cancer Center ( Site 9702) — Nagoya
• National Cancer Center Hospital East ( Site 9701) — Kashiwa
• National Cancer Center Hospital ( Site 9700) — Chūō

South Korea · 3 centers

• National Cancer Center ( Site 9902) — Goyang-si
• Asan Medical Center ( Site 9901) — Seoul
• Samsung Medical Center ( Site 9900) — Seoul

Italy · 2 centers

• Ospedale San Raffaele-Oncologia Medica ( Site 9201) — Milan
• Istituto Oncologico Veneto IRCCS ( Site 9202) — Padova

Switzerland · 2 centers

• Kantonsspital Graubuenden ( Site 1700) — Chur
• Hopitaux Universitaires de Geneve HUG. ( Site 1701) — Geneva

Thailand · 2 centers

• Ramathibodi Hospital ( Site 1103) — Ratchathewi
• Songklanagarind hospital ( Site 1101) — Hat Yai

United States · 1 center

• UPMC Hillman Cancer Center ( Site 1904) — Pittsburgh

Czechia · 1 center

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

Norway · 1 center

• Oslo Universitetssykehus Radiumhospitalet ( Site 1501) — Oslo

Singapore · 1 center

• National University Hospital ( Site 9800) — Singapore

Identifiers

NCT: NCT06780111 · 3475-06E · MK-3475-06E · 2024-514273-22-00 · U1111-1307-6484 · jRCT2041240166

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗