Clinical trial NCT06780111: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Esophageal Squamous Cell Carcinoma
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo
First posted: 2025-01-17
Enrollment: 228
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 ifinatamab deruxtecan (I-DXd), a study medicine, with or without chemotherapy to treat ESCC. 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 I-DXd 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.

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/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).
* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load.
* Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable.
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

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.
* 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 treatment with orlotamab, enoblituzumab, or other humanized anti-B7 homologue 3 (B7-H3)-targeted agents.
* Has received prior treatment with a topoisomerase-I inhibitor, including antibody-drug conjugate (ADC).
* 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.
* Has active autoimmune disease that has required systemic treatment in the past 2 years.
* Has had (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease, and/or suspected interstitial lung disease (ILD)/pneumonitis that cannot be ruled out by imaging at Screening.
* 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.
* Has severe hypersensitivity (≥Grade 3) to treatment with a monoclonal antibody (mAb) or known sensitivity or intolerance to pembrolizumab, I-DXd, study chemotherapy agents and/or to any of their excipients, murine proteins, or platinum containing products.
* Has had allogeneic tissue/solid organ transplant.
* Have not adequately recovered from major surgery or have ongoing surgical complications.
* Are incapacitated.

Primary outcomes:
measure: Percentage of Participants who Experience Dose Limiting Toxicities (DLTs) During the Safety Lead-In Phase
timeFrame: Up to approximately 21 days
measure: Percentage of Participants who Experience an Adverse Event (AE)
timeFrame: Up to approximately 28 months
measure: Percentage of Participants Who Discontinue Study Intervention Due to an AE
timeFrame: Up to approximately 25 months
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 73 months
Secondary outcomes:
measure: Duration of Response (DOR)
timeFrame: Up to approximately 73 months
measure: Progression-Free Survival (PFS)
timeFrame: Up to approximately 73 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 73 months
measure: Disease Control Rate (DCR)
timeFrame: Up to approximately 73 months
measure: Maximum Plasma Concentration (Cmax) of I-DXd
timeFrame: At designated time points up to approximately 25 months
measure: Time to Maximum Plasma Concentration (Tmax) of I-DXd
timeFrame: At designated time points up to approximately 25 months
measure: Area Under the Concentration-Time Curve from Time 0 to Last Measurable Plasma Concentration (AUC0-Last) of I-DXd
timeFrame: At designated time points up to approximately 25 months
measure: Area Under the Concentration-Time Curve from Time 0 to the End of the Dosing Period (AUC-tau) of I-DXd
timeFrame: At designated time points up to approximately 25 months
measure: The Percentage of Participants with Antidrug Antibodies (ADA) Against I-DXd
timeFrame: Up to approximately 73 months
measure: The Percentage of Participants with Treatment-Emergent ADA Against I-DXd
timeFrame: Up to approximately 73 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: