This is a Phase 1/2, multicenter, randomized, open-label umbrella platform study to evaluate the safety and efficacy of investigational agents with or without pembrolizumab and/or chemotherapy, for the treatment of participants with second line (2L) esophageal squamous cell carcinoma (ESCC) who have previously been exposed to PD-1/PD-L1 based treatment.
None
Histologically or cytologically confirmed diagnosis of metastatic or locally advanced unresectable esophageal squamous cell carcinoma (ESCC)
Has experienced investigator documented radiographic or clinical disease progression on one prior line of standard therapy, that includes a platinum agent and previous exposure to an anti-programmed cell death 1 (PD1)/programmed cell death ligand 1 (PD-L1) based immune oncology (IO) therapy
Has provided an archival or most recent tumor tissue sample obtained as part of clinical practice
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
Parallel
Paclitaxel
Drug80-100 mg/m\^2 IV infusion, administered on days 1, 8, and 15 of every 28-day cycle.
Irinotecan
Drug180 mg/m\^2 IV infusion, administered on day 1 of every 14-day cycle.
Pembrolizumab
Biological/Vaccine200 mg IV infusion, administered every Q3W up to 35 infusions.
MK-4830
Biological/Vaccine800 mg IV infusion, administered Q3W up to 35 infusions.
Lenvatinib
Drug20 mg oral administration every day.
Sacituzumab tirumotecan
Biological/Vaccine4 mg/kg or 5 mg/kg IV infusion on Days 1, 15, and 29 of each 42-day cycle.
Antihistamine
DrugAdministered per product label.
H2 Receptor Antagonist
DrugAdministered per product label.
Acetaminophen (or equivalent)
DrugAdministered per product label.
Dexamethasone (or equivalent)
DrugAdministered per product label.
Steroid Mouthwash (dexamethasone or equivalent)
DrugAdministered per product label.
Supportive care measures
DrugParticipants are allowed to take supportive care measures for the management of adverse events associated with study intervention at the discretion of the investigator. Artificial tear drops or ointment may be given as a supportive care for Ocular Surface Toxicity.
Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) During Safety Lead-in Phase
A DLT is defined as any drug-related 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.
Number of Participants Who Experienced 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.
Number of Participants Who Discontinue Study Treatment Due to an AE During Safety Lead-in Phase
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented.
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.
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.
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.
Overall Survival (OS)
OS is defined as the time from the date of allocation to death from any cause.
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.
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