Substudy 06E: Umbrella Study of Combination Therapies in Esophageal Cancer (MK-3475-06E/KEYMAKER-U06)
- Conditions
- Esophageal Squamous Cell Carcinoma
- Interventions
- Registration Number
- NCT06780111
- Lead Sponsor
- Merck Sharp & Dohme LLC
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 209
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pembrolizumab + Chemotherapy Pembrolizumab Participants will receive 200 mg of pembrolizumab via intravenous (IV) infusion every three weeks (Q3W) on Day 1 of each 21 day cycle up to 35 cycles, and mFOLFOX6 chemotherapy: oxaliplatin 85 mg/m\^2 via IV infusion every 2 weeks (Q2W); leucovorin 400 mg/m2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W; 5-fluorouracil (5-FU) 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W. Pembrolizumab + Chemotherapy Leucovorin Participants will receive 200 mg of pembrolizumab via intravenous (IV) infusion every three weeks (Q3W) on Day 1 of each 21 day cycle up to 35 cycles, and mFOLFOX6 chemotherapy: oxaliplatin 85 mg/m\^2 via IV infusion every 2 weeks (Q2W); leucovorin 400 mg/m2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W; 5-fluorouracil (5-FU) 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W. Pembrolizumab + Chemotherapy Levoleucovorin Participants will receive 200 mg of pembrolizumab via intravenous (IV) infusion every three weeks (Q3W) on Day 1 of each 21 day cycle up to 35 cycles, and mFOLFOX6 chemotherapy: oxaliplatin 85 mg/m\^2 via IV infusion every 2 weeks (Q2W); leucovorin 400 mg/m2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W; 5-fluorouracil (5-FU) 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W. Pembrolizumab + Chemotherapy 5-Fluorouracil (5-FU) Participants will receive 200 mg of pembrolizumab via intravenous (IV) infusion every three weeks (Q3W) on Day 1 of each 21 day cycle up to 35 cycles, and mFOLFOX6 chemotherapy: oxaliplatin 85 mg/m\^2 via IV infusion every 2 weeks (Q2W); leucovorin 400 mg/m2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W; 5-fluorouracil (5-FU) 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W. Pembrolizumab + Chemotherapy Oxaliplatin Participants will receive 200 mg of pembrolizumab via intravenous (IV) infusion every three weeks (Q3W) on Day 1 of each 21 day cycle up to 35 cycles, and mFOLFOX6 chemotherapy: oxaliplatin 85 mg/m\^2 via IV infusion every 2 weeks (Q2W); leucovorin 400 mg/m2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W; 5-fluorouracil (5-FU) 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W. Pembrolizumab + I-DXd Pembrolizumab Participants will receive 200 mg of pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle for up to 35 cycles. Participants will also receive 12 mg/kg I-XDd via IV infusion until progressive disease (PD) or toxicity. Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin Pembrolizumab Participants will receive 200 mg pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles. Participants will also receive I-DXd 12 mg/kg via IV infusion on Day 1 of each cycle, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity. Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin Leucovorin Participants will receive 200 mg pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles. Participants will also receive I-DXd 12 mg/kg via IV infusion on Day 1 of each cycle, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity. Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin Levoleucovorin Participants will receive 200 mg pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles. Participants will also receive I-DXd 12 mg/kg via IV infusion on Day 1 of each cycle, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity. Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin 5-Fluorouracil (5-FU) Participants will receive 200 mg pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles. Participants will also receive I-DXd 12 mg/kg via IV infusion on Day 1 of each cycle, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity. Pembrolizumab + I-DXd + 5-FU IV + Oxaliplatin Pembrolizumab Participants will receive 200 mg of pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles. Participants will also receive 12mg/kg I-DXd via IV infusion, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W, and 60mg/m\^2 oxaliplatin via IV infusion Q2W until PD or toxicity. Pembrolizumab + I-DXd + 5-FU IV + Oxaliplatin 5-Fluorouracil (5-FU) Participants will receive 200 mg of pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles. Participants will also receive 12mg/kg I-DXd via IV infusion, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W, and 60mg/m\^2 oxaliplatin via IV infusion Q2W until PD or toxicity. Pembrolizumab + I-DXd + 5-FU IV + Oxaliplatin Oxaliplatin Participants will receive 200 mg of pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles. Participants will also receive 12mg/kg I-DXd via IV infusion, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W, and 60mg/m\^2 oxaliplatin via IV infusion Q2W until PD or toxicity. Pembrolizumab + I-DXd I-DXd Participants will receive 200 mg of pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle for up to 35 cycles. Participants will also receive 12 mg/kg I-XDd via IV infusion until progressive disease (PD) or toxicity. Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin I-DXd Participants will receive 200 mg pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles. Participants will also receive I-DXd 12 mg/kg via IV infusion on Day 1 of each cycle, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 48 hour IV infusion Q2W, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity.
- Primary Outcome Measures
Name Time Method Percentage of Participants who Experience Dose Limiting Toxicities (DLTs) During the Safety Lead-In Phase Up to approximately 21 days A DLT is defined as any of the following toxicities, if determined to be related to study treatment:
* Grade 4 nonhematologic toxicity;
* Grade 4 hematologic toxicity lasting \>7 days;
* Grade 4 thrombocytopenia of any duration;
* Grade 3 thrombocytopenia associated with clinically significant bleeding;
* Any nonhematologic adverse event (AE) ≥Grade 3 in severity, with exceptions;
* Any Grade 3 or Grade 4 nonhematologic laboratory value, with exceptions;
* Febrile neutropenia Grade 3 or Grade 4
* Prolonged delay (\>2 weeks) in initiating Cycle 2 due to study intervention-related toxicity
* Any study intervention-related toxicity that causing participant discontinuation intervention during Cycle 1
* Missing \>25% of study intervention doses as a result of drug-related AEs during the first cycle
* Grade 5 toxicity The number of participants who experience at least one DLT during the safety lead-in phase (approximately 21 days after the first dose of treatment) will be reported.Percentage of Participants who Experience an Adverse Event (AE) Up to approximately 28 months 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.
Percentage of Participants Who Discontinue Study Intervention Due to an AE Up to approximately 25 months 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 discontinue study intervention due to an AE will be reported.
Objective Response Rate (ORR) Up to approximately 73 months 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.
- Secondary Outcome Measures
Name Time Method Duration of Response (DOR) Up to approximately 73 months 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 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.
Progression-Free Survival (PFS) Up to approximately 73 months PFS is defined as the time from randomization to the first documented progressive disease (PD) or death from any cause, whichever occurs first. 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. PFS as assessed by BICR will be presented.
Overall Survival (OS) Up to approximately 73 months OS is defined as the time from allocation/randomization to death due to any cause.
Disease Control Rate (DCR) Up to approximately 73 months DCR is defined as a confirmed complete response (CR) or partial response (PR), or stable disease (SD) with at least 6 months PFS per RECIST 1.1 as assessed by BICR.
Maximum Plasma Concentration (Cmax) of I-DXd At designated time points up to approximately 25 months Cmax is defined as the peak level I-DXd reaches in the blood plasma. Blood samples collected predose and at multiple timepoints postdose will be used to determine the Cmax of I-DXd when co-administered with other investigational agents.
Time to Maximum Plasma Concentration (Tmax) of I-DXd At designated time points up to approximately 25 months Tmax is defined as the time it took I-DXd to reach its peak level in blood plasma. Blood samples collected predose and at designated timepoints postdose will be used to determine the Tmax of I-DXd when co-administered with other investigational agents.
Area Under the Concentration-Time Curve from Time 0 to Last Measurable Plasma Concentration (AUC0-Last) of I-DXd At designated time points up to approximately 25 months AUC0-last is defined as the area under the concentration-time curve from time zero to time of last measurable concentration of I-DXd in the blood plasma. Blood samples collected at predose and at designated timepoints postdose will be used to determine the AUC0-last of I-DXd in combination with other agents.
Area Under the Concentration-Time Curve from Time 0 to the End of the Dosing Period (AUC-tau) of I-DXd At designated time points up to approximately 25 months AUC-tau is defined as the area under the concentration-time curve from time zero to the end of the dosing period. Blood samples collected at predose and at designated timepoints postdose will be used to determine the AUC-tau of I-DXd in combination with other agents.
The Percentage of Participants with Antidrug Antibodies (ADA) Against I-DXd Up to approximately 73 months Blood samples collected at designated timepoints will be used to determine the ADA response to I-DXd. The percentage of participants with ADA will be reported.
The Percentage of Participants with Treatment-Emergent ADA Against I-DXd Up to approximately 73 months Blood samples collected at designated timepoints will be used to determine the treatment-emergent ADA response to I-DXd. The percentage of participants who have treatment-emergent I-DXd ADA will be reported.
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