Metastatic Esophageal Squamous Cell Carcinoma
Conditions
Keywords
programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1)
Brief summary
The purpose of this study is to assess the efficacy and safety of pembrolizumab plus lenvatinib plus chemotherapy compared with pembrolizumab plus chemotherapy as first-line intervention in participants with metastatic esophageal carcinoma. The primary hypotheses are that pembrolizumab plus lenvatinib plus chemotherapy is superior to pembrolizumab plus chemotherapy with respect to overall survival (OS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR). As of Amendment 09, Study MK-7902-014 will begin close out activities. Any participant who discontinues study intervention for any reason will be discontinued from the study without further follow-up. Second Course and treatment beyond disease progression will no longer be offered. No safety concerns contributed to the termination of this study.
Detailed description
There will be 2 parts to the study: the cisplatin and 5-fluorouracil (5-FU) (FP) and paclitaxel and cisplatin (TP) Safety Run-in (Part 1) and the Main Study (Part 2). In Part 1 (FP and TP Safety Run-in), participants will be treated with pembrolizumab plus lenvatinib plus FP or TP. Dose-limiting toxicities, safety, and tolerability will be assessed. In Part 2 (Main Study), participants (not including those participating in Part 1) will be treated with pembrolizumab plus lenvatinib plus chemotherapy or pembrolizumab plus chemotherapy. Efficacy, safety, and tolerability will be assessed.
Interventions
BIOLOGICALPembrolizumab
400 mg once every 6-week-cycle, via IV infusion.
DRUGLenvatinib
8 mg QD (Induction) or 20 mg QD (Consolidation) via oral capsule.
DRUGCisplatin
80 mg/m\^2 Q3W via IV infusion, as part of investigator's choice FP chemotherapy or 75 mg/m\^2 Q3W via infusion, as part of investigator's choice TP chemotherapy.
DRUG5-FU
4000 mg/m\^2 Q3W via IV infusion, as part of investigator's choice FP chemotherapy or 400 mg/m\^2 Q2W via bolus IV infusion followed by 2400 mg/m\^2 Q2W via continuous IV infusion, as part of investigator's choice mFOLFOX6 chemotherapy.
DRUGOxaliplatin
85 mg/m\^2 Q2W via IV infusion, as part of investigator's choice mFOLFOX6 chemotherapy.
DRUGLeucovorin
400 mg/m\^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.
DRUGLevoleucovorin
200 mg/m\^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.
DRUGPaclitaxel
175 mg/m\^2 Q3W via IV infusion, as part of investigator's choice TP chemotherapy.
Sponsors
Eisai Inc.
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a histologically or cytologically confirmed diagnosis of metastatic squamous cell carcinoma of the esophagus * Male participants are abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 7 days after the last dose of lenvatinib or 90 days after the last dose of chemotherapy, whichever comes last; 7 days after lenvatinib is stopped, if the participant is on pembrolizumab only and is greater than 90 days post chemotherapy, no male contraception is needed * Female participant is not pregnant or breastfeeding and is not a woman of childbearing potential (WOCBP) or is a WOCBP using a contraceptive method that is highly effective or is abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 120 days after the last dose of pembrolizumab, 30 days after the last dose of lenvatinib, or 180 days after the last dose of chemotherapy, whichever occurs last, and agrees not to donate eggs during this period * Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP≤150/90 millimeters of mercury (mm Hg) with no change in antihypertensive medications within 1 week prior to randomization * Has adequate organ function
Exclusion criteria
* Has had previous therapy for locally advanced unresectable or metastatic esophageal cancer * Has locally advanced esophageal carcinoma * Has metastatic adenocarcinoma of the esophagus * Has direct invasion into adjacent organs such as the aorta or trachea * Has radiographic evidence of encasement of a major blood vessel, or of intratumoral cavitation * Has perforation risks or significant gastrointestinal (GI) bleeding * Has had clinically significant hemoptysis within 3 weeks prior to the first dose of study drug or tumor bleeding within 2 weeks prior to the first dose of study intervention * Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention * Has GI obstruction, poor oral intake, difficulty in taking oral medication, or existing esophageal stent * Has had major surgery, open biopsy, or significant traumatic injury within 3 weeks prior to first dose of study interventions * Has received prior radiotherapy within 2 weeks of start of study intervention or have had a history of radiation pneumonitis * Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention; administration of killed vaccines is allowed * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any form of immunosuppressive therapy within 7 days prior to the first dose of study intervention, or has a history of organ transplant, including allogeneic stem cell transplant * Has a 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 an active autoimmune disease that has required systemic treatment in past 2 years; replacement therapy is not considered a form of systemic treatment and is allowed * Has a history of non-infectious pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease * Has poorly controlled diarrhea * Has clinically significant cardiovascular disease within 12 months from first dose of study intervention * Has peripheral neuropathy ≥Grade 2 * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of Hepatitis B or know active Hepatitis C virus infection * Has a weight loss of \>20% within the last 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 (FP and TP Safety Run-in): Number of Participants With Dose Limiting Toxicities (DLTs) | Up to ~21 days | Hematologic DLTs are defined as Grade 4 neutropenia lasting for ≥7 days, Grade 3 or Grade 4 febrile neutropenia, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia, or Grade 4 anemia. Other nonhematologic toxicities considered a DLT include any other Grade 4 or Grade 5 toxicity, Grade 3 toxicities lasting \>3 days (excluding nausea, vomiting, and diarrhea controlled by medical intervention within 72 hours, and Grade 3 rash in the absence of desquamation with no mucosal involvement), Grade 3 hypertension not able to be controlled by medication, ≥Grade 3 gastrointestinal perforation, ≥Grade 3 wound dehiscence requiring medical or surgical intervention, any grade thromboembolic event or any Grade 3 nonhematologic laboratory value requiring medical intervention or hospitalization. The number of participants in Part 1 with DLTs will be presented. |
| Part 1 (FP and TP Safety Run-in): Number of Participants With Adverse Events (AEs) | Up to ~53 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 number of participants in Part 1 with AEs will be presented. |
| Part 1 (FP and TP Safety Run-in): Number of Participants who Discontinued Study Treatment Due to an AE | Up to ~53 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 number of participants in Part 1 who discontinue study treatment due to an AE will be presented. |
| Part 2 (Main Study): Overall Survival (OS) in all Participants | Up to ~48 months | OS is defined as the time from randomization to death due to any cause. OS in Part 2 for all randomized participants will be presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2 (Main Study): PFS per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10 | Up to ~42 months | PFS is defined as the time from randomization to the first documented PD per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, 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. RECIST 1.1 has been adjusted to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. PFS in Part 2 for randomized participants with PD-L1 CPS ≥10 will be presented. |
| Part 2 (Main Study): ORR per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10 | Up to ~42 months | ORR is defined as the percentage of participants with CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions), per RECIST 1.1 adjusted to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. ORR in Part 2 for randomized participants with PD-L1 CPS ≥10 will be presented. |
| Part 2 (Main Study): Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in all Participants | Up to ~42 months | PFS is defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, 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. RECIST 1.1 has been adjusted to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. PFS in Part 2 for all randomized participants will be presented. |
| Part 2 (Main Study): Number of Participants With AEs | Up to ~53 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 number of participants in Part 2 with AEs will be presented. |
| Part 2 (Main Study): Number of Participants who Discontinued Study Treatment Due to an AE | Up to ~53 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 number of participants in Part 2 who discontinue study treatment due to an AE will be presented. |
| Part 2 (Main Study): DOR per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10 | Up to ~42 months | For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions), per RECIST 1.1 by BICR, 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. RECIST 1.1 has been adjusted to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. DOR in Part 2 for randomized participants with PD-L1 CPS ≥10 will be presented. |
| Part 2 (Main Study): Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR in all Participants | Up to ~42 months | 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 RECIST 1.1 adjusted to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. ORR in Part 2 for all randomized participants will be presented. |
| Part 2 (Main Study): Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR in all Participants | Up to ~42 months | For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions), per RECIST 1.1 by BICR, 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. RECIST 1.1 has been adjusted to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. DOR in Part 2 for all randomized participants will be presented. |
| Part 2 (Main Study): OS in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | Up to ~48 months | OS is defined as the time from randomization to death due to any cause. OS in Part 2 for randomized participants with PD-L1 CPS ≥10 will be presented. |
Countries
Argentina, Canada, Chile, China, Costa Rica, Denmark, France, Guatemala, Hong Kong, Hungary, Italy, Japan, Malaysia, Romania, Russia, Singapore, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Outcome results
None listed