Efficacy and Safety of Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) Plus Chemotherapy in Participants With Metastatic Esophageal Carcinoma (MK-7902-014/E7080-G000-320/LEAP-014)
|
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04949256 |
|
Recruitment Status :
Recruiting
First Posted : July 2, 2021
Last Update Posted : May 7, 2024
|
Sponsor:
Merck Sharp & Dohme LLC
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
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) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Metastatic Esophageal Squamous Cell Carcinoma | Drug: Pembrolizumab Drug: Lenvatinib Drug: Cisplatin Drug: 5-FU Drug: Oxaliplatin Drug: Leucovorin Drug: Levoleucovorin Drug: Paclitaxel | Phase 3 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 862 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 3, Randomized Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) + Lenvatinib (E7080/MK-7902) + Chemotherapy Compared With Standard of Care as First-line Intervention in Participants With Metastatic Esophageal Carcinoma |
| Actual Study Start Date : | July 28, 2021 |
| Estimated Primary Completion Date : | December 29, 2025 |
| Estimated Study Completion Date : | December 29, 2025 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Pembrolizumab + Lenvatinib + Chemotherapy
Participants receive pembrolizumab intravenously (IV) plus lenvatinib orally in combination with FP or TP in Part 1, or in combination with investigator's choice of chemotherapy with FP IV or TP IV or oxaliplatin, 5-FU and leucovorin (mFOLFOX6) IV in Part 2. Induction consists of pembrolizumab 400 mg once every 6-weeks (Q6W) for up to ~12 weeks plus lenvatinib 8 mg once daily (QD) for up to ~12 weeks plus chemotherapy with FP (cisplatin 80 mg/m^2 and 5-FU 4000 mg/m^2) or TP (paclitaxel 175 mg/m^2 and cisplatin 75 mg/m^2) once every 3 weeks (Q3W) for up to ~12 weeks or mFOLFOX6 (oxaliplatin 85 mg/m^2, 5-FU 400 mg/m^2 followed by 2400 mg/m^2, and leucovorin 400 mg/m^2 [or levoleucovorin 200 mg/m^2] once every 2 weeks [Q2W] for up to ~12 weeks). This is followed by consolidation with pembrolizumab 400 mg Q6W for up to 16 cycles (each cycle = 6 weeks; total pembrolizumab treatment duration is ~2 years) plus lenvatinib 20 mg QD until progressive disease or discontinuation.
|
Drug: Pembrolizumab
400 mg once every 6-week-cycle, via IV infusion.
Other Names:
Drug: Lenvatinib 8 mg QD (induction) or 20 mg QD (consolidation) via oral capsule.
Other Names:
Drug: Cisplatin 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.
Other Name: PLATINOL® Drug: 5-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.
Other Name: ADRUCIL® Drug: Oxaliplatin 85 mg/m^2 Q2W via IV infusion, as part of investigator's choice mFOLFOX6 chemotherapy.
Other Name: ELOXATIN® Drug: Leucovorin 400 mg/m^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.
Other Names:
Drug: Levoleucovorin 200 mg/m^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.
Other Names:
Drug: Paclitaxel 175 mg/m^2 Q3W via IV infusion, as part of investigator's choice TP chemotherapy.
Other Names:
|
|
Active Comparator: Pembrolizumab + Chemotherapy
Participants receive pembrolizumab 400 mg IV Q6W for up to 18 cycles (each cycle = 6 weeks; total pembrolizumab treatment duration is ~2 years) in combination with investigator's choice of chemotherapy with FP (cisplatin 80 mg/m^2 IV Q3W for up to 6 administrations [up to ~18 weeks] and 5-FU 4000 mg/m^2 IV Q3W for up to 35 administrations [up to ~2 years]) or TP (paclitaxel 175 mg/m^2 and cisplatin 75 mg/m^2 Q3W for up 6 administrations [up to ~18 weeks]) or in combination with mFOLFOX6 (oxaliplatin 85 mg/m^2, 5-FU 400 mg/m^2 followed by 2400 mg/m^2 and leucovorin 400 mg/m^2 [or levoleucovorin 200 mg/m^2] IV Q2W for up to 52 administrations [approximately 2 years]), during Part 2.
|
Drug: Pembrolizumab
400 mg once every 6-week-cycle, via IV infusion.
Other Names:
Drug: Cisplatin 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.
Other Name: PLATINOL® Drug: 5-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.
Other Name: ADRUCIL® Drug: Oxaliplatin 85 mg/m^2 Q2W via IV infusion, as part of investigator's choice mFOLFOX6 chemotherapy.
Other Name: ELOXATIN® Drug: Leucovorin 400 mg/m^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.
Other Names:
Drug: Levoleucovorin 200 mg/m^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.
Other Names:
Drug: Paclitaxel 175 mg/m^2 Q3W via IV infusion, as part of investigator's choice TP chemotherapy.
Other Names:
|
Primary Outcome Measures :
- Part 1 (FP and TP Safety Run-in): Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: 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) [ Time Frame: Up to ~51 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 [ Time Frame: Up to ~51 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 [ Time Frame: Up to ~49 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.
- 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 [ Time Frame: Up to ~41 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.
Secondary Outcome Measures :
- Part 2 (Main Study): Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR in all Participants [ Time Frame: Up to ~34 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 [ Time Frame: Up to ~34 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 [ Time Frame: Up to ~49 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.
- Part 2 (Main Study): PFS per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10 [ Time Frame: Up to ~41 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 [ Time Frame: Up to ~34 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): DOR per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10 [ Time Frame: Up to ~34 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): Number of Participants With AEs [ Time Frame: Up to ~49 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 [ Time Frame: Up to ~49 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): Change From Baseline in Health-related Quality of life (HRQoL) Score Using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) [ Time Frame: Baseline and ~24 months ]The EORTC QLQ-C30 is a questionnaire to assess the overall HRQoL. Participant responses to the question " How would you rate your overall quality of life (QoL) during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall QoL. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in HRQoL EORTC QLQ-C30 score in participants in Part 2 will be presented.
- Part 2 (Main Study): Change From Baseline in HRQoL Score Using EORTC Quality of Life Questionnaire-Oesophageal Module (QLQ-OES18) [ Time Frame: Baseline and ~24 months ]The EORTC QLQ-OES18 is a disease-specific questionnaire to assess measurements specific to esophageal cancer. It contains 18 items and is based on four subscales-dysphagia, eating, reflux and pain. All items are scored using a four-point scale that offers these response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. A higher score indicates worse level of symptoms. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in HRQoL QLQ-OES18 score in participants in Part 2 will be presented.
- Part 2 (Main Study): Time to Deterioration (TTD) in HRQoL Score Using EORTC QLQ-C30 [ Time Frame: Up to ~ 24 months ]TTD is defined as the time from baseline to the first onset of a ≥10-point change from baseline in the HRQoL EORTC QLQ-C30 score. The EORTC QLQ-C30 is a questionnaire to assess the overall HRQoL. Participant responses to the question " How would you rate your overall QoL during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall QoL. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A longer TTD indicates a better outcome. The TTD in HRQoL EORTC QLQ-C30 score in participants in Part 2 will be presented.
- Part 2 (Main Study): TTD in HRQoL Score Using EORTC QLQ-OES18 [ Time Frame: Up to ~ 24 months ]TTD is defined as the time from baseline to the first onset of a ≥10-point change from baseline in the HRQoL EORTC QLQ-OES18 score. The EORTC QLQ-OES18 is a disease-specific questionnaire to assess measurements specific to esophageal cancer. It contains 18 items and is based on four subscales-dysphagia, eating, reflux and pain. All items are scored using a four-point scale that offers these response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. A higher score indicates worse level of symptoms. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A longer TTD indicates a better outcome. The TTD in HRQoL QLQ-OES18 score in participants in Part 2 will be presented.
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04949256
Contacts
| Contact: Toll Free Number | 1-888-577-8839 | Trialsites@merck.com |
Locations
Show 192 study locations
Sponsors and Collaborators
Merck Sharp & Dohme LLC
Eisai Inc.
Investigators
| Study Director: | Medical Director | Merck Sharp & Dohme LLC |
Additional Information:
| Responsible Party: | Merck Sharp & Dohme LLC |
| ClinicalTrials.gov Identifier: | NCT04949256 |
| Other Study ID Numbers: |
7902-014 MK-7902-014 ( Other Identifier: Merck ) LEAP-014 ( Other Identifier: Merck ) E7080-G000-320 ( Other Identifier: Eisai ) U1111-1280-1020 ( Other Identifier: WHO ) 2022-501342-29 ( Registry Identifier: EU CT ) 2020-001911-26 ( EudraCT Number ) |
| First Posted: | July 2, 2021 Key Record Dates |
| Last Update Posted: | May 7, 2024 |
| Last Verified: | May 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf |
| URL: | http://engagezone.msd.com/ds_documentation.php |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Merck Sharp & Dohme LLC:
|
programmed cell death 1 (PD-1, PD1) programmed cell death ligand 1 (PD-L1, PDL1) |
Additional relevant MeSH terms:
|
Carcinoma Esophageal Squamous Cell Carcinoma Esophageal Neoplasms Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Carcinoma, Squamous Cell Neoplasms, Squamous Cell Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Head and Neck Neoplasms Digestive System Diseases Esophageal Diseases Gastrointestinal Diseases |
Calcium, Dietary Leucovorin Paclitaxel Pembrolizumab Oxaliplatin Lenvatinib Calcium Levoleucovorin Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological |