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Efficacy and Safety of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) for Advanced Melanoma in Anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/L1)-Exposed Participants (MK-7902-004/E7080-G000-225/LEAP-004)

Primary Purpose

Advanced Melanoma

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
lenvatinib
pembrolizumab
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Melanoma focused on measuring programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1), programmed cell death ligand 2 (PD-L2, PDL2)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Has histologically or cytologically confirmed melanoma
  • Has unresectable Stage III or Stage IV melanoma per American Joint Committee on Cancer (AJCC) staging system version 8 that is not amenable to local therapy
  • Has the presence of โ‰ฅ1 measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 as confirmed by BICR.
  • Has progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies
  • Has submitted pre-trial imaging
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
  • Has provided a baseline tumor biopsy
  • Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If participant received major surgery or radiation therapy of >30 Gray (Gy), they must have recovered from the toxicity and/or complications from the Intervention
  • Male participants must agree to use approved contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period
  • Female participants are not pregnant and not breastfeeding, and are not a woman of childbearing potential (WOCBP) or are a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study intervention
  • Has adequate organ function

Exclusion Criteria:

  • Has a 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 before the first dose of study treatment
  • Has a known additional malignancy that is progressing or requires active treatment
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Has ocular melanoma
  • Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody
  • Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
  • Has an active infection requiring systemic therapy
  • Has known history of Human Immunodeficiency Virus (HIV) or HIV 1/2 antibodies
  • Has known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (HCV RNA qualitative] is detected)
  • Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
  • Has a history of active tuberculosis (Bacillus tuberculosis)
  • Has presence of a gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
  • Has had major surgery within 4 weeks prior to first dose of study interventions (adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility)
  • Has a pre-existing Grade โ‰ฅ3 gastrointestinal or non-gastrointestinal fistula
  • Has radiographic evidence of major blood vessel invasion/infiltration
  • Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
  • Has clinically significant cardiovascular disease within 12 months from first dose of study drug, 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 received prior radiotherapy within 2 weeks of Cycle 1 Day 1 with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to Cycle 1 Day 1
  • Has received a live vaccine within 30 days before the first dose of study treatment
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
  • Has a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
  • Has had an allogeneic tissue/solid organ transplant
  • Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study

Sites / Locations

  • Ironwood Cancer & Research Centers ( Site 0312)
  • John Wayne Cancer Institute ( Site 0301)
  • Advocate Medical Group-Park Ridge ( Site 0313)
  • Southeast Nebraska Cancer Center ( Site 0316)
  • Texas Oncology-Baylor Charles A. Sammons Cancer Center ( Site 0317)
  • Inova Schar Cancer Institute ( Site 0314)
  • Melanoma Institute Australia ( Site 0152)
  • Princess Alexandra Hospital ( Site 0154)
  • Box Hill Hospital ( Site 0157)
  • Fiona Stanley Hospital ( Site 0156)
  • Lismore Base Hospital ( Site 0153)
  • Sunnybrook Research Institute ( Site 0654)
  • Princess Margaret Cancer Centre ( Site 0655)
  • Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0652)
  • McGill University Health Centre ( Site 0651)
  • Hospital Clinic i Provincial Barcelona ( Site 0001)
  • Hospital General Universitario Gregorio Maranon ( Site 0003)
  • Hospital Universitario Virgen de la Macarena ( Site 0004)
  • Hospital General Universitario de Valencia ( Site 0002)
  • Sahlgrenska Universitetssjukhuset ( Site 0052)
  • Skanes Universitetssjukhus ( Site 0053)
  • Karolinska Universitetssjukhuset ( Site 0051)
  • Norrlands Universitetssjukhus ( Site 0056)

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

lenvatinib plus pembrolizumab

Arm Description

Participants receive lenvatinib 20 mg orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
ORR is defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline SOD) per RECIST 1.1 as assessed by blinded independent central review (BICR). RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Secondary Outcome Measures

Progression-free Survival (PFS) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
PFS is defined as the time from the first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to the RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Overall Survival (OS)
OS is defined as the time from the first day of study treatment to death due to any cause.
Duration of Response (DOR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
DOR is defined as the time from first documented evidence of CR or PR, per RECIST 1.1 as assessed by BICR, until disease progression or death due to any cause, whichever occurs first. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Percentage of Participants Who Experience At Least One Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants who experience at least one AE will be reported.
Percentage of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants who discontinue study treatment due to an AE will be reported.
Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf)
Blood samples will be obtained on Day 1 and Day 15 of Cycle 1 (21-day cycle) and Day 1 of Cycle 2 (21-day cycle) for pharmacokinetic (PK) analysis to determine the AUC of lenvatinib.

Full Information

First Posted
December 13, 2018
Last Updated
October 16, 2023
Sponsor
Merck Sharp & Dohme LLC
Collaborators
Eisai Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03776136
Brief Title
Efficacy and Safety of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) for Advanced Melanoma in Anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/L1)-Exposed Participants (MK-7902-004/E7080-G000-225/LEAP-004)
Official Title
A Multicenter, Open-label, Phase 2 Trial to Assess the Efficacy and Safety of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Melanoma Previously Exposed to an Anti-PD-1/L1 Agent (LEAP-004)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Completed
Study Start Date
January 30, 2019 (Actual)
Primary Completion Date
October 11, 2023 (Actual)
Study Completion Date
October 11, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
Collaborators
Eisai Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will evaluate the safety and efficacy of combination therapy of lenvatinib (E7080/MK-7902) and pembrolizumab following approximately 2 years of pembrolizumab therapy and approximately 2 years or more lenvatinib therapy in adult participants with unresectable or advanced melanoma who have been exposed to anti-PD-1/L1 agents approved for unresectable or metastatic melanoma. No statistical hypothesis will be tested in this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Melanoma
Keywords
programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1), programmed cell death ligand 2 (PD-L2, PDL2)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
103 (Actual)

8. Arms, Groups, and Interventions

Arm Title
lenvatinib plus pembrolizumab
Arm Type
Experimental
Arm Description
Participants receive lenvatinib 20 mg orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
lenvatinib
Other Intervention Name(s)
MK-7902, E7080, LENVIMAโ„ข
Intervention Description
Administered orally once a day during each 21-day cycle.
Intervention Type
Biological
Intervention Name(s)
pembrolizumab
Other Intervention Name(s)
MK-3475, Keytrudaยฎ
Intervention Description
Administered as an IV infusion on Day 1 Q3W.
Primary Outcome Measure Information:
Title
Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
Description
ORR is defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline SOD) per RECIST 1.1 as assessed by blinded independent central review (BICR). RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Time Frame
Up to 3 years
Secondary Outcome Measure Information:
Title
Progression-free Survival (PFS) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
Description
PFS is defined as the time from the first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to the RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Time Frame
Up to 3 years
Title
Overall Survival (OS)
Description
OS is defined as the time from the first day of study treatment to death due to any cause.
Time Frame
Up to 3 years
Title
Duration of Response (DOR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
Description
DOR is defined as the time from first documented evidence of CR or PR, per RECIST 1.1 as assessed by BICR, until disease progression or death due to any cause, whichever occurs first. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Time Frame
Up to 3 years
Title
Percentage of Participants Who Experience At Least One Adverse Event (AE)
Description
An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants who experience at least one AE will be reported.
Time Frame
Up to 3 years
Title
Percentage of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
Description
An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants who discontinue study treatment due to an AE will be reported.
Time Frame
Up to 3 years
Title
Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf)
Description
Blood samples will be obtained on Day 1 and Day 15 of Cycle 1 (21-day cycle) and Day 1 of Cycle 2 (21-day cycle) for pharmacokinetic (PK) analysis to determine the AUC of lenvatinib.
Time Frame
At designated time points on Day 1 and Day 15 of Cycle 1 (21-day cycle) and Day 1 of Cycle 2 (21-day cycle)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Has histologically or cytologically confirmed melanoma Has unresectable Stage III or Stage IV melanoma per American Joint Committee on Cancer (AJCC) staging system version 8 that is not amenable to local therapy Has the presence of โ‰ฅ1 measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 as confirmed by BICR. Has progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies Has submitted pre-trial imaging Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 Has provided a baseline tumor biopsy Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If participant received major surgery or radiation therapy of >30 Gray (Gy), they must have recovered from the toxicity and/or complications from the Intervention Male participants must agree to use approved contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period Female participants are not pregnant and not breastfeeding, and are not a woman of childbearing potential (WOCBP) or are a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study intervention Has adequate organ function Exclusion Criteria: Has a 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 before the first dose of study treatment Has a known additional malignancy that is progressing or requires active treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Has ocular melanoma Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) Has an active infection requiring systemic therapy Has known history of Human Immunodeficiency Virus (HIV) or HIV 1/2 antibodies Has known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (HCV RNA qualitative] is detected) Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease Has a history of active tuberculosis (Bacillus tuberculosis) Has presence of a gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib Has had major surgery within 4 weeks prior to first dose of study interventions (adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility) Has a pre-existing Grade โ‰ฅ3 gastrointestinal or non-gastrointestinal fistula Has radiographic evidence of major blood vessel invasion/infiltration Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug Has clinically significant cardiovascular disease within 12 months from first dose of study drug, 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 received prior radiotherapy within 2 weeks of Cycle 1 Day 1 with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to Cycle 1 Day 1 Has received a live vaccine within 30 days before the first dose of study treatment Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment Has a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator Has had an allogeneic tissue/solid organ transplant Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
Facility Information:
Facility Name
Ironwood Cancer & Research Centers ( Site 0312)
City
Chandler
State/Province
Arizona
ZIP/Postal Code
85224
Country
United States
Facility Name
John Wayne Cancer Institute ( Site 0301)
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States
Facility Name
Advocate Medical Group-Park Ridge ( Site 0313)
City
Park Ridge
State/Province
Illinois
ZIP/Postal Code
60068
Country
United States
Facility Name
Southeast Nebraska Cancer Center ( Site 0316)
City
Lincoln
State/Province
Nebraska
ZIP/Postal Code
68510
Country
United States
Facility Name
Texas Oncology-Baylor Charles A. Sammons Cancer Center ( Site 0317)
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
Inova Schar Cancer Institute ( Site 0314)
City
Fairfax
State/Province
Virginia
ZIP/Postal Code
22031-4867
Country
United States
Facility Name
Melanoma Institute Australia ( Site 0152)
City
Wollstonecraft
State/Province
New South Wales
ZIP/Postal Code
2065
Country
Australia
Facility Name
Princess Alexandra Hospital ( Site 0154)
City
Woolloongabba
State/Province
Queensland
ZIP/Postal Code
4102
Country
Australia
Facility Name
Box Hill Hospital ( Site 0157)
City
Box Hill
State/Province
Victoria
ZIP/Postal Code
3128
Country
Australia
Facility Name
Fiona Stanley Hospital ( Site 0156)
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6150
Country
Australia
Facility Name
Lismore Base Hospital ( Site 0153)
City
Lismore
ZIP/Postal Code
2480
Country
Australia
Facility Name
Sunnybrook Research Institute ( Site 0654)
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4N 3M5
Country
Canada
Facility Name
Princess Margaret Cancer Centre ( Site 0655)
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0652)
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2X 3E4
Country
Canada
Facility Name
McGill University Health Centre ( Site 0651)
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H4A 3J1
Country
Canada
Facility Name
Hospital Clinic i Provincial Barcelona ( Site 0001)
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital General Universitario Gregorio Maranon ( Site 0003)
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Facility Name
Hospital Universitario Virgen de la Macarena ( Site 0004)
City
Sevilla
ZIP/Postal Code
41009
Country
Spain
Facility Name
Hospital General Universitario de Valencia ( Site 0002)
City
Valencia
ZIP/Postal Code
46014
Country
Spain
Facility Name
Sahlgrenska Universitetssjukhuset ( Site 0052)
City
Goteborg
ZIP/Postal Code
413 45
Country
Sweden
Facility Name
Skanes Universitetssjukhus ( Site 0053)
City
Lund
ZIP/Postal Code
221 85
Country
Sweden
Facility Name
Karolinska Universitetssjukhuset ( Site 0051)
City
Solna
ZIP/Postal Code
171 64
Country
Sweden
Facility Name
Norrlands Universitetssjukhus ( Site 0056)
City
Umea
ZIP/Postal Code
901 85
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Citations:
PubMed Identifier
35867951
Citation
Arance A, de la Cruz-Merino L, Petrella TM, Jamal R, Ny L, Carneiro A, Berrocal A, Marquez-Rodas I, Spreafico A, Atkinson V, Costa Svedman F, Mant A, Khattak MA, Mihalcioiu C, Jang S, Cowey CL, Smith AD, Hawk N, Chen K, Diede SJ, Krepler C, Long GV. Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination. J Clin Oncol. 2023 Jan 1;41(1):75-85. doi: 10.1200/JCO.22.00221. Epub 2022 Jul 22. Erratum In: J Clin Oncol. 2023 May 1;41(13):2454.
Results Reference
derived
Links:
URL
https://www.merckclinicaltrials.com/
Description
Merck Clinical Trials Information

Learn more about this trial

Efficacy and Safety of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) for Advanced Melanoma in Anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/L1)-Exposed Participants (MK-7902-004/E7080-G000-225/LEAP-004)

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