Efficacy and Safety of Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) in Previously Treated Participants With Select Solid Tumors (MK-7902-005/E7080-G000-224/LEAP-005)

Colorectal Cancer Clinical Trial

Official title:

A Multicenter, Open-label Phase 2 Study of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) in Previously Treated Subjects With Selected Solid Tumors (LEAP-005)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03797326
• Other study ID #: 7902-005
• Secondary ID: MK-7902-005E7080
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: February 12, 2019
• Est. completion date: December 20, 2024

Study information

• Verified date: October 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the safety and efficacy of combination therapy with pembrolizumab (MK-3475) and lenvatinib (E7080/MK-7902) in participants with triple negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (CRC), glioblastoma (GBM), biliary tract cancers (BTC), or pancreatic cancer.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 590
• Est. completion date: December 20, 2024
• Est. primary completion date: December 20, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Has a histologically or cytologically-documented, advanced (metastatic and/or unresectable) solid tumor that is incurable and for which prior standard systemic therapy has failed in one of the following cohorts: TNBC, Ovarian Cancer, Gastric Cancer, Colorectal Cancer, GBM, BTC (intrahepatic, extrahepatic cholangiocarcinoma and gall bladder cancer; excludes Ampulla of Vater), Pancreatic Cancer
• Must have progressed on or since the last treatment
• Has measurable disease per RECIST 1.1 (RANO for the GBM cohort) as assessed by the local site investigator/radiology and confirmed by BICR
• Has provided a PD-L1 evaluable archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Male participants agree to use approved contraception during the treatment period for at least 7 days after the last dose of lenvatinib, or refrain from heterosexual intercourse during this period
• Female participants are not pregnant or breastfeeding, and are not a woman of childbearing potential (WOCBP), OR are a WOCBP that agrees to use contraception during the treatment period (or 14 days prior to the initiation of study treatment for oral contraception) and for at least 120 days post pembrolizumab, or 30 days post lenvatinib, whichever occurs last
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 3 days of study treatment initiation
• Has adequate organ function

For Triple Negative Breast Cancer Participants:

• Has received one or 2 prior lines of therapy
• Has Lactate Dehydrogenase (LDH) <2.0 x Upper Limit of Normal (ULN)
• Has locally determined results for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 tumor analyses

For Ovarian Cancer Participants:

• Has primary ovarian cancer and has received 3 prior lines of therapy.

For Gastric Cancer Participants:

• Has received 2 prior lines of therapy. Note: Gastric cancer will include participants with both gastric and gastroesophageal junction (GEJ) adenocarcinoma. Participants with squamous cell carcinoma histology are not eligible

For Colorectal Cancer Participants:

• Has received 2 prior lines of therapy

For GBM Participants:

• Has failed initial systemic therapy for newly diagnosed GBM
• Have the following time periods elapsed before the projected start of scheduled study treatment: 1) at least 3 weeks from prior surgical resection, 2) at least 1 week from stereotactic biopsy, 3) at least 6 months from completion of prior radiotherapy, 4) at least 4 weeks (or 5 half-lives, whichever is shorter) from any investigational agent, 5) at least 4 weeks from cytotoxic therapy, 6) at least 6 weeks from antibodies, 7) at least 4 weeks (or 5 half-lives, whichever is shorter) from other antitumor therapies and 1 week for cancer vaccines
• Be neurologically stable (e.g. without a progression of neurologic symptoms or requiring escalating doses of systemic steroid therapy within last 2 weeks) and clinically stable
• Has histologically confirmed World Health Organization (WHO) Grade IV GBM
• Has locally determined result for O^6-methylguanine-DNA methyltransferase (MGMT) analysis

For Biliary Tract Cancer Participants:

• Has received 1 prior line of therapy
• Child-Pugh Score, Class A: well-compensated disease. Child-Pugh Score of 5-6

For Pancreatic Cancer Participants:

• Has pathologically (histologically or cytologically) confirmed pancreatic ductal adenocarcinoma that is metastatic at enrollment
• Has received one or 2 prior lines of therapy
• Has received prior therapy with at least 1 (platinum-containing regimen or gemcitabine-containing regimen) but no more than 2 prior systemic therapies for unresectable or metastatic pancreatic cancer

Exclusion Criteria:

• Has gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
• Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment (applies to all cohorts except the ovarian cancer cohort)
• Has radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation. Participants with portal vein invasion (Vp4), inferior vena cava, or cardiac involvement based on imaging in the BTC cohort are not eligible for enrollment
• Has clinical significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study treatment
• Has significant cardiovascular impairment within 12 months of the first dose of study treatment, such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA), or cardiac arrhythmia associated with hemodynamic instability
• Has a history of arterial thromboembolism within 12 months of start of study treatment
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Has a serious nonhealing wound, ulcer or bone fracture
• Has had major surgery within 3 weeks prior to first dose of study interventions
• Has biologic response modifiers therapy (e.g. granulocyte colony-stimulating factor) within 4 weeks before study entry
• Has preexisting =Grade 3 gastrointestinal (GI) or non-gastrointestinal fistula
• Has received prior therapy with lenvatinib, an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], Tumor necrosis factor receptor superfamily, member 4 [OX 40], tumor necrosis factor receptor superfamily member 9 [CD137])
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study treatment start
• If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• Has received a live vaccine within 30 days prior to the first dose of study treatment
• Has known intolerance to lenvatinib (and/or any of the excipients)
• 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 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 prior the first dose of study treatment
• Has known active CNS metastases and/or carcinomatous meningitis
• Has tumors involving the brain stem
• Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients
• Has an active autoimmune disease that has required systemic treatment in past 2 years
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of hepatitis B or known active hepatitis C virus infection
• Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
• Has had an allogenic tissue/solid organ transplant (large organ transplants, stem-cell transplant requiring chronic immunosuppressant therapy necessary to prevent graft rejection)

For GBM Participants:

• Has carcinomatous meningitis
• Has recurrent tumor greater than 6 cm in maximum diameter
• Has tumor primarily localized to the brainstem or spinal cord
• Has presence of multifocal tumor, diffuse leptomeningeal or extracranial disease
• Has evidence of intratumoral or peritumoral hemorrhage on baseline magnetic resonance imaging (MRI) scan other than those that are grade = 1 and either post-operative or stable on at least 2 consecutive MRI scans
• Has received Optune® TTFields within 2 weeks of study intervention

Related Conditions & MeSH terms

• Advanced Solid Tumors
• Biliary Tract Cancers
• Biliary Tract Neoplasms
• Colorectal Cancer
• Gastric Cancer
• Glioblastoma
• Ovarian Cancer
• Pancreatic Cancer
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

Intervention

Biological:
• Pembrolizumab
Administered as an IV infusion on Day 1 Q3W.

Drug:
• Lenvatinib
Administered orally once a day during each 21-day cycle.

Locations

Country	Name	City	State
Argentina	CEMIC ( Site 2104)	Buenos Aires
Argentina	Hospital Aleman ( Site 2100)	Buenos Aires	Caba
Argentina	IDIM Instituto de Diagnostico e Investigaciones Metabolicas ( Site 2101)	Caba
Argentina	Fundacion Favaloro para la Docencia e Investigacion Medica ( Site 2106)	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Hospital Britanico de Buenos Aires ( Site 2109)	Ciudad de Buenos Aires	Caba
Argentina	Instituto de Oncologia de Rosario ( Site 2105)	Rosario	Santa Fe
Australia	Royal Brisbane and Women s Hospital ( Site 0901)	Herston	Queensland
Australia	Alfred Health ( Site 0902)	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital ( Site 0903)	Nedlands	Western Australia
Canada	BC Cancer - Abbotsford ( Site 0200)	Abbotsford	British Columbia
Canada	Hamilton Health Sciences-Juravinski Cancer Centre ( Site 0208)	Hamilton	Ontario
Canada	Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0210)	Montreal	Quebec
Canada	CHU de Quebec Universite de Laval ( Site 0206)	Quebec
Canada	Princess Margaret Cancer Centre ( Site 0202)	Toronto	Ontario
Canada	Sunnybrook Research Institute ( Site 0207)	Toronto	Ontario
Canada	CancerCare Manitoba ( Site 0201)	Winnipeg	Manitoba
Chile	Fundacion Arturo Lopez Perez ( Site 1201)	Santiago	Region M. De Santiago
Chile	Hospital Clinico Universidad de Chile ( Site 1200)	Santiago	Region M. De Santiago
Chile	Pontificia Universidad Catolica de Chile ( Site 1202)	Santiago	Region M. De Santiago
Chile	Centro Investigación del Cáncer James Lind ( Site 1203)	Temuco	Araucania
Colombia	Instituto Nacional de Cancerologia E.S.E ( Site 1102)	Bogota	Distrito Capital De Bogota
Colombia	Fundacion Valle del Lili ( Site 1101)	Cali	Valle Del Cauca
Colombia	Fundacion Colombiana de Cancerologia Clinica Vida ( Site 1105)	Medellin	Antioquia
Colombia	Oncologos del Occidente S.A. ( Site 1106)	Pereira	Risaralda
France	Centre Oscar Lambret ( Site 0401)	Lille	Nord
France	Centre Leon Berard ( Site 0405)	Lyon	Auvergne
France	Centre Antoine Lacassagne ( Site 0404)	Nice	Alpes-Maritimes
France	Institut de Cancerologie de l Ouest Centre Rene Gauducheau ( Site 0402)	Saint-Herblain	Val-de-Marne
France	Institut Claudius Regaud IUCT Oncopole ( Site 0403)	Toulouse	Haute-Garonne
France	Institut Gustave Roussy ( Site 0400)	Villejuif	Val-de-Marne
Germany	Universitaetsklinikum Frankfurt ( Site 0306)	Frankfurt am Main	Hessen
Germany	SRH Wald-Klinikum Gera GmbH ( Site 0309)	Gera	Thuringen
Germany	Universitaetsklinikum Jena ( Site 0302)	Jena	Thuringen
Germany	Universitaetsklinikum Regensburg ( Site 0304)	Regensburg	Bayern
Germany	Robert Bosch GmbH ( Site 0307)	Stuttgart	Baden-Wurttemberg
Germany	HELIOS Dr. Horst Schmidt Kliniken Wiesbaden ( Site 0301)	Wiesbaden	Hessen
Israel	Soroka Medical Center ( Site 0601)	Beer Sheva
Israel	Rambam Medical Center ( Site 0602)	Haifa
Israel	Hadassah Ein Kerem Medical Center ( Site 0604)	Jerusalem
Israel	Chaim Sheba Medical Center ( Site 0600)	Ramat Gan
Israel	Sourasky Medical Center ( Site 0603)	Tel Aviv
Italy	Istituto Nazionale Tumori Fondazione Pascale ( Site 1400)	Napoli
Italy	Fondazione Policlinico Universitario A. Gemelli ( Site 1403)	Roma
Italy	Istituto Clinico Humanitas Research Hospital ( Site 1402)	Rozzano	Milano
Italy	Policlinico Le Scotte - A.O. Senese ( Site 1401)	Siena	Toscana
Korea, Republic of	Seoul National University Hospital ( Site 1000)	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System ( Site 1001)	Seoul
Korea, Republic of	Asan Medical Center ( Site 1002)	Songpagu	Seoul
Russian Federation	Arkhangelsk Clinical Oncological Dispensary ( Site 1600)	Arkhangelsk	Arkhangel Skaya Oblast
Russian Federation	Republican Clinical Oncology Dispensary of Tatarstan MoH ( Site 1603)	Kazan	Tatarstan, Respublika
Russian Federation	Russian Oncological Research Center n.a. N.N. Blokhin ( Site 1604)	Moscow	Moskva
Russian Federation	City Clinical Oncology Center ( Site 1608)	Saint-Petersburg	Sankt-Peterburg
Russian Federation	Leningrad Regional Oncology Center ( Site 1609)	Saint-Petersburg	Sankt-Peterburg
Russian Federation	Scientific Research Oncology Institute n.a. N.N.Petrov ( Site 1610)	Saint-Petersburg	Sankt-Peterburg
Spain	Hospital Clinic i Provincial ( Site 0703)	Barcelona
Spain	Clinica Universitaria de Navarra ( Site 0704)	Madrid
Spain	Hospital Ramon y Cajal ( Site 0702)	Madrid
Spain	Hospital Universitario Gregorio Maranon ( Site 0701)	Madrid
Switzerland	Ospedale Regionale di Bellinzona e Valli ( Site 1703)	Bellinzona	Ticino
Switzerland	Inselspital Universitaetsspital Bern ( Site 1705)	Bern	Berne
Switzerland	Kantonsspital Graubuenden ( Site 1704)	Chur	Grisons
Switzerland	Hopitaux Universitaires de Geneve HUG ( Site 1701)	Geneve
Switzerland	Kantonsspital St. Gallen ( Site 1702)	St. Gallen	Sankt Gallen
Switzerland	Universitaetsspital Zurich ( Site 1700)	Zurich
Taiwan	National Cheng Kung University Hospital ( Site 3003)	Tainan
Taiwan	National Taiwan University Hospital ( Site 3000)	Taipei
Thailand	Chulalongkorn University ( Site 5001)	Bangkok	Krung Thep Maha Nakhon
Thailand	Ramathibodi Hospital. ( Site 5002)	Bangkok	Krung Thep Maha Nakhon
Thailand	Siriraj Hospital ( Site 5003)	Bangkok	Krung Thep Maha Nakhon
United Kingdom	Cambridge University Hospitals NHS Trust ( Site 0803)	Cambridge	Cambridgeshire
United Kingdom	Leicester Royal Infirmary. Univ. Hosp. of Leicester NHS Trust ( Site 0804)	Leicester	Leicestershire
United Kingdom	Guy's Hospital ( Site 0806)	London	London, City Of
United Kingdom	Royal Marsden Hospital (Sutton) ( Site 0800)	London	Surrey
United Kingdom	Christie NHS Foundation Trust ( Site 0805)	Manchester
United States	Lehigh Valley Hospital- Cedar Crest ( Site 0047)	Allentown	Pennsylvania
United States	University of Colorado, Anschutz Cancer Pavilion ( Site 0007)	Aurora	Colorado
United States	Mary Crowley Cancer Research Centers - Medical City Hospital ( Site 0049)	Dallas	Texas
United States	City of Hope ( Site 0002)	Duarte	California
United States	Sanford Fargo Medical Center ( Site 0059)	Fargo	North Dakota
United States	West Cancer Center - East Campus ( Site 0018)	Germantown	Tennessee
United States	Cedars Sinai Medical Center ( Site 0003)	Los Angeles	California
United States	University of Wisconsin Carbone Cancer Center ( Site 0017)	Madison	Wisconsin
United States	Rutgers Cancer Institute of New Jersey ( Site 0009)	New Brunswick	New Jersey
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone Health ( Site 0023)	New York	New York
United States	University of Florida-Health Cancer Center-Orlando ( Site 0015)	Orlando	Florida
United States	University of California Davis Comprehensive Cancer Center ( Site 0005)	Sacramento	California
United States	Swedish Medical Center ( Site 0021)	Seattle	Washington
United States	Sanford Cancer Center ( Site 0058)	Sioux Falls	South Dakota

Sponsors (2)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC	Eisai Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Canada,  Chile,  Colombia,  France,  Germany,  Israel,  Italy,  Korea, Republic of,  Russian Federation,  Spain,  Switzerland,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO) Criteria for Glioblastoma (GBM) by Investigator Assessment in Initial Cohorts	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) as assessed by the investigator per RECIST 1.1, which is modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. For participants with GBM, response will be assessed by the investigator based on RANO criteria (CR: disappearance of all target lesions, PR: sum of products of diameters [SPD] decreased by = 50% from baseline value). For participants in the pancreatic cancer cohort, response will be assessed by blinded independent central review (BICR).	Up to approximately 72 months
Primary	ORR per RECIST 1.1 or RANO (GBM) by Blinded Independent Central Review (BICR) in Expanded Cohorts (Combined with Initial Cohorts)	ORR is defined as the percentage of participants who have a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD) as assessed by BICR per RECIST 1.1, which is modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. For participants with GBM, response will be assessed based on RANO criteria (CR: disappearance of all target lesions, PR: SPD decreased by = 50% from baseline value).	Up to approximately 72 months
Primary	Percentage of Participants Receiving Pembrolizumab Plus Lenvatinib who Experience 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 receiving pembrolizumab plus lenvatinib who experience at least one AE will be reported.	Up to approximately 72 months
Primary	Percentage of Participants Receiving Pembrolizumab Plus Lenvatinib who Discontinue Study Treatment Due to an 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 receiving pembrolizumab plus lenvatinib who discontinue study treatment due to an AE will be reported.	Up to approximately 72 months
Primary	Percentage of Participants Receiving Lenvatinib Monotherapy who Experience an 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 receiving lenvatinib monotherapy who experience at least one AE will be reported.	Up to approximately 72 months
Primary	Percentage of Participants Receiving Lenvatinib Monotherapy 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 receiving lenvatinib monotherapy who discontinue study treatment due to an AE will be reported.	Up to approximately 72 months
Secondary	Disease Control Rate (DCR) per RECIST 1.1 by Investigator Assessment in Initial Cohorts	DCR is defined as the percentage of participants who have a best overall response of CR, PR, or stable disease (SD) per RECIST 1.1. 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. DCR will be assessed by the investigator for all initial cohorts except for the pancreatic cancer cohort, will be assessed by BICR.	Up to approximately 72 months
Secondary	Duration of Response (DOR) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts	DOR is determined by disease assessment and is defined as the time from the earliest date of qualifying response until earliest date of disease progression or death from any cause, whichever comes 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. DOR will be assessed by the investigator for all initial cohorts except for the pancreatic cancer cohort, will be assessed by BICR.	Up to approximately 72 months
Secondary	Progression Free Survival (PFS) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts	PFS is defined as the time from date of study treatment to the first documented disease progression based on RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ (or RANO for GBM participants), or death due to any cause, whichever occurs first. PFS will be assessed by the investigator for all initial cohorts except for the pancreatic cancer cohort, will be assessed by BICR.	Up to approximately 72 months
Secondary	Overall Survival (OS) in Initial Cohorts	OS is defined as the time from the date of study treatment to the date of death due to any cause.	Up to approximately 72 months
Secondary	DCR per RECIST 1.1 by BICR in Expanded Cohorts (Combined with Initial Cohorts)	DCR is defined as the percentage of participants who have a best overall response of CR, PR, or (SD) per RECIST 1.1. 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, and will be assessed by BICR for this outcome measure.	Up to approximately 72 months
Secondary	DOR per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts)	DOR is determined by disease assessment and is defined as the time from the earliest date of qualifying response until earliest date of disease progression or death from any cause, whichever comes 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, and will be assessed by BICR for this outcome measure.	Up to approximately 72 months
Secondary	PFS per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts)	PFS is defined as the time from date of study treatment to the first documented disease progression based on RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ (or RANO for GBM participants), or death due to any cause, whichever occurs first, as assessed by BICR.	Up to approximately 72 months
Secondary	OS in Expanded Cohorts (Combined with Initial Cohorts)	OS is defined as the time from the date of study treatment to the date of death due to any cause.	Up to approximately 72 months
Secondary	ORR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm	ORR is defined as the percentage of participants who have a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD) as assessed by BICR per RECIST 1.1, which is modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.	Up to approximately 72 months
Secondary	DCR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm	DCR is defined as the percentage of participants who have a best overall response of CR, PR, or SD per RECIST 1.1. 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, and will be assessed by BICR for this outcome measure.	Up to approximately 72 months
Secondary	DOR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm	DOR is determined by disease assessment and is defined as the time from the earliest date of qualifying response until earliest date of disease progression or death from any cause, whichever comes 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, and will be assessed by BICR for this outcome measure.	Up to approximately 72 months
Secondary	PFS per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm	PFS is defined as the time from date of study treatment to the first documented disease progression based on RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ (or RANO for GBM participants), or death due to any cause, whichever occurs first, as assessed by BICR.	Up to approximately 72 months
Secondary	OS in Lenvatinib Monotherapy Arm	OS is defined as the time from the date of study treatment to the date of death due to any cause.	Up to approximately 72 months
Secondary	Plasma Concentration of Lenvatinib	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 plasma concentration of lenvatinib.	Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose and 2-12 hours post-dose; Cycle 2 Day 1: pre-dose, 0.5-4 hours, and 6-10 hours post-dose (up to approximately 23 days). Each cycle is 21 days.

External Links

•   Merck Clinical Trials Information