Clinical trial NCT04776148: Study of Lenvatinib (MK-7902/E7080) in Combination With Pembrolizumab (MK-3475) Versus Standard of Care in Participants With Metastatic Colorectal Cancer (MK-7902-017/E7080-G000-325/LEAP-017)
Official title: A Phase 3 Randomized Study of Lenvatinib in Combination With Pembrolizumab Versus Standard of Care in Participants With Metastatic Colorectal Cancer Who Have Received and Progressed On or After or Became Intolerant to Prior Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Neoplasms
Keywords: Programmed Cell Death Receptor 1 (PD-1)
Programmed Cell Death Receptor Ligand 1 (PD-L1)
Programmed Cell Death Receptor Ligand 2 (PD-L2)
PD-1
PDL1
PD-L1
PD-L2
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Eisai Inc.
First posted: 2021-03-01
Enrollment: 480
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the safety and efficacy of lenvatinib (MK-7902/E7080) in combination with pembrolizumab (MK-3475) in participants with metastatic colorectal cancer. The study will also compare lenvatinib plus pembrolizumab with the standard of care treatment of regorafenib and TAS-102 (trifluridine and tipiracil hydrochloride).

The primary study hypothesis is that lenvatinib plus pembrolizumab is superior to standard of care with respect to overall survival.


Eligibility criteria: Inclusion Criteria:

* Has histologically or cytologically confirmed diagnosis of unresectable and metastatic colorectal adenocarcinoma (Stage IV A, B and C as defined by American Joint Committee on Cancer \[AJCC\] 8th edition). Note: Tumor must be determined to be NOT microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) by local testing
* Has been previously treated for their disease and has shown disease progression as defined by RECIST 1.1 on or after or could not tolerate standard treatment, which must include ALL of the following agents if approved and locally available in the country where the participant is randomized:

  1. fluoropyrimidine, irinotecan and oxaliplatin
  2. with or without an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (bevacizumab)
  3. with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) for RAS (KRAS/NRAS) wild-type (WT) participants
  4. BRAF inhibitor (in combination with cetuximab +/- binimetinib) for BRAF V600E mutated metastatic colon cancer (mCRC)
* Has measurable disease per RECIST 1.1 assessed by the investigator
* Has provided to a designated central laboratory an archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion which has not been previously irradiated
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 3 days prior to randomization
* Has a life expectancy of at least 3 months, based on the investigator assessment
* Has the ability to swallow capsules or ingest a suspension orally or by a feeding tube
* Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 millimeter of mercury (mmHg) with no change in antihypertensive medications within 1 week prior to randomization
* Male participants must agree to the following during the treatment period and for at least 90 days after the last dose of regorafenib or TAS-102 and at least 7 days after the last dose of lenvatinib: refrain from donating sperm PLUS either be abstinent from heterosexual intercourse as their preferred and usual lifestyle or use contraception. The male contraception period should continue for at least 7 days after discontinuation of lenvatinib
* A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of childbearing potential (WOCBP) OR is a WOCBP and using a highly-effective contraceptive method during the treatment period and for at least 30 days after the last dose of lenvatinib, 120 days after the last dose of pembrolizumab, and 180 days after the last dose of regorafenib or TAS-102 (whichever is last) AND agrees not to donate eggs (ova, oocytes)
* A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 24 hours before the first dose of study treatment

Exclusion Criteria:

* Has a tumor that is microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) per local testing
* Has presence of gastrointestinal condition, eg, malabsorption, that might affect the absorption of study drug.
* Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment
* Has radiographic evidence of encasement or invasion of a major blood vessel invasion or of intratumoral cavitation. In the chest, major blood vessels include the main pulmonary artery, the left and right pulmonary arteries, the 4 major pulmonary veins, the superior or inferior vena cava, and the aorta
* 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 intervention, 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.

Participants with cardiac failure NYHA Class II, III and IV are not allowed to be assigned to the regorafenib in Arm B

* Has a history of arterial thromboembolism within 12 months of start of study drug
* Has urine protein ≥1 gram/24 hour
* Has prolongation of QT interval corrected with Fridericia's formula (QTcF interval) to \>480 milliseconds
* Has left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with certain exceptions
* Has serious nonhealing wound, ulcer or bone fracture
* Has had major surgery within 3 weeks prior to first dose of study treatment
* Has received biologic response modifiers (eg, granulocyte colony-stimulating factor) within 4 weeks before study entry
* Has preexisting ≥Grade 3 gastrointestinal or nongastrointestinal fistula
* Has received prior treatment with a combination of an anti-PD-1, anti-PD-L1, or anti PD-L2 agent with anti-VEGF monoclonal antibodies or vascular endothelial growth factor receptor (VEGFR) inhibitors
* Has previously received regorafenib or TAS-102
* Has received prior systemic anti-cancer therapy including investigational agents within 28 days prior to randomization
* Has received prior radiotherapy within 2 weeks of start of study treatment
* Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study treatment
* Has known intolerance to lenvatinib, regorafenib, or TAS-102 and/or any of their excipients
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 28 days prior to the first dose of study treatment
* Has known central nervous system (CNS) metastases and/or carcinomatous meningitis.
* 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 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 medication
* 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 history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's 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 a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
* Has had an allogenic tissue/solid organ transplant

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to approximately 22 months
Secondary outcomes:
measure: 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)
timeFrame: Up to approximately 22 months
measure: Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 22 months
measure: Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 22 months
measure: Number of Participants Who Experience an Adverse Event (AE)
timeFrame: Up to approximately 22 months
measure: Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 22 months
measure: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score
timeFrame: Baseline and 8 weeks
measure: Change From Baseline in EORTC QLQ-C30 Physical Functioning (Items 1-5) Score
timeFrame: Baseline and 8 weeks
measure: Change From Baseline in EORTC QLQ-C30 Appetite Loss (Item 13) Score
timeFrame: Baseline and 8 weeks
measure: Change From Baseline in EORTC Quality of Life Questionnaire-Colorectal Cancer-Specific 29 Items (QLQ-CR29) Bloating (Item 37) Score
timeFrame: Baseline and 8 weeks
measure: Time to Deterioration (TTD) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score
timeFrame: Up to approximately 21 months
measure: TTD in EORTC QLQ-C30 Physical Functioning (Items 1-5) Score
timeFrame: Up to approximately 21 months
measure: TTD in EORTC QLQ-C30 Appetite Loss (Item 13) Score
timeFrame: Up to approximately 21 months
measure: TTD in EORTC Quality of Life Questionnaire-Colorectal Cancer-Specific 29 Items (QLQ-CR29) Bloating (Item 37) Score
timeFrame: Up to approximately 21 months
Other outcomes:
Locations:
city: Monterey
country: United States
facility: Pacific Cancer Care ( Site 0031)
state: California
city: Marietta
country: United States
facility: Northwest Georgia Oncology Centers, a Service of Wellstar Cobb Hospital ( Site 0021)
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center-Medicine - Section of Hematology/Oncology - Gastrointestinal P
state: Illinois
city: Baltimore
country: United States
facility: MFSMC-HJWCI-Oncology Research ( Site 0012)
state: Maryland
city: Baltimore
country: United States
facility: MedStar Good Samaritan Hospital-Oncology Research ( Site 0038)
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Hospital ( Site 0024)
state: Michigan
city: Billings
country: United States
facility: St. Vincent Frontier Cancer Center ( Site 0005)
state: Montana
city: Portland
country: United States
facility: Providence Portland Medical Center ( Site 0019)
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University - Clinical Trials Office ( Site 0027)
state: Pennsylvania
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute ( Site 0022)
state: Virginia
city: Roanoke
country: United States
facility: Blue Ridge Cancer Care ( Site 0036)
state: Virginia
city: Tacoma
country: United States
facility: Northwest Medical Specialties, PLLC ( Site 0033)
state: Washington
city: Ciudad autónoma de Buenos Aires
country: Argentina
facility: Hospital Británico de Buenos Aires-Oncology ( Site 0308)
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Fundación favaloro para la Docencia e Investigación Médica-Oncología ( Site 0301)
state: Caba
city: Rosario
country: Argentina
facility: Instituto de Oncología de Rosario ( Site 0305)
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Centro de Educación Médica e Investigaciones Clínicas (CEMIC)-Medical Oncology ( Site 0303)
city: Buenos Aires
country: Argentina
facility: IDIM - Instituto de Diagnóstico e Investigaciones Metabólicas ( Site 0300)
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital-Medical Oncology Clinical Trials Unit, Cancer Care Services ( Si
state: Queensland
city: Greenslopes
country: Australia
facility: Gallipoli Medical Research Foundation-GMRF CTU ( Site 1500)
state: Queensland
city: Woodville
country: Australia
facility: The Queen Elizabeth Hospital-Cancer Clinical Trials ( Site 1503)
state: South Australia
city: Melbourne
country: Australia
facility: Epworth Freemasons ( Site 1506)
state: Victoria
city: St Albans
country: Australia
facility: Western Health-Sunshine & Footscray Hospitals ( Site 1501)
state: Victoria
city: Perth
country: Australia
facility: Hollywood Private Hospital-Medical Oncology ( Site 1507)
state: Western Australia
city: Edmonton
country: Canada
facility: Cross Cancer Institute-Department of Medical Oncology ( Site 0207)
state: Alberta
city: Halifax
country: Canada
facility: NSHA-QEII Health Sciences Centre-Dickson Bldg-Dept. of Medical Oncology ( Site 0200)
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences-Juravinski Cancer Centre ( Site 0205)
state: Ontario
city: Toronto
country: Canada
facility: North York General Hospital ( Site 0206)
state: Ontario
city: Montreal
country: Canada
facility: CIUSSS de l'Est-de-l'Île-de-Montréal ( Site 0211)
state: Quebec
city: Québec
country: Canada
facility: CHU de Quebec - Université Laval - Hotel Dieu de Quebec-Hemato-Dermato-Gyneco-Oncology ( Site 0203)
state: Quebec
city: Foshan
country: China
facility: The First People's Hospital of Foshan-Gastrointestinal oncology ( Site 1604)
state: Guangdong
city: Guangzhou
country: China
facility: SUN YAT-SEN UNIVERSITY CANCER CENTRE ( Site 1600)
state: Guangdong
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital-Medical Oncology ( Site 1606)
state: Zhejiang
city: Copenhagen
country: Denmark
facility: Rigshospitalet ( Site 0702)
state: Hovedstaden
city: Copenhagen
country: Denmark
facility: Herlev and Gentofte Hospital-Department of Oncology ( Site 0704)
state: Hovedstaden
city: Odense
country: Denmark
facility: Odense Universitetshospital ( Site 0700)
state: Syddanmark
city: Vejle
country: Denmark
facility: Vejle Sygehus-Department of Oncology ( Site 0701)
state: Syddanmark
city: Reutlingen
country: Germany
facility: Klinikum am Steinenberg-Kreiskliniken Reutlingen GmbH ( Site 0908)
state: Baden-Wurttemberg
city: Munich
country: Germany
facility: klinikum rechts der isar der technischen universität münchen-Klinik und Poliklinik für Innere Mediz
state: Bayern
city: Gütersloh
country: Germany
facility: Onkodok GmbH ( Site 0907)
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: Charité Universitaetsmedizin Berlin - Campus Mitte ( Site 0901)
city: Hamburg
country: Germany
facility: Asklepios Altona-Oncology ( Site 0903)
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology ( Site 0800)
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center-Oncology ( Site 0804)
city: Jerusalem
country: Israel
facility: Hadassah Medical Center-Oncology ( Site 0802)
city: Ramat Gan
country: Israel
facility: Sheba Medical Center ( Site 0803)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center-Oncology ( Site 0801)
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital ( Site 1701)
state: Aichi
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East ( Site 1700)
state: Chiba
city: Kobe
country: Japan
facility: Kobe City Medical Center General Hospital ( Site 1707)
state: Hyogo
city: Kita
country: Japan
facility: Kagawa University Hospital ( Site 1708)
state: Kagawa
city: Yokohama
country: Japan
facility: Kanagawa cancer center ( Site 1705)
state: Kanagawa
city: Osakasayama
country: Japan
facility: Kindai University Hospital- Osakasayama Campus-Medical Oncology ( Site 1704)
state: Osaka
city: Ina-machi
country: Japan
facility: Saitama Prefectural Cancer Center ( Site 1703)
state: Saitama
city: Nagaizumi
country: Japan
facility: Shizuoka Cancer Center ( Site 1706)
state: Shizuoka
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Cancer Center ( Site 1709)
city: Tokyo
country: Japan
facility: National Cancer Center Hospital ( Site 1702)
city: Tokyo
country: Japan
facility: Japanese Foundation for Cancer Research-GI Oncology ( Site 1710)
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital ( Site 1806)
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital-Internal Medicine ( Site 1800)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System-Medical oncology ( Site 1801)
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center ( Site 1803)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center-Division of Hematology/Oncology ( Site 1804)
city: Seoul
country: Korea, Republic of
facility: The Catholic Univ. of Korea Seoul St. Mary's Hospital ( Site 1802)
city: Ufa
country: Russian Federation
facility: GBUZ Republican Clinical Oncological Dispensary-Antitumor drug therapy department ( Site 1109)
state: Baskortostan, Respublika
city: Saint Petersburg
country: Russian Federation
facility: Saint-Petersburg City Clinical Oncology Dispensary-Department of chemotherapy ( Site 1100)
state: Leningradskaya Oblast
city: Moscow
country: Russian Federation
facility: The National Medico-Surgical Center N.I. Pirogov ( Site 1102)
state: Moskva
city: Moscow
country: Russian Federation
facility: Fed State Budgetary Inst N.N. Blokhin Med Center of Oncology MHRF ( Site 1107)
state: Moskva
city: Moscow
country: Russian Federation
facility: First Moscow State Medical University I.M. Sechenov-Interhospital Institution ""Health Management (
state: Moskva
city: Ekaterinburg
country: Russian Federation
facility: SVERDLOVSK REGIONAL ONCOLOGY DISPENSARY ( Site 1108)
state: Sverdlovskaya Oblast
city: Sankt-Peterburg
country: Russian Federation
facility: SHBI Leningrad Regional Clinical Oncology Dispensary-Clinical Trials Department ( Site 1111)
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias-Digestive ( Site 1200)
state: Asturias
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla ( Site 1201)
state: Cantabria
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron-Oncology ( Site 1204)
city: Madrid
country: Spain
facility: HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 1205)
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de Valme-Departamento de Oncologia ( Site 1207)
city: Taichung
country: Taiwan
facility: China Medical University Hospital-Surgical Department ( Site 1903)
city: Tainan
country: Taiwan
facility: NATIONAL CHENG-KUNG UNI. HOSP. ( Site 1904)
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital ( Site 1900)
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital-Oncology ( Site 1901)
city: Taoyuan
country: Taiwan
facility: Chang Gung Medical Foundation.Linkou Branch ( Site 1902)
city: Ankara
country: Turkey
facility: Hacettepe Universitesi-oncology hospital ( Site 1302)
city: Ankara
country: Turkey
facility: Memorial Ankara Hastanesi-Medical Oncology ( Site 1304)
city: Edirne
country: Turkey
facility: Trakya University-Oncology ( Site 1303)
city: İstanbul
country: Turkey
facility: Acıbadem Maslak Hastanesi ( Site 1307)
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Cerrahpasa-Medical Oncology ( Site 1300)
city: Istanbul
country: Turkey
facility: TC Saglik Bakanligi Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi-oncology ( Site 1301)
city: Izmir
country: Turkey
facility: Ege University Medicine of Faculty-Medical Oncology ( Site 1305)
city: Malatya
country: Turkey
facility: İnönü Üniversitesi Turgut Özal Tıp Merkezi ( Site 1306)
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital ( Site 1407)
state: Cambridgeshire
city: London
country: United Kingdom
facility: UCLH-Cancer Clinical Trials Unit ( Site 1400)
state: Essex
city: London
country: United Kingdom
facility: Guy's & St Thomas' NHS Foundation Trust ( Site 1404)
state: London, City Of
city: London
country: United Kingdom
facility: ROYAL MARSDEN HOSPITAL (CHELSEA) ( Site 1403)
state: London, City Of
city: Edinburgh
country: United Kingdom
facility: Western General Hospital ( Site 1401)
state: Midlothian
city: London
country: United Kingdom
facility: Royal Marsden Hospital (Sutton) ( Site 1409)
state: Surrey
city: Manchester
country: United Kingdom
facility: The Christie-Medical Oncology ( Site 1411)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Kawazoe A, Xu RH, Garcia-Alfonso P, Passhak M, Teng HW, Shergill A, Gumus M, Qvortrup C, Stintzing S, Towns K, Kim TW, Shiu KK, Cundom J, Ananda S, Lebedinets A, Fu R, Jain R, Adelberg D, Heinemann V, Yoshino T, Elez E; LEAP-017 Investigators. Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study. J Clin Oncol. 2024 Aug 20;42(24):2918-2927. doi: 10.1200/JCO.23.02736. Epub 2024 Jun 4.