Clinical trial NCT04428151: Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) vs. Standard Chemotherapy and Lenvatinib Monotherapy in Participants With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma That Progressed After Platinum Therapy and Immunotherapy (MK-7902-009/E7080-G000-228/LEAP-009)
Official title: A Phase 2, Randomized, Open-label Three-arm Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) Versus Standard of Care Chemotherapy and Lenvatinib Monotherapy in Participants With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) That Have Progressed After Platinum Therapy and Immunotherapy (PD-1/PD-L1 Inhibitors) (LEAP-009)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of Head and Neck
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Eisai Inc.
First posted: 2020-06-11
Enrollment: 408
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: Researchers are looking for new ways to treat people with head and neck cancer whose cancer has come back after treatment (recurrent) or whose cancer has spread to other parts of the body (metastatic). Some people with recurrent or metastatic head and neck cancer are treated with chemotherapy and immunotherapy, but the cancer gets worse.

The goal of this study is to learn if more people who receive lenvatinib and pembrolizumab have a better overall survival rate than people who receive standard chemotherapy treatment.

Detailed description: With Amendment 7, participants will discontinue lenvatinib and pembrolizumab and lenvatinib monotherapy, unless discussed with the Sponsor.

A protocol-specified periodic safety review was completed with a data cut-off of 31-May-2024 (Primary Completion Date) and served as the final analysis of the primary outcome measure. Per protocol, 34 participants enrolled after the primary completion date and will be analyzed in the End of Trial analysis.

Eligibility criteria: Inclusion Criteria:

* Pathologically confirmed recurrent (not amenable to curative treatment with local and/or systemic therapies) or metastatic (disseminated) head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies
* Disease progression at any time during or after treatment with a platinum-containing (e.g., carboplatin or cisplatin) regimen
* Disease progression on or after treatment with a programmed cell death protein 1/programmed death-ligand 1 monoclonal antibody (anti-PD-1/PD-L1 mAb)
* Pre-study imaging that demonstrates evidence of disease progression based on investigator review of at least 2 pre-study images per RECIST 1.1, following initiation of treatment with a PD-1/PD-L1 inhibitor
* Measurable disease by computed tomography scan (CT) or magnetic resonance imaging (MRI) based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as verified by blinded independent central review (BICR). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of the first dose of study intervention
* Male participants are eligible to participate if they agree to the following during the intervention period and for at least 1 week after the last dose of lenvatinib, 3 months after the last dose of capecitabine and paclitaxel, and 6 months after the last dose of docetaxel:

  * Refrain from donating sperm
  * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception unless confirmed to be azoospermic
  * Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
* 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)
  * Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 120 days post pembrolizumab or 1 month post lenvatinib, whichever occurs last (Arms 1 and 3), or during the intervention period and for at least 6 months after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last dose of cetuximab (Arm 2)
  * Female participants who randomize to Arm 2 must also agree not to donate or freeze/store eggs during the intervention period and for at least 6 months after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last dose of cetuximab
* Adequately controlled blood pressure (BP) with or without antihypertensive medications
* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization
* Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening
* Adequate organ function

Exclusion Criteria:

* Disease that is suitable for local therapy administered with curative intent
* Life expectancy of less than 3 months and/or has rapidly progressing disease in the opinion of the treating investigator
* History of (noninfectious) pneumonitis/interstitial lung disease that required steroids, or has current pneumonitis/interstitial lung disease
* Active infection requiring systemic therapy
* 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 to the first dose of study drug
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Known additional malignancy that is progressing or has required active systemic treatment within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ that have undergone potentially curative therapy
* Active autoimmune disease that has required systemic treatment in the past 2 years
* Had an allogeneic tissue/solid organ transplant
* Known history of human immunodeficiency virus (HIV) infection
* History of any contraindication or has a severe hypersensitivity to any components of pembrolizumab, lenvatinib or SOC chemotherapy.
* Pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula
* History of a gastrointestinal malabsorption or any other condition or procedure that may affect oral study drug absorption
* Had major surgery within 3 weeks prior to first dose of study interventions
* Clinically significant cardiovascular impairment within 12 months of the first dose of study drug
* Active tuberculosis
* Has difficulty swallowing capsules or ingesting a suspension orally, or by a feeding tube
* Prior treatment with lenvatinib
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 or has not recovered from adverse events (AEs) due to a previously administered agent. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible
* Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Administration of killed vaccines is allowed
* Previously treated with 4 or more systemic regimens given for recurrent/metastatic disease
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
* Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to approximately 45 months
Secondary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: Up to approximately 45 months
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 45 months
measure: Duration of Response (DOR)
timeFrame: Up to approximately 45 months
measure: Number of Participants Who Experienced One or More Adverse Events (AEs)
timeFrame: Up to approximately 5 years
measure: Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE)
timeFrame: Up to approximately 5 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope ( Site 1519)
state: California
city: Los Angeles
country: United States
facility: UCLA Hematology/Oncology - Westwood (Building 100) ( Site 1568)
state: California
city: New Haven
country: United States
facility: Yale-New Haven Hospital-Yale Cancer Center ( Site 1505)
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center ( Site 1520)
state: District of Columbia
city: Gainesville
country: United States
facility: UF Health ( Site 1554)
state: Florida
city: Orange City
country: United States
facility: Mid Florida Hematology and Oncology Center ( Site 1606)
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida ( Site 1596)
state: Florida
city: Augusta
country: United States
facility: Georgia Cancer Center at Augusta University ( Site 1575)
state: Georgia
city: Marietta
country: United States
facility: Northwest Georgia Oncology Centers, a Service of Wellstar Cobb Hospital-Research ( Site 1521)
state: Georgia
city: Savannah
country: United States
facility: Memorial Health University Medical Center ( Site 1626)
state: Georgia
city: Post Falls
country: United States
facility: Beacon Cancer Care ( Site 1599)
state: Idaho
city: Chicago
country: United States
facility: Rush University Medical Center ( Site 1560)
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem - Evanston Hospital ( Site 1614)
state: Illinois
city: Muncie
country: United States
facility: IU Health Ball Memorial Hospital, Inc.-IU Health Ball Memorial Cancer Center ( Site 1612)
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa ( Site 1572)
state: Iowa
city: Westwood
country: United States
facility: University of Kansas Cancer Center ( Site 1538)
state: Kansas
city: Louisville
country: United States
facility: Norton Hospital-Norton Cancer Institute - Downtown ( Site 1601)
state: Kentucky
city: Paducah
country: United States
facility: Mercy Health-Paducah Cancer Center ( Site 1623)
state: Kentucky
city: Baton Rouge
country: United States
facility: Our Lady of the Lake RMC-Clinical Research ( Site 1624)
state: Louisiana
city: Baton Rouge
country: United States
facility: Mary Bird Perkins Cancer Center Baton Rouge ( Site 1622)
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Cancer Center ( Site 1522)
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center ( Site 1605)
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Chan Medical School ( Site 1616)
state: Massachusetts
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System ( Site 1584)
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute ( Site 1566)
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System ( Site 1544)
state: Michigan
city: Hattiesburg
country: United States
facility: Hattiesburg Clinic ( Site 1515)
state: Mississippi
city: Jackson
country: United States
facility: Jackson Oncology Associates, PLLC-Clinical Trials ( Site 1625)
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine ( Site 1500)
state: Missouri
city: Billings
country: United States
facility: St. Vincent Frontier Cancer Center ( Site 1507)
state: Montana
city: Omaha
country: United States
facility: University Of Nebraska Medical Center ( Site 1570)
state: Nebraska
city: Omaha
country: United States
facility: Oncology Hematology West P.C. dba Nebraska Cancer Specialists ( Site 1627)
state: Nebraska
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center ( Site 1555)
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey ( Site 1523)
state: New Jersey
city: Mineola
country: United States
facility: Perlmutter Cancer Center at Winthrop Oncology Hematology Associates NYU Langone Health ( Site 1597)
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center ( Site 1582)
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute ( Site 1590)
state: North Carolina
city: Durham
country: United States
facility: Duke Cancer Institute ( Site 1541)
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center ( Site 1567)
state: Ohio
city: Cleveland
country: United States
facility: University Hospital Cleveland ( Site 1578)
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Main ( Site 1598)
state: Ohio
city: Columbus
country: United States
facility: The James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive C
state: Ohio
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute, LLC ( Site 1508)
state: Oklahoma
city: Gettysburg
country: United States
facility: Gettysburg Cancer Center ( Site 1594)
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Hershey Medical Center ( Site 1561)
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center ( Site 1502)
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina ( Site 1579)
state: South Carolina
city: Greenville
country: United States
facility: St Francis Cancer Center-Research Office ( Site 1607)
state: South Carolina
city: Fort Worth
country: United States
facility: The Center For Cancer And Blood Disorders ( Site 1569)
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists ( Site 1621)
state: Utah
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute ( Site 1532)
state: Utah
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute ( Site 1550)
state: Virginia
city: Fredericksburg
country: United States
facility: Hematology Oncology Associates of Fredericksburg ( Site 1537)
state: Virginia
city: Tacoma
country: United States
facility: MultiCare Health System-MultiCare Oncology - Puget Sound ( Site 1609)
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin Clinical Cancer Center ( Site 1574)
state: Wisconsin
city: Port Macquarie
country: Australia
facility: Mid North Coast Cancer Institute ( Site 0109)
state: New South Wales
city: Sydney
country: Australia
facility: Blacktown Hospital ( Site 0101)
state: New South Wales
city: Douglas
country: Australia
facility: The Townsville Hospital ( Site 0107)
state: Queensland
city: Greenslopes
country: Australia
facility: Gallipoli Medical Research Ltd-GMRF CTU ( Site 0105)
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital ( Site 0110)
state: South Australia
city: Clayton
country: Australia
facility: Monash Health ( Site 0102)
state: Victoria
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceição-Centro Integrado de Pesquisa em Oncologia ( Site 0806)
state: Rio Grande Do Sul
city: Sao Paulo
country: Brazil
facility: A. C. Camargo Cancer Center ( Site 0809)
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre ( Site 0304)
state: Alberta
city: Vancouver
country: Canada
facility: BC Cancer-Vancouver Center ( Site 0306)
state: British Columbia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences-Juravinski Cancer Centre ( Site 0307)
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Research Institute ( Site 0308)
state: Ontario
city: Medellin
country: Colombia
facility: Instituto de Cancerología ( Site 0408)
state: Antioquia
city: Valledupar
country: Colombia
facility: Sociedad De Oncologia Y Hematologia Del Cesar ( Site 0404)
state: Cesar
city: Montería
country: Colombia
facility: Oncomédica S.A.S ( Site 0409)
state: Cordoba
city: Bogotá
country: Colombia
facility: Administradora Country S.A.S - Clínica del Country ( Site 0407)
state: Cundinamarca
city: Copenhagen
country: Denmark
facility: Rigshospitalet University Hospital Copenhagen ( Site 1000)
state: Hovedstaden
city: Marseille
country: France
facility: Hopital La Timone ( Site 0503)
state: Bouches-du-Rhone
city: Montpellier
country: France
facility: Centre de Cancerologie du Grand Montpellier ( Site 0508)
state: Herault
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin - Centre Régional de Lutte contre le Cancer d'Auvergne-ONCOLOGY ( Site 0510)
state: Puy-de-Dome
city: Rouen
country: France
facility: Centre de Lutte Contre le Cancer - Centre Henri Becquerel Normandie Rouen ( Site 0509)
state: Seine-Maritime
city: Villejuif
country: France
facility: Institut Gustave Roussy ( Site 0505)
state: Val-de-Marne
city: Paris
country: France
facility: Institut Curie ( Site 0500)
city: Be'er Sheva
country: Israel
facility: Soroka Medical Center-Oncology ( Site 0604)
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology Division ( Site 0602)
city: Jerusalem
country: Israel
facility: Hadassah Medical Center. Ein Kerem ( Site 0601)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center ( Site 0600)
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital ( Site 1801)
state: Kyonggi-do
city: Suwon
country: Korea, Republic of
facility: Ajou University Hospital ( Site 1802)
state: Kyonggi-do
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System ( Site 1800)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 1803)
city: Oslo
country: Norway
facility: Oslo universitetssykehus, Radiumhospitalet ( Site 1102)
city: Vila Nova de Gaia
country: Portugal
facility: Unidade Local de Saude Gaia/Espinho - Hospital Eduardo Santos Silva ( Site 1401)
state: Porto
city: Porto
country: Portugal
facility: Inst. Portugues de Oncologia de Porto Francisco Gentil EPE ( Site 1400)
city: București
country: Romania
facility: Spitalul Clinic Colțea ( Site 1708)
state: Bucuresti
city: Cluj Napoca
country: Romania
facility: Cardiomed SRL Cluj-Napoca ( Site 1701)
state: Cluj
city: Cluj Napoca
country: Romania
facility: Institutul Oncologic Prof.Dr. Ion Chiricuta Cluj-Napoca ( Site 1702)
state: Cluj
city: Floresti
country: Romania
facility: S.C. Radiotherapy Center Cluj S.R.L ( Site 1706)
state: Cluj
city: Craiova
country: Romania
facility: S.C. Centrul de Oncologie Sf. Nectarie SRL ( Site 1704)
state: Dolj
city: Timișoara
country: Romania
facility: Cabinet Medical Oncomed ( Site 1707)
state: Timis
city: Bucuresti
country: Romania
facility: S.C.Focus Lab Plus S.R.L ( Site 1703)
city: Hospitalet de Llobregat
country: Spain
facility: Instituto Catalan de Oncologia ICO - Hospital Duran i Reynals ( Site 0700)
state: Barcelona
city: Barcelona
country: Spain
facility: HOSPITAL CLÍNIC DE BARCELONA ( Site 0707)
state: Cataluna
city: A Coruna
country: Spain
facility: Centro Oncologico de Galicia ( Site 0706)
state: Galicia
city: Valencia
country: Spain
facility: Hospital General de Valencia ( Site 0703)
state: Valenciana, Comunitat
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d Hebron ( Site 0701)
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal ( Site 0705)
city: Malaga
country: Spain
facility: Hospital Virgen de la Victoria ( Site 0702)
city: Taoyuan County
country: Taiwan
facility: Chang Gung Memorial Hospital - Linkou Branch ( Site 1203)
state: Taoyuan
city: Kaohsiung
country: Taiwan
facility: Chang Gung Medical Foundation - Kaohsiung ( Site 1204)
city: Taichung
country: Taiwan
facility: China Medical University Hospital ( Site 1205)
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital ( Site 1206)
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital ( Site 1202)
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital ( Site 1200)
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital ( Site 1201)
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary ( Site 0911)
state: Aberdeen City
city: Cottingham
country: United Kingdom
facility: Castle Hill Hospital ( Site 0910)
state: East Riding Of Yorkshire
city: Glasgow
country: United Kingdom
facility: The Beatson West of Scotland Cancer Centre ( Site 0909)
state: Glasgow City
city: London
country: United Kingdom
facility: Guy s and St Thomas Hospital NHS Foundation Trust ( Site 0903)
state: Great Britain
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust ( Site 0905)
state: Hampshire
city: London
country: United Kingdom
facility: Royal Marsden Hospital ( Site 0902)
state: London, City Of
city: London
country: United Kingdom
facility: Charing Cross Hospital ( Site 0908)
state: London, City Of
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital ( Site 0904)
state: Somerset
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital. ( Site 0901)
state: Surrey
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust ( Site 0907)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Taylor MH, Schmidt EV, Dutcus C, Pinheiro EM, Funahashi Y, Lubiniecki G, Rasco D. The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Future Oncol. 2021 Feb;17(6):637-648. doi: 10.2217/fon-2020-0937. Epub 2020 Dec 10.