Safety and Efficacy Study of Pembrolizumab (MK-3475) in Combination With Investigational Agents for the Treatment of Extensive-Stage Small Cell Lung Cancer (ES-SCLC) in Need of Second-Line Therapy (MK-3475-B98/KEYNOTE-B98)

Small Cell Lung Carcinoma Clinical Trial

Official title:

A Phase 1b/2 Study to Evaluate the Efficacy and Safety of Pembrolizumab in Combination With Investigational Agents for the Treatment of Participants With PD-1/L1-refractory Extensive-Stage Small Cell Lung Cancer in Need of Second-Line Therapy (KEYNOTE-B98)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04938817
• Other study ID #: 3475-B98
• Secondary ID: MK-3475-B98KEYNO
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: August 19, 2021
• Est. completion date: November 2, 2026

Study information

• Verified date: April 2024
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a rolling arm study of pembrolizumab in combination with investigational agents in participants with anti-programmed cell death 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) refractory ES-SCLC in need of second-line treatment. This study will have 2 parts: an initial safety lead-in to determine safety and tolerability for experimental combinations of investigational agents without an established recommended phase 2 dose (RP2D) followed by an efficacy evaluation. Investigational agents will initiate directly in or be added to the efficacy evaluation after an initial evaluation of safety and tolerability of the investigational agent has been completed in a separate study or in the safety lead-in of this study. If an RP2D for a combination being evaluated in the safety lead-in is established from another study, then the efficacy evaluation may begin at the determined RP2D. There will be no hypothesis testing in this study.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 80
• Est. completion date: November 2, 2026
• Est. primary completion date: November 2, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Has histologically or cytologically confirmed diagnosis of ES-SCLC in need of second-line therapy
• Has progressed on or after treatment with an anti-programmed cell death 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) monoclonal antibody (mAb) administered as part of first-line platinum-based systemic therapy for ES-SCLC
• Has ES-SCLC defined as Stage IV (T any, N any, M1a/b/c) by the American Joint Committee on Cancer, Eighth Edition
• Has received 1 prior line of systemic therapy for small cell lung cancer (SCLC)
• Male participants must be abstinent from heterosexual intercourse or agree to use contraception during treatment for at least 7 days after the last dose of lenvatinib. No contraception is required if the participant is receiving pembrolizumab, pembrolizumab/quavonlimab, MK-4830, or favezelimab/pembrolizumab
• Female participants are not pregnant or breastfeeding and are not a woman of childbearing potential (WOCBP) or if are a WOCBP, are abstinent from heterosexual intercourse or are using contraception during the intervention period and for at least 120 days after the last dose of pembrolizumab, pembrolizumab/quavonlimab, MK-4830, or favezelimab/pembrolizumab or 30 days after the last dose of lenvatinib, whichever occurs last
• Female participants must abstain from breastfeeding during the intervention period and for at least 120 days after the last dose of pembrolizumab, pembrolizumab/quavonlimab, MK-4830, or favezelimab/pembrolizumab or 7 days after the last dose of lenvatinib, whichever occurs last
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study treatment
• Has measurable disease per RECIST 1.1 as assessed by local site investigator/radiology and verified by BICR
• Has submitted an archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 7 days before allocation/randomization
• 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 before randomization
• Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening
• Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP =150/90 millimeters of mercury (mm Hg) with no change in antihypertensive medications within 1 week before allocation/randomization
• Has a predicted life expectancy of >3 months

Exclusion Criteria:

• Has had major surgery within 3 weeks before first dose of study treatment
• Has a preexisting =Grade 3 gastrointestinal or non-gastrointestinal fistula
• Has clinically significant cardiovascular disease or major arterial thromboembolic event within 12 months before 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
• Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks before the first dose of study treatment
• Has gastrointestinal malabsorption or any other condition that might affect oral study intervention absorption
• Has serious nonhealing wound, ulcer, or bone fracture within 28 days before the start of study treatment
• Has any major hemorrhage or venous thromboembolic events within 3 months before the start of study treatment
• Has a history of inflammatory bowel disease
• Has a history of a gastrointestinal perforation within 6 months before the start of study treatment
• Has a known history of, or active, neurologic paraneoplastic syndrome
• Has received prior therapy with a receptor tyrosine kinase (RTK) inhibitor or anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-immunoglobulin-like transcript (ILT)-4, or anti-lymphocyte-activation gene 3 (LAG-3) agents
• Has received prior therapy with an anti-PD-1/L1 agent and was permanently discontinued from that treatment due to a treatment-related adverse event
• Has received prior systemic anticancer therapy including investigational agents within 4 weeks before start of study treatment
• Has received prior radiotherapy within 2 weeks of start of study treatment
• Has received lung radiation therapy >30 Gray (Gy) within 6 months before the first dose of study treatment
• Has received a live or live attenuated vaccine within 30 days before the first dose of study treatment
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
• Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
• Has symptomatic ascites, pleural effusion, or pericardial effusion
• 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 a known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with brain metastases may participate only if they satisfy all of the following: completed treatment (e.g., whole brain radiation treatment, stereotactic radiosurgery, or equivalent) =14 days before the first dose of study intervention; have no evidence of new or enlarging brain metastases confirmed by post-treatment repeat brain imaging (using the same modality) performed =4 weeks after pretreatment brain imaging; and are neurologically stable without the need for steroids for =7 days before the first dose of study intervention as per local site assessment. Participants with untreated brain metastases will be allowed if they are asymptomatic, the investigator determines there is no immediate CNS-specific treatment required, there is no significant surrounding edema, and the brain metastases are of 5 millimeter (mm) or less in size and 3 or less in number.
• Has a history of severe hypersensitivity reaction (=Grade 3) to any study treatment and/or any of its excipients
• Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid)
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection requiring systemic therapy
• Has a known history of Human Immunodeficiency Virus (HIV) infection
• Has concurrent active HBV or HCV
• Has progressive disease as initial response to first-line systemic chemotherapy in combination with PD-1/L1 inhibitor for ES-SCLC
• Has had an allogenic tissue/solid organ transplant

Related Conditions & MeSH terms

• Small Cell Lung Carcinoma

Intervention

Biological:
• coformulation pembrolizumab/quavonlimab
Intravenous (IV) infusion

Drug:
• lenvatinib
Oral administration

Biological:
• MK-4830
IV infusion
• coformulation favezelimab/pembrolizumab
IV infusion

Locations

Country	Name	City	State
Australia	The Prince Charles Hospital-Oncology Clinical Trials ( Site 4003)	Brisbane	Queensland
Australia	Monash Health-Oncology Research ( Site 4005)	Clayton	Victoria
Australia	Hollywood Private Hospital-Medical Oncology ( Site 4001)	Perth	Western Australia
Australia	Westmead Hospital-Department of Medical Oncology ( Site 4004)	Westmead	New South Wales
Austria	Klinik Penzing-2. Lungenabteilung ( Site 3101)	Vienna	Wien
Austria	Klinik Floridsdorf-Abteilung für Innere Medizin und Pneumologie ( Site 3100)	Wien
Canada	Cross Cancer Institute ( Site 3004)	Edmonton	Alberta
Canada	St. Marys Hospital Center ( Site 3000)	Montreal	Quebec
Canada	Princess Margaret Cancer Centre ( Site 3003)	Toronto	Ontario
Hungary	Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Onkologiai Kozpont ( Site 3800)	Szolnok	Jasz-Nagykun-Szolnok
Israel	Rambam Health Care Campus-Oncology ( Site 3600)	Haifa
Israel	Shaare Zedek Medical Center-Oncology ( Site 3602)	Jerusalem
Israel	Meir Medical Center ( Site 3601)	Kfar Saba
Israel	Rabin Medical Center-Oncology ( Site 3604)	Petah Tikva
Israel	Sheba Medical Center-ONCOLOGY ( Site 3603)	Ramat Gan
Italy	Istituto Europeo di Oncologia IRCCS-Divisione di Oncologia Toracica ( Site 3304)	Milano
Italy	Ospedale San Raffaele-Oncologia Medica ( Site 3303)	Milano	Lombardia
Italy	Humanitas-U.O di Oncologia medica ed Ematologia ( Site 3301)	Rozzano	Milano
Italy	ospedale le scotte-U.O.C. Immunoterapia Oncologica ( Site 3300)	Siena	Toscana
Korea, Republic of	Chungbuk National University Hospital ( Site 4106)	Cheongju-si	Chungbuk
Korea, Republic of	Seoul National University Bundang Hospital-Medical Oncology ( Site 4104)	Seongnam	Kyonggi-do
Korea, Republic of	Asan Medical Center-Lung Cancer Center ( Site 4103)	Seoul
Korea, Republic of	Samsung Medical Center ( Site 4100)	Seoul
Korea, Republic of	Seoul National University Hospital ( Site 4101)	Seoul
Poland	Samodzielny Publiczny Zespó Grulicy i Chorób Puc w Olsztynie-Oddzial Onkologii z Pododdzialem Chemi	Olsztyn	Warminsko-mazurskie
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Klinika Nowotworow Pluca i Klatki Pier	Warszawa	Mazowieckie
Russian Federation	Krasnoyarsk Regional Oncology Dispensary, Named after Krizhanovsky ( Site 3708)	Krasnoyarsk	Krasnoyarskiy Kray
Russian Federation	N.N.Petrov Research Institute of Oncology-Department of Chemotherapy and Innovative Technologies ( S	Saint Petersburg	Sankt-Peterburg
Russian Federation	Saint-Petersburg City Clinical Oncology Dispensary-Department of chemotherapy ( Site 3702)	Saint Petersburg	Leningradskaya Oblast
Russian Federation	GBUZ "SPb CRPCstmc(o)" ( Site 3705)	Saint-Petersburg	Sankt-Peterburg
Russian Federation	GBUZ LOKB-Oncology department #1 ( Site 3701)	Saint-Petersburg	Sankt-Peterburg
Russian Federation	Scientific research institution of oncology named after N.N. Petrov-Thoracic oncology ( Site 3704)	Sankt-Peterburg
Spain	Hospital Universitari Vall d'Hebron-Oncology ( Site 3401)	Barcelona
Spain	Instituto Catalan de Oncologia - Hospital Duran i Reynals ( Site 3403)	L'Hospitalet de Llobregat	Cataluna
Switzerland	Cantonal Hospital St.Gallen-Oncology & Hematology ( Site 3502)	st.Gallen	Sankt Gallen
United States	Georgia Cancer Specialists ( Site 0156)	Atlanta	Georgia
United States	MFSMC-HJWCI-Oncology Research ( Site 0178)	Baltimore	Maryland
United States	Cleveland Clinic-Taussig Cancer Center ( Site 0166)	Cleveland	Ohio
United States	Parkview Research Center at Parkview Regional Medical Center ( Site 0180)	Fort Wayne	Indiana
United States	Banner MD Anderson Cancer Center ( Site 0152)	Gilbert	Arizona
United States	St Francis Cancer Center-Research Office ( Site 0167)	Greenville	South Carolina
United States	Baptist Health Lexington-Research ( Site 0158)	Lexington	Kentucky
United States	University of Kentucky Chandler Medical Center-Medical Oncology ( Site 0157)	Lexington	Kentucky
United States	Oncology Hematology West, PC dba Nebraska Cancer Specialists ( Site 0172)	Omaha	Nebraska
United States	Oncology Hematology West, PC dba Nebraska Cancer Specialists ( Site 0179)	Omaha	Nebraska
United States	UPMC Hillman Cancer Center ( Site 0177)	Pittsburgh	Pennsylvania
United States	Virginia Cancer Institute ( Site 0169)	Richmond	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Hungary,  Israel,  Italy,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)	DLTs = =1 of the following treatment-related toxicities: Grade (G)4 nonhematologic toxicity; G4 hematologic toxicity lasting >7 days OR G4 platelet count decreased OR G3 platelet count decreased if associated with bleeding; G3 nonhematologic toxicity including G3 fatigue (lasting >3 days), G3 diarrhea, nausea, vomiting lasting =72 hours, G3 rash =7 days despite treatment, G3 uncontrolled hypertension; G3/4 nonhematologic laboratory abnormality if requires medical intervention, hospitalization, or persists for >1 week; G 3/4 febrile neutropenia, alanine aminotransferase, aspartate aminotransferase and/or bilirubin increase; drug-induced liver injury meeting the Hy's law; G4 creatinine increase; G4 electrolyte abnormalities; treatment related adverse event causing study intervention discontinuation during the first 21 days or administration delay >14 days during the first 21 days; G5 toxicity. The number of participants with =1 DLTs in the safety lead-in phase will be presented.	Up to 21 days in Cycle 1 (Cycle 1 = 21 days)
Primary	Number of Participants Who Experience at Least One Adverse Event (AE)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experience at least one AE will be presented.	Up to approximately 60 months
Primary	Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinue study treatment due to an AE will be presented.	Up to approximately 60 months
Primary	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 with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 that has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.	Up to approximately 60 months
Secondary	Progression-free Survival (PFS) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)	PFS is defined as the time from randomization to the first documented disease progression (PD) or death due to any cause, whichever occurs first. PD is defined as at least a 20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. PFS as assessed by blinded independent central review (BICR) will be presented.	Up to approximately 60 months
Secondary	Duration of Response (DOR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)	For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions), DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters (SOD) of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. DOR as assessed by Blinded Independent Central Review (BICR) will be presented.	Up to approximately 60 months

External Links

•   Merck Oncology Clinical Trials Information
•   Plain Language Summary