Clinical trial NCT04938817: Safety and Efficacy Study of Investigational Agents as Monotherapy or in Combination With Pembrolizumab (MK-3475) for the Treatment of Extensive-Stage Small Cell Lung Cancer (ES-SCLC) in Need of Second-Line Therapy (MK-3475-B98/KEYNOTE-B98)
Official title: A Phase 1b/2 Study to Evaluate the Efficacy and Safety of Investigational Agents as Monotherapy or in Combination With Pembrolizumab for the Treatment of Participants With PD-1/L1-refractory Extensive-Stage Small Cell Lung Cancer in Need of Second-Line Therapy (KEYNOTE-B98)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Small Cell Lung Carcinoma
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: Daiichi Sankyo
First posted: 2021-06-24
Enrollment: 110
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: This study is a rolling arm study of investigational agents as monotherapy or in combination with pembrolizumab 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.


Eligibility criteria: Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

* Arms A-E:

  * 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)
  * If a woman of childbearing potential (WOCBP), participant must have a negative highly sensitive pregnancy test within 24 hours (for a urine test) or 72 hours (for a serum test) 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 a predicted life expectancy of \>3 months
* Arms A-D:

  * 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 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
* 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
* Arm E:

  * If capable of producing sperm, the participant agrees to refrain from donating sperm and abstain from penile-vaginal intercourse or use a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant. The length of time required to continue contraception for the study intervention R-Dx-d is 120 days
  * If a person of childbearing potential (POCBP) must use a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency, or if they adhere to penile-vaginal intercourse abstinence as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate the study intervention after the last dose of study intervention. In addition, the participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction. The length of time required to continue contraception for the study intervention R-Dx-d is 210 days

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

* Arms A-E:

  * 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 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
* Arms A-D:

  * 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 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 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
* Arm E:

  * Received prior treatment with a CDH6-targeted agent or an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan, datopotamab deruxtecan)
  * Has received an investigational agent or has used an investigational device within 4 weeks (or 5 half-lives, whichever is shorter) prior to study intervention administration
  * Has Chronic steroid treatment (\>10 mg/day prednisone \[or equivalent\] per day), except for inhaled steroids for asthma or COPD, mineralocorticoids (e.g., fludrocortisone) for participants with orthostatic hypotension, topical steroids for mild skin conditions, low-dose supplemental corticosteroids for adrenocortical insufficiency, Premedication for treatment groups and/or premedication in case of any hypersensitivity, or intra-articular steroid injections
  * Is an HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease

Primary outcomes:
measure: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)
timeFrame: Up to 21 days in Cycle 1 (Cycle 1 = 21 days)
measure: Number of Participants Who Experience at Least One Adverse Event (AE)
timeFrame: Up to approximately 60 months
measure: Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 60 months
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to approximately 60 months
Secondary outcomes:
measure: Progression-free Survival (PFS) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to approximately 60 months
measure: Duration of Response (DOR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to approximately 60 months
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center ( Site 0152)
state: Arizona
city: Atlanta
country: United States
facility: Northside Hospital-Northside Hospital Oncology Network ( Site 0156)
state: Georgia
city: Fort Wayne
country: United States
facility: Parkview Research Center at Parkview Regional Medical Center ( Site 0180)
state: Indiana
city: Lexington
country: United States
facility: Baptist Health Lexington-Research ( Site 0158)
state: Kentucky
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center-Medical Oncology ( Site 0157)
state: Kentucky
city: Baltimore
country: United States
facility: MFSMC-HJWCI-Oncology Research ( Site 0178)
state: Maryland
city: Omaha
country: United States
facility: Oncology Hematology West, PC dba Nebraska Cancer Specialists ( Site 0172)
state: Nebraska
city: Omaha
country: United States
facility: Oncology Hematology West, PC dba Nebraska Cancer Specialists ( Site 0179)
state: Nebraska
city: Cleveland
country: United States
facility: Cleveland Clinic-Taussig Cancer Center ( Site 0166)
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center ( Site 0177)
state: Pennsylvania
city: Greenville
country: United States
facility: St Francis Cancer Center-Research Office ( Site 0167)
state: South Carolina
city: Richmond
country: United States
facility: Virginia Cancer Institute ( Site 0169)
state: Virginia
city: Westmead
country: Australia
facility: Westmead Hospital-Department of Medical Oncology ( Site 4004)
state: New South Wales
city: Brisbane
country: Australia
facility: The Prince Charles Hospital-Oncology Clinical Trials ( Site 4003)
state: Queensland
city: Clayton
country: Australia
facility: Monash Health-Oncology Research ( Site 4005)
state: Victoria
city: Perth
country: Australia
facility: Hollywood Private Hospital-Medical Oncology ( Site 4001)
state: Western Australia
city: Wien
country: Austria
facility: Standort Penzing der Klinik Ottakring-Abteilung für Atemwegs-und Lungenkrankheiten ( Site 3101)
city: Wien
country: Austria
facility: Klinik Floridsdorf-Abteilung für Innere Medizin und Pneumologie ( Site 3100)
city: Edmonton
country: Canada
facility: Cross Cancer Institute ( Site 3004)
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 3003)
state: Ontario
city: Montreal
country: Canada
facility: St. Marys Hospital Center ( Site 3000)
state: Quebec
city: Szolnok
country: Hungary
facility: Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Onkologiai Kozpont ( Site 3800)
state: Jasz-Nagykun-Szolnok
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology ( Site 3600)
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center-Oncology ( Site 3602)
city: Kfar Saba
country: Israel
facility: Meir Medical Center. ( Site 3601)
city: Petah Tikva
country: Israel
facility: Rabin Medical Center-Oncology ( Site 3604)
city: Ramat Gan
country: Israel
facility: Sheba Medical Center-ONCOLOGY ( Site 3603)
city: Rozzano
country: Italy
facility: Humanitas-U.O di Oncologia medica ed Ematologia ( Site 3301)
state: Milano
city: Siena
country: Italy
facility: ospedale le scotte-U.O.C. Immunoterapia Oncologica ( Site 3300)
state: Toscana
city: Milano
country: Italy
facility: Ospedale San Raffaele-Oncologia Medica ( Site 3303)
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia IRCCS-Divisione di Oncologia Toracica ( Site 3304)
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital ( Site 4106)
state: Chungbuk
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital-Medical Oncology ( Site 4104)
state: Kyonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital ( Site 4101)
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center-Lung Cancer Center ( Site 4103)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 4100)
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Klinika Nowotworow Pluca i Klatki Pier ( Site 3900)
state: Mazowieckie
city: Olsztyn
country: Poland
facility: Warminsko-Mazurskie Centrum Chorob Płuc w Olsztynie ( Site 3903)
state: Warminsko-mazurskie
city: Krasnoyarsk
country: Russian Federation
facility: Krasnoyarsk Regional Oncology Dispensary, Named after Krizhanovsky ( Site 3708)
state: Krasnoyarskiy Kray
city: Saint Petersburg
country: Russian Federation
facility: Saint-Petersburg City Clinical Oncology Dispensary-Department of chemotherapy ( Site 3702)
state: Leningradskaya Oblast
city: Saint Petersburg
country: Russian Federation
facility: N.N.Petrov Research Institute of Oncology-Department of Chemotherapy and Innovative Technologies ( Site 3703)
state: Sankt-Peterburg
city: Saint-Petersburg
country: Russian Federation
facility: GBUZ LOKB-Oncology department #1 ( Site 3701)
state: Sankt-Peterburg
city: Saint-Petersburg
country: Russian Federation
facility: GBUZ "SPb CRPCstmc(o)" ( Site 3705)
state: Sankt-Peterburg
city: Sankt-Peterburg
country: Russian Federation
facility: Scientific research institution of oncology named after N.N. Petrov-Thoracic oncology ( Site 3704)
city: L'Hospitalet de Llobregat
country: Spain
facility: Instituto Catalan de Oncologia - Hospital Duran i Reynals ( Site 3403)
state: Cataluna
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron-Oncology ( Site 3401)
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona ( Site 3404)
city: St.Gallen
country: Switzerland
facility: Cantonal Hospital St.Gallen-Oncology & Hematology ( Site 3502)
state: Sankt Gallen
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: