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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)

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ClinicalTrials.gov Identifier: NCT04938817
Recruitment Status : Recruiting
First Posted : June 24, 2021
Last Update Posted : July 22, 2021
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief 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.


Condition or disease Intervention/treatment Phase
Small Cell Lung Carcinoma Biological: coformulation pembrolizumab/quavonlimab Drug: lenvatinib Biological: MK-4830 Biological: coformulation favezelimab/pembrolizumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Estimated Study Start Date : August 6, 2021
Estimated Primary Completion Date : November 2, 2026
Estimated Study Completion Date : November 2, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Coformulation Pembrolizumab/Quavonlimab
Participants receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) administered by intravenous (IV) infusion once every 6 weeks (Q6W) for up to 18 infusions (up to approximately 2 years) or until progressive disease or discontinuation.
Biological: coformulation pembrolizumab/quavonlimab
Intravenous (IV) infusion
Other Name: MK-1308A

Experimental: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib
Participants receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered by intravenous (IV) infusion once every 6 weeks (Q6W) for up to 18 infusions (up to approximately 2 years) or until progressive disease or discontinuation. Lenvatinib will be administered orally once-daily (QD) until progressive disease or discontinuation.
Biological: coformulation pembrolizumab/quavonlimab
Intravenous (IV) infusion
Other Name: MK-1308A

Drug: lenvatinib
Oral administration
Other Names:
  • LENVIMA®
  • KISPLYX®
  • MK-7902
  • E7080

Experimental: Coformulation Pembrolizumab/Quavonlimab + MK-4830
Participants receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS MK-4830 800 mg. Pembrolizumab/quavonlimab will be administered by intravenous (IV) infusion once every 6 weeks (Q6W) for up to 18 infusions (up to approximately 2 years) or until progressive disease or discontinuation. MK-4830 will be administered by IV infusion once every 3 weeks (Q3W) for up to 36 infusions (up to approximately 2 years) or until progressive disease or discontinuation.
Biological: coformulation pembrolizumab/quavonlimab
Intravenous (IV) infusion
Other Name: MK-1308A

Biological: MK-4830
IV infusion

Experimental: Coformulation Favezelimab/Pembrolizumab
Participants receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg) administered by intravenous (IV) infusion once every 3 weeks (Q3W) for up to 36 infusions (up to approximately 2 years) or until progressive disease or discontinuation.
Biological: coformulation favezelimab/pembrolizumab
IV infusion
Other Name: MK-4280A




Primary Outcome Measures :
  1. Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) [ Time Frame: Up to 21 days in Cycle 1 (Cycle 1 = 21 days) ]
    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.

  2. Number of Participants Who Experience at Least One Adverse Event (AE) [ Time Frame: Up to approximately 60 months ]
    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.

  3. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 60 months ]
    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.

  4. Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 60 months ]
    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.


Secondary Outcome Measures :
  1. Progression-free Survival (PFS) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 60 months ]
    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.

  2. Duration of Response (DOR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 60 months ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  • 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
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study treatment
  • 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 (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04938817


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
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United States, South Carolina
St Francis Cancer Center-Research Office ( Site 0167) Recruiting
Greenville, South Carolina, United States, 29607
Contact: Study Coordinator    864-255-1901      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT04938817    
Other Study ID Numbers: 3475-B98
2020-005628-12 ( EudraCT Number )
MK-3475-B98 ( Other Identifier: Merck )
KEYNOTE-B98 ( Other Identifier: Merck )
First Posted: June 24, 2021    Key Record Dates
Last Update Posted: July 22, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme Corp.:
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
Additional relevant MeSH terms:
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Small Cell Lung Carcinoma
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Pembrolizumab
Lenvatinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action