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A Study of Biomarker-Directed, Pembrolizumab (MK-3475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (MK-3475-495)

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ClinicalTrials.gov Identifier: NCT03516981
Recruitment Status : Recruiting
First Posted : May 7, 2018
Last Update Posted : January 21, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
This study will investigate the utility of biomarker-based triage for study participants with advanced non-small cell lung cancer (NSCLC) without prior systemic therapy. Study participants within groups defined by a biomarker-based classifier (gene expression profile [GEP] and tumor mutational burden [TMB]) will be randomized to receive pembrolizumab in combination with MK-4280 or lenvatinib. The primary hypotheses are as follows: In participants receiving pembrolizumab in combination with either MK-4280 or lenvatinib, the Objective Response Rate (ORR) will be 1) greater than 5% among participants with low GEP and low TMB, 2) greater than 20% among participants with low GEP and high TMB, 3) greater than 20% among participants with high GEP and low TMB, and 4) greater than 45% among participants with high GEP and high TMB.

Condition or disease Intervention/treatment Phase
Advanced Non-Small Cell Lung Cancer Biological: Pembrolizumab Biological: MK-4280 Drug: Lenvatinib Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 192 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Precision Oncology Study of Biomarker-Directed, Pembrolizumab-(MK-3475, SCH 900475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (KEYNOTE-495; KeyImPaCT)
Actual Study Start Date : October 1, 2018
Estimated Primary Completion Date : May 30, 2022
Estimated Study Completion Date : May 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: GEP low TMB low: Pembrolizumab + MK-4280
Participants receive pembrolizumab 200 mg Q3W plus MK-4280 200 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
Biological: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion Q3W
Other Name: MK-3475

Biological: MK-4280
200 mg MK-4280 solution for IV infusion Q3W

Experimental: GEP low TMB low: Pembrolizumab + Lenvatinib
Participants receive pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years). Participants completing 35 infusions of pembrolizumab may continue with lenvatinib alone until disease progression or toxicity.
Biological: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion Q3W
Other Name: MK-3475

Drug: Lenvatinib
20 mg lenvatinib capsules orally once daily

Experimental: GEP low TMB hi: Pembrolizumab + MK-4280
Participants receive pembrolizumab 200 mg Q3W plus MK-4280 200 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
Biological: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion Q3W
Other Name: MK-3475

Biological: MK-4280
200 mg MK-4280 solution for IV infusion Q3W

Experimental: GEP low TMB hi: Pembrolizumab + Lenvatinib
Participants receive pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years). Participants completing 35 infusions of pembrolizumab may continue with lenvatinib alone until disease progression or toxicity.
Biological: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion Q3W
Other Name: MK-3475

Drug: Lenvatinib
20 mg lenvatinib capsules orally once daily

Experimental: GEP hi TMB low: Pembrolizumab + MK-4280
Participants receive pembrolizumab 200 mg Q3W plus MK-4280 200 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
Biological: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion Q3W
Other Name: MK-3475

Biological: MK-4280
200 mg MK-4280 solution for IV infusion Q3W

Experimental: GEP hi TMB low: Pembrolizumab + Lenvatinib
Participants receive pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years). Participants completing 35 infusions of pembrolizumab may continue with lenvatinib alone until disease progression or toxicity.
Biological: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion Q3W
Other Name: MK-3475

Drug: Lenvatinib
20 mg lenvatinib capsules orally once daily

Experimental: GEP hi TMB hi: Pembrolizumab + MK-4280
Participants receive pembrolizumab 200 mg Q3W plus MK-4280 200 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
Biological: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion Q3W
Other Name: MK-3475

Biological: MK-4280
200 mg MK-4280 solution for IV infusion Q3W

Experimental: GEP hi TMB hi: Pembrolizumab + Lenvatinib
Participants receive pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years). Participants completing 35 infusions of pembrolizumab may continue with lenvatinib alone until disease progression or toxicity.
Biological: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion Q3W
Other Name: MK-3475

Drug: Lenvatinib
20 mg lenvatinib capsules orally once daily




Primary Outcome Measures :
  1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) [ Time Frame: Up to ~2 years ]
    ORR was defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline sum diameters) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by local site.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) per RECIST 1.1 [ Time Frame: Up to ~2 years ]
    PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 as assessed by local site.

  2. Overall Survival (OS) [ Time Frame: Up to ~2 years ]
    OS is defined as the time from randomization to death due to any cause.

  3. Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to ~2 years ]
    An AE is any untoward medical occurrence in participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An 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 treatment. The number of participants in each treatment arm experiencing an AE will be reported.

  4. Number of Participants Discontinuing Study Drug Due to AEs [ Time Frame: Up to ~2 years ]
    An AE is any untoward medical occurrence in participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An 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 treatment. The number of participants in each treatment arm that discontinued study drug due to an AE will be reported.



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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 a histologically- or cytologically-confirmed diagnosis of Stage IV (American Joint Committee on Cancer [AJCC] v 8) NSCLC and has not had prior systemic therapy for advanced disease
  • Has confirmation that epidermal growth factor receptor- (EGFR-), anaplastic lymphoma kinase- (ALK-), c-ros oncogene 1- (ROS1-), or B isoform of rapidly accelerated fibrosarcoma- (B-Raf-) directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR or B-Raf mutations AND absence of ALK or ROS1 gene rearrangements)
  • Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology
  • Male participants must agree to use contraception during the treatment period and for ≥120 days, after the last dose of study treatment and refrain from donating sperm during this period. Male participants with pregnant partners must agree to use a condom
  • Female participants eligible to participate if not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP) or is a WOCBP who agrees to follow contraceptive guidance during the treatment period and for ≥120 days after the last dose of study treatment
  • Provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
  • Has adequate organ function

Exclusion Criteria:

  • Has significant cardiovascular impairment within 12 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with hemodynamic instability, significant cardiovascular impairment, or a left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram
  • Prolongation of QTc interval to >480 milliseconds (ms)
  • History of transient ischemic attack within the previous 6 months
  • Has symptomatic ascites or pleural effusion
  • Has had an allogenic tissue/solid organ transplant
  • WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment
  • Has not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy
  • Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
  • Radiographic evidence of major blood vessel invasion/infiltration
  • Active hemoptysis (bright red blood of at least 0.5 teaspoon) or tumor bleeding within 3 weeks prior to the first dose of study drug
  • Has received prior systemic chemotherapy treatment for metastatic/recurrent NSCLC
  • Has current NSCLC disease that can be treated with curative intent with surgical resection, localized radiotherapy, or chemoradiation
  • Is expected to require any other form of systemic or localized antineoplastic therapy while on study (including maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical resection)
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor
  • Has received previous treatment with another agent targeting the Lymphocyte-activation gene 3 (LAG-3) receptor
  • Has received previous treatment with another agent targeting endothelial growth factor (VEGF) or the VEGF receptor
  • Has received prior anticancer therapy including investigational agents within 4 weeks prior to randomization
  • Has received prior radiotherapy within 3 weeks of start of study treatment
  • Has received a live vaccine within 30 days prior to 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 prior to the first dose of study treatment.
  • 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
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab, MK-4280, or lenvatinib and/or any of its excipients
  • Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs)
  • Has a history of (noninfectious) 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 (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
  • Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
  • 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 known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study

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): NCT03516981


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

  Show 31 Study Locations
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03516981     History of Changes
Other Study ID Numbers: 3475-495
MK-3475-495 ( Other Identifier: Merck Protocol Number )
First Posted: May 7, 2018    Key Record Dates
Last Update Posted: January 21, 2019
Last Verified: January 2019
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

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 1 (PD-1)
programmed death ligand 1 (PD-L1)
anti-PD-1
anti PD-1

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Pembrolizumab
Lenvatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action