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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/KEYNOTE-495)

NCT03516981

Description:

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-1308, MK-4280, or lenvatinib. The primary hypotheses are as follows: In participants receiving pembrolizumab in combination with either MK-1308, 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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Biomarker-Directed, Pembrolizumab (MK-3475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (MK-3475-495/KEYNOTE-495)
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: 3475-495
  • SECONDARY ID: MK-3475-495
  • SECONDARY ID: 194621
  • SECONDARY ID: KEYNOTE-495
  • NCT ID: NCT03516981

Conditions

  • Advanced Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
PembrolizumabMK-3475GEP low TMB low: Pembrolizumab + MK-1308
MK-4280GEP low TMB low: Pembrolizumab + MK-4280
LenvatinibGEP low TMB low: Pembrolizumab + Lenvatinib
MK-1308GEP low TMB low: Pembrolizumab + MK-1308

Purpose

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-1308, MK-4280, or lenvatinib. The primary hypotheses are as follows: In participants receiving pembrolizumab in combination with either MK-1308, 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.

Detailed Description

      After Amendment 5, participants can receive 800 mg of MK-4280 every 3 weeks (Q3W)
    

Trial Arms

NameTypeDescriptionInterventions
GEP low TMB low: Pembrolizumab + MK-1308ExperimentalParticipants receive pembrolizumab 200 mg Q3W plus MK-1308 at the Recommended Phase 2 Dose ([RP2D], dose and schedule based on study NCT03179436) until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
  • Pembrolizumab
  • MK-1308
GEP low TMB low: Pembrolizumab + MK-4280ExperimentalParticipants receive pembrolizumab 200 mg Q3W plus MK-4280 200 mg or 800 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
  • Pembrolizumab
  • MK-4280
GEP low TMB low: Pembrolizumab + LenvatinibExperimentalParticipants 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.
  • Pembrolizumab
  • Lenvatinib
GEP low TMB hi: Pembrolizumab + MK-1308ExperimentalParticipants receive pembrolizumab 200 mg Q3W plus MK-1308 at the RP2D (dose and schedule based on study NCT03179436) until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
  • Pembrolizumab
  • MK-1308
GEP low TMB hi: Pembrolizumab + MK-4280ExperimentalParticipants receive pembrolizumab 200 mg Q3W plus MK-4280 200 mg or 800 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
  • Pembrolizumab
  • MK-4280
GEP low TMB hi: Pembrolizumab + LenvatinibExperimentalParticipants 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.
  • Pembrolizumab
  • Lenvatinib
GEP hi TMB low: Pembrolizumab + MK-1308ExperimentalParticipants receive pembrolizumab 200 mg Q3W plus MK-1308 at the RP2D (dose and schedule based on study NCT03179436) until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
  • Pembrolizumab
  • MK-1308
GEP hi TMB low: Pembrolizumab + MK-4280ExperimentalParticipants receive pembrolizumab 200 mg Q3W plus MK-4280 200 mg or 800 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
  • Pembrolizumab
  • MK-4280
GEP hi TMB low: Pembrolizumab + LenvatinibExperimentalParticipants 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.
  • Pembrolizumab
  • Lenvatinib
GEP hi TMB hi: Pembrolizumab + MK-1308ExperimentalParticipants receive pembrolizumab 200 mg Q3W plus MK-1308 at the RP2D (dose and schedule based on study NCT03179436) until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
  • Pembrolizumab
  • MK-1308
GEP hi TMB hi: Pembrolizumab + MK-4280ExperimentalParticipants receive pembrolizumab 200 mg Q3W plus MK-4280 200 mg or 800 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).
  • Pembrolizumab
  • MK-4280
GEP hi TMB hi: Pembrolizumab + LenvatinibExperimentalParticipants 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.
  • Pembrolizumab
  • Lenvatinib

Eligibility 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 mutations, B-Raf mutations, ALK
             gene rearrangements, and 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)

          -  Has symptomatic ascites or pleural effusion

          -  Has had an allogenic tissue/solid organ transplant

          -  WOCBP who has a positive urine pregnancy test within 24 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, or has had major surgery within 3 weeks prior to first dose
             of study intervention

          -  Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula,
             gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition
             that might affect the absorption of lenvatinib

          -  Radiographic evidence of major blood vessel invasion/infiltration

          -  Clinically significant hemoptysis or tumor bleeding within 2 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 vascular 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 2 weeks of start of study treatment or received
             lung radiation therapy of >30 Gy within 6 months prior to the first dose of study
             intervention

          -  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

          -  Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             (females and males) after the last dose of study treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)
Time Frame:Up to ~2 years
Safety Issue:
Description: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

Measure:Progression Free Survival (PFS) per RECIST 1.1
Time Frame:Up to ~2 years
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:Up to ~2 years
Safety Issue:
Description:OS is defined as the time from randomization to death due to any cause.
Measure:Number of Participants Experiencing Adverse Events (AEs)
Time Frame:Up to ~2 years
Safety Issue:
Description: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.
Measure:Number of Participants Discontinuing Study Drug Due to AEs
Time Frame:Up to ~2 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)

Last Updated

December 12, 2019