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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03516981




Registration number
NCT03516981
Ethics application status
Date submitted
27/04/2018
Date registered
7/05/2018
Date last updated
25/06/2020

Titles & IDs
Public title
A Study of Biomarker-Directed, Pembrolizumab (MK-3475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (MK-3475-495/KEYNOTE-495)
Scientific 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)
Secondary ID [1] 0 0
MK-3475-495
Secondary ID [2] 0 0
3475-495
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Non-Small Cell Lung Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lung - Mesothelioma
Cancer 0 0 0 0
Lung - Non small cell
Cancer 0 0 0 0
Lung - Small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Pembrolizumab
Other interventions - MK-4280
Treatment: Drugs - Lenvatinib
Treatment: Drugs - MK-1308

Experimental: GEP low TMB low: Pembrolizumab + MK-1308 - Participants 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).

Experimental: GEP low TMB low: Pembrolizumab + MK-4280 - Participants 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).

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.

Experimental: GEP low TMB hi: Pembrolizumab + MK-1308 - Participants 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).

Experimental: GEP low TMB hi: Pembrolizumab + MK-4280 - Participants 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).

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.

Experimental: GEP hi TMB low: Pembrolizumab + MK-1308 - Participants 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).

Experimental: GEP hi TMB low: Pembrolizumab + MK-4280 - Participants 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).

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.

Experimental: GEP hi TMB hi: Pembrolizumab + MK-1308 - Participants 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).

Experimental: GEP hi TMB hi: Pembrolizumab + MK-4280 - Participants 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).

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.


Other interventions: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion administered Q3W

Other interventions: MK-4280
200 mg or 800 mg MK-4280 solution for IV infusion administered Q3W

Treatment: Drugs: Lenvatinib
20 mg lenvatinib capsules administered orally once daily

Treatment: Drugs: MK-1308
MK-1308 solution for IV infusion administered at the RP2D (dose and schedule based on study NCT03179436)

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) - 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.
Timepoint [1] 0 0
Up to ~2 years
Secondary outcome [1] 0 0
Progression Free Survival (PFS) per RECIST 1.1 - 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.
Timepoint [1] 0 0
Up to ~2 years
Secondary outcome [2] 0 0
Overall Survival (OS) - OS is defined as the time from randomization to death due to any cause.
Timepoint [2] 0 0
Up to ~2 years
Secondary outcome [3] 0 0
Number of Participants Experiencing Adverse Events (AEs) - 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.
Timepoint [3] 0 0
Up to ~2 years
Secondary outcome [4] 0 0
Number of Participants Discontinuing Study Drug Due to AEs - 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.
Timepoint [4] 0 0
Up to ~2 years

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 0 0
Blacktown Hospital Western Sydney Local Health District ( Site 0200) - Blacktown
Recruitment hospital [2] 0 0
Greenslopes Private Hospital ( Site 0202) - Greenslopes
Recruitment hospital [3] 0 0
Fiona Stanley Hospital ( Site 0201) - Murdoch
Recruitment postcode(s) [1] 0 0
2148 - Blacktown
Recruitment postcode(s) [2] 0 0
4120 - Greenslopes
Recruitment postcode(s) [3] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Maryland
Country [6] 0 0
United States of America
State/province [6] 0 0
Minnesota
Country [7] 0 0
United States of America
State/province [7] 0 0
New Jersey
Country [8] 0 0
United States of America
State/province [8] 0 0
New York
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Pennsylvania
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
Country [12] 0 0
United States of America
State/province [12] 0 0
Virginia
Country [13] 0 0
United States of America
State/province [13] 0 0
Washington
Country [14] 0 0
United States of America
State/province [14] 0 0
Wisconsin
Country [15] 0 0
Canada
State/province [15] 0 0
Ontario
Country [16] 0 0
Canada
State/province [16] 0 0
Quebec
Country [17] 0 0
Hong Kong
State/province [17] 0 0
Hong Kong
Country [18] 0 0
Ireland
State/province [18] 0 0
Dublin
Country [19] 0 0
Ireland
State/province [19] 0 0
Limerick
Country [20] 0 0
Italy
State/province [20] 0 0
Forli-Cesena
Country [21] 0 0
Italy
State/province [21] 0 0
Milano
Country [22] 0 0
Italy
State/province [22] 0 0
Torino
Country [23] 0 0
Italy
State/province [23] 0 0
Verona
Country [24] 0 0
Italy
State/province [24] 0 0
Messina
Country [25] 0 0
Italy
State/province [25] 0 0
Napoli
Country [26] 0 0
Italy
State/province [26] 0 0
Roma
Country [27] 0 0
Italy
State/province [27] 0 0
Siena
Country [28] 0 0
Japan
State/province [28] 0 0
Tokyo
Country [29] 0 0
Korea, Republic of
State/province [29] 0 0
Kyonggi-do
Country [30] 0 0
Korea, Republic of
State/province [30] 0 0
Seoul-teukbyeolsi [Seoul]
Country [31] 0 0
Poland
State/province [31] 0 0
Dolnoslaskie
Country [32] 0 0
Poland
State/province [32] 0 0
Mazowieckie
Country [33] 0 0
Poland
State/province [33] 0 0
Wielkopolskie
Country [34] 0 0
Russian Federation
State/province [34] 0 0
Baskortostan, Respublika
Country [35] 0 0
Russian Federation
State/province [35] 0 0
Moskva
Country [36] 0 0
Russian Federation
State/province [36] 0 0
Omskaya Oblast'
Country [37] 0 0
Russian Federation
State/province [37] 0 0
Sankt-Peterburg
Country [38] 0 0
Russian Federation
State/province [38] 0 0
Tatarstan, Respublika
Country [39] 0 0
Singapore
State/province [39] 0 0
Central Singapore
Country [40] 0 0
South Africa
State/province [40] 0 0
Gauteng
Country [41] 0 0
South Africa
State/province [41] 0 0
Kwazulu-Natal
Country [42] 0 0
South Africa
State/province [42] 0 0
Western Cape
Country [43] 0 0
Spain
State/province [43] 0 0
Barcelona [Barcelona]
Country [44] 0 0
Spain
State/province [44] 0 0
Madrid
Country [45] 0 0
Switzerland
State/province [45] 0 0
Basel-Stadt
Country [46] 0 0
Switzerland
State/province [46] 0 0
Geneve
Country [47] 0 0
Switzerland
State/province [47] 0 0
Grisons
Country [48] 0 0
Switzerland
State/province [48] 0 0
Sankt Gallen
Country [49] 0 0
Switzerland
State/province [49] 0 0
Zurich
Country [50] 0 0
Taiwan
State/province [50] 0 0
Kaohsiung
Country [51] 0 0
Taiwan
State/province [51] 0 0
Tainan
Country [52] 0 0
Taiwan
State/province [52] 0 0
Taipei
Country [53] 0 0
United Kingdom
State/province [53] 0 0
London, City Of
Country [54] 0 0
United Kingdom
State/province [54] 0 0
Cambridge
Country [55] 0 0
United Kingdom
State/province [55] 0 0
Plymouth

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
Address
Country

Ethics approval
Ethics application status

Summary
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-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.
Trial website
https://clinicaltrials.gov/show/NCT03516981
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Toll Free Number
Address 0 0
Country 0 0
Phone 0 0
1-888-577-8839
Fax 0 0
Email 0 0
Trialsites@merck.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03516981