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Study of Pemetrexed+Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Participants With First Line Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-3475-189/KEYNOTE-189)

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ClinicalTrials.gov Identifier: NCT02578680
Recruitment Status : Recruiting
First Posted : October 19, 2015
Last Update Posted : December 1, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:

This is an efficacy and safety study of pembrolizumab (MK-3475) combined with pemetrexed/platinum chemotherapy versus pemetrexed/platinum chemotherapy alone in participants with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have not previously received systemic therapy for advanced disease. Participants will be randomly assigned to receive pembrolizumab combined with pemetrexed/platinum (Investigators choice of cisplatin or carboplatin), OR pemetrexed/platinum (Investigators choice of cisplatin or carboplatin).

The primary hypothesis is that pembrolizumab in combination with pemetrexed/platinum chemotherapy prolongs Progression-Free Survival (PFS) and Overall Survival (OS) compared to pemetrexed/platinum chemotherapy alone.


Condition or disease Intervention/treatment Phase
Non-Small-Cell Lung Carcinoma Biological: Pembrolizumab 200 mg Drug: Cisplatin Drug: Carboplatin Drug: Pemetrexed Dietary Supplement: Folic acid 350-1000 μg Dietary Supplement: Vitamin B12 1000 μg Drug: Dexamethsone 4 mg Drug: Saline solution Phase 3

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 646 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Phase III Study of Platinum+Pemetrexed Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Non-squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-189)
Actual Study Start Date : January 15, 2016
Estimated Primary Completion Date : February 4, 2019
Estimated Study Completion Date : February 4, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Pembrolizumab
Participants receive pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 (with vitamin supplementation) IV PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 every 3 weeks (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.
Biological: Pembrolizumab 200 mg
IV infusion
Drug: Cisplatin
IV infusion
Drug: Carboplatin
IV infusion
Drug: Pemetrexed
IV infusion
Dietary Supplement: Folic acid 350-1000 μg
Orally; at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed.
Dietary Supplement: Vitamin B12 1000 μg
Intramuscular injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration.
Drug: Dexamethsone 4 mg
For prophylaxis; orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.
Active Comparator: Control
Participants receive saline placebo IV PLUS pemetrexed 500 mg/m^2 (with vitamin supplementation) IV PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 Q3W for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If progression occurs, participants may be able to receive pembrolizumab Q3W for the remainder of the study or until documented progression.
Drug: Cisplatin
IV infusion
Drug: Carboplatin
IV infusion
Drug: Pemetrexed
IV infusion
Dietary Supplement: Folic acid 350-1000 μg
Orally; at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed.
Dietary Supplement: Vitamin B12 1000 μg
Intramuscular injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration.
Drug: Dexamethsone 4 mg
For prophylaxis; orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.
Drug: Saline solution
IV infusion


Outcome Measures

Primary Outcome Measures :
  1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging [ Time Frame: Up to 24 months ]
  2. Overall Survival (OS) [ Time Frame: Up to 24 months ]

Secondary Outcome Measures :
  1. Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging [ Time Frame: Up to 24 months ]
  2. Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging [ Time Frame: Up to 24 months ]
  3. Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to 27 months ]
  4. Number of Participants Who Discontinue Study Treatment Due to an AE [ Time Frame: Up to 24 months ]

Other Outcome Measures:
  1. Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria [ Time Frame: Up to 24 months ]

Eligibility Criteria

Information from the National Library of Medicine

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

Inclusion Criteria:

  • Has a histologically-confirmed or cytologically confirmed diagnosis of stage IV nonsquamous NSCLC.
  • Has confirmation that epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-directed therapy is not indicated.
  • Has measurable disease.
  • Has not received prior systemic treatment for their advanced/metastatic NSCLC.
  • Can provide tumor tissue.
  • Has a life expectancy of at least 3 months.
  • Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
  • Has adequate organ function
  • If female of childbearing potential, is willing to use adequate contraception for the course of the study through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.
  • If male with a female partner(s) of child-bearing potential, must agree to use adequate contraception starting with the first dose of study medication through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.

Exclusion Criteria:

  • Has predominantly squamous cell histology NSCLC.
  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab.
  • Before the first dose of study medication: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease, b) Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib, cetuximab), c) Had major surgery (<3 weeks prior to first dose)
  • Received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study medication.
  • Completed palliative radiotherapy within 7 days of the first dose of study medication.
  • Is expected to require any other form of antineoplastic therapy while on study.
  • Received a live-virus vaccination within 30 days of planned start of study medication.
  • Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, peritoneal carcinomatosis.
  • Known history of prior malignancy except if participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy, except for successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
  • Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).
  • Known sensitivity to any component of cisplatin, carboplatin or pemetrexed.
  • Has active autoimmune disease that has required systemic treatment in past 2 years.
  • Is on chronic systemic steroids.
  • Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
  • Is unable or unwilling to take folic acid or vitamin B12 supplementation.
  • Had prior treatment with any other anti-programmed cell death-1 (PD-1), or PD-ligand 1 (PD-L1) or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms. Has participated in any other pembrolizumab study and has been treated with pembrolizumab.
  • Has an active infection requiring therapy.
  • Has known history of Human Immunodeficiency Virus (HIV).
  • Has known active Hepatitis B or C.
  • Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
  • Is a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
  • Has symptomatic ascites or pleural effusion.
  • Has interstitial lung disease or a history of pneumonitis that required oral of IV glucocorticoids to assist with management.
  • Is pregnant or breastfeeding, or expecting to conceive or father children prior to 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.
Contacts and Locations

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): NCT02578680


Contacts
Contact: Toll Free Number 1-888-577-8839

Locations
Japan
MSD K.K. Recruiting
Chiyoda-Ku, Tokyo, Japan, 102-8667
Contact: Japan Call Center    81-3-6272-1957      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
More Information

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT02578680     History of Changes
Other Study ID Numbers: 3475-189
2015-003694-15 ( EudraCT Number )
163421 ( Registry Identifier: JAPIC-CTI )
MK-3475-189 ( Other Identifier: Merck Protocol Number )
First Posted: October 19, 2015    Key Record Dates
Last Update Posted: December 1, 2017
Last Verified: November 2017

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.:
PD1
PD-1
PDL1
PD-L1
Non-Small-Cell Lung Cancer

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
Vitamins
Folic Acid
Vitamin B 12
Hydroxocobalamin
Pembrolizumab
Cisplatin
Carboplatin
Pemetrexed
Vitamin B Complex
Micronutrients
Growth Substances
Physiological Effects of Drugs
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Hematinics