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Biomarkers of Response to Pembrolizumab Combined With Chemotherapy in Non-Small Cell Lung Cancer (KEYNOTE-782, MK-3475-782) (KEYNOTE-782)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03664024
Recruitment Status : Active, not recruiting
First Posted : September 10, 2018
Last Update Posted : June 14, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
Participants with Stage IV nonsquamous non-small cell lung cancer (NSCLC) without prior systemic treatment will be treated with standard of care pembrolizumab combined with platinum-doublet chemotherapy for 4 cycles, then pembrolizumab plus pemetrexed maintenance for up to 31 additional cycles. The platinum doublet would be pemetrexed plus the investigator's choice of either cisplatin or carboplatin. The primary hypothesis is to evaluate if total baseline tumor mutation burden (TMB) in circulating free DNA (cfDNA) is predictive of objective response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by the investigator by estimating the level of association.

Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer Drug: Pembrolizumab Drug: Pemetrexed Drug: Carboplatin Drug: Cisplatin Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial to Investigate Genetic Markers of Response to Pembrolizumab (MK-3475, SCH 900475) Combined With Chemotherapy as a First-line Treatment for Non-Small Cell Lung Cancer (KEYNOTE-782)
Actual Study Start Date : October 30, 2018
Estimated Primary Completion Date : December 12, 2019
Estimated Study Completion Date : July 14, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Pembrolizumab Standard of Care
Participants will receive standard of care pembrolizumab combined with platinum-doublet chemotherapy for 4 cycles, then pembrolizumab plus pemetrexed maintenance for up to 31 additional cycles. The platinum doublet would be pemetrexed plus the investigator's choice of either cisplatin or carboplatin.
Drug: Pembrolizumab
Pembrolizumab, 200 mg, Day 1 of each 21-day cycle (Q3W), intravenous infusion (IV), standard of care in most countries

Drug: Pemetrexed
Pemetrexed, 500 mg/m^2 infusion, standard of care, Q3W, IV

Drug: Carboplatin
Carboplatin AUC 5 mg/mL/min, IV infusion, Day 1 of each 21-day cycle for 4 cycles (Cycles 1 - 4). Investigator's choice of either cisplatin or carboplatin.

Drug: Cisplatin
Cisplatin, 75 mg/m^2, IV infusion, Day 1 of each 21-day cycle for 4 cycles (Cycles 1 - 4). Investigator's choice of either cisplatin or carboplatin.




Primary Outcome Measures :
  1. Objective Response (OR) [ Time Frame: Up to approximately 25 months ]
    Objective response rate is the proportion of participants who have a confirmed complete response (CR) or partial response (PR). Objective response rate is assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  2. Tumor Mutation Burden (TMB) [ Time Frame: Baseline ]
    Circulating cell-free DNA (cfDNA) allows the exploration of the mechanisms of progression on and resistance to pembrolizumab and chemotherapy, and assesses the role of the metagenomics (microbiome) and metabolomics in response to pembrolizumab + chemotherapy in NSCLC. The tumor mutation burden in circulating cfDNA will be estimated in blood.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Up to approximately 25 months ]
    PFS is defined as the time from enrollment to the first documented disease progression or death due to any cause, whichever occurs first assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

  2. Overall Survival (OS) [ Time Frame: Up to approximately 25 months ]
    OS is defined as the time from the start of treatment to death due to any cause.

  3. Adverse Events (AEs) [ Time Frame: Up to 30 days after last dose of study treatment (Up to approximately 26 months) ]
    Percentage of participants who experienced one or more AEs.

  4. Discontinuations from Study Drug Due to an Adverse Event [ Time Frame: Up to approximately 25 months ]
    Percentage of participants discontinuing study treatment(s) due to an AE.



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 a histologically-confirmed or cytologically-confirmed diagnosis of stage IV (M1a, M1b, or M1c [AJCC 8th edition]) nonsquamous NSCLC.
  • Have confirmation that epidermal growth factor receptor- (EGFR-), anaplastic lymphoma kinase- (ALK-), c-ros oncogene 1 (ROS1), or B isoform of rapidly accelerated fibrosarcoma (BRAF) directed therapy is not indicated as primary therapy. Documentation of the absence of tumor activating EGFR mutations, BRAF mutations, ALK gene rearrangements, and ROS1 gene rearrangements is required.
  • Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  • Has not received prior systemic treatment for their advanced/metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease.
  • Have provided sufficient evaluable Stage IV, archival, solid tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (that was not previously irradiated) for biomarker analysis (Fine Needle Aspiration [FNA] samples will not be accepted). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 10 days prior to the first dose of study treatment.
  • A male participant must agree to use contraception through the end of treatment and for at least 120 days, and refrain from donating sperm during this period.
  • A female participant is eligible to participate if she is not pregnant, not breastfeeding, and if participant is a woman of childbearing potential (WOCBP), agrees to follow the contraceptive guidance as provided in the protocol through the end of treatment.
  • Has adequate organ function.
  • Has provided blood for Circulating Free DNA (cfDNA) analysis that has been received and determined to be of sufficient quality and quantity by the designated laboratory for the primary endpoint.

Exclusion Criteria:

  • Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type.
  • Has small cell elements present in NSCLC tumor.
  • A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment allocation.
  • Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, peritoneal carcinomatosis.
  • Has a known history of prior malignancy except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 2 years since initiation of that therapy.
  • Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
  • If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study intervention.
  • Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system disease.
  • Has received prior therapy with a multiple programmed cell death 1 (PD-1)/ (PD-1) receptor/programmed cell death ligand 1 (PD-L1) receptor inhibitor.
  • Is expected to require any other form of antineoplastic therapy while on study (including maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical resection).
  • Has received a live vaccine within 30 days prior to treatment.
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients or to another monoclonal antibody.
  • Has a known sensitivity to any component of cisplatin, carboplatin or pemetrexed.
  • Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
  • Is on chronic systemic steroids. Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
  • Is unable or unwilling to take folic acid or vitamin B12 supplementation.
  • 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 intervention.
  • 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 drug.
  • Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
  • Has a history of (non-infectious) 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. No HIV testing is required unless mandated by local health authority.
  • 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 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 a known psychiatric or substance abuse disorder 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 after the last dose of study intervention.
  • 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): NCT03664024


Locations
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United States, Colorado
University Of Colorado ( Site 0908)
Aurora, Colorado, United States, 80045
United States, Maryland
Harry & Jeanette Weinberg Cancer Institute ( Site 0901)
Baltimore, Maryland, United States, 21237
United States, Michigan
Henry Ford Health System ( Site 0903)
Detroit, Michigan, United States, 48202
Canada, Ontario
Kingston General Hospital ( Site 0800)
Kingston, Ontario, Canada, K7L 2V7
Canada, Quebec
CISSS de la Monteregie-Centre ( Site 0801)
Greenfield Park, Quebec, Canada, J4V 2H1
Hungary
Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 0400)
Budapest, Hungary, 1121
Petz Aladar Megyei Oktato Korhaz ( Site 0402)
Gyor, Hungary, 9024
Jasz Nagykun Szolnok Megyei Hetenyi Geza Korhaz Rendelointezet ( Site 0401)
Szolnok, Hungary, 5000
Israel
Meir Medical Center ( Site 0501)
Kfar-Saba, Israel, 4428164
Chaim Sheba Medical Center ( Site 0500)
Ramat Gan, Israel, 5262000
Spain
Hospital Universitario Insular de Gran Canaria ( Site 0700)
Las Palmas de Gran Canaria, Gran Canaria, Spain, 35001
Hospital Puerta de Hierro ( Site 0702)
Majadahonda, Madrid, Spain, 28222
H.U. Vall de Hebron ( Site 0701)
Barcelona, Spain, 08035
Hospital General Universitario 12 de Octubre ( Site 0703)
Madrid, Spain, 28041
Hospital Universitario Central de Asturias ( Site 0704)
Oviedo, Spain, 33011
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: NCT03664024     History of Changes
Other Study ID Numbers: 3475-782
2018-002598-22 ( EudraCT Number )
MK-3475-782 ( Other Identifier: Merck Protocol Number )
First Posted: September 10, 2018    Key Record Dates
Last Update Posted: June 14, 2019
Last Verified: June 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

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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 1
PD1
PD-1
Programmed Cell Death Ligand 1
PDL1
PD-L1
Additional relevant MeSH terms:
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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
Cisplatin
Carboplatin
Pembrolizumab
Pemetrexed
Antineoplastic Agents
Antineoplastic Agents, Immunological
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors