Clinical Trials /

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

NCT03664024

Description:

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.

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

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 3475-782
  • SECONDARY ID: 2018-002598-22
  • SECONDARY ID: MK-3475-782
  • NCT ID: NCT03664024

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
PembrolizumabPembrolizumab Standard of Care
PemetrexedPembrolizumab Standard of Care
CarboplatinPembrolizumab Standard of Care
CisplatinPembrolizumab Standard of Care

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab Standard of CareExperimentalParticipants 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.
  • Pembrolizumab
  • Pemetrexed
  • Carboplatin
  • Cisplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Has a histologically-confirmed or cytologically-confirmed diagnosis of stage IV (M1a,
             M1b, or M1c [AJCC 8th edition]) nonsquamous NSCLC.

          -  Has confirmation that epidermal growth factor receptor (EGFR-), B isoform of rapidly
             accelerated fibrosarcoma (B-RAF)-, c-ros oncogene 1 (ROS1-), or anaplastic lymphoma
             kinase (ALK-) directed therapy is not indicated (documentation of absence of
             tumor-activating EGFR or B-RAF mutations, AND absence of ALK or ROS1 gene
             rearrangements OR presence of a Kirsten RAt Sarcoma virus oncogene; [KRAS] mutation).

          -  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.

          -  Has provided an evaluable archival 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.

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response (OR)
Time Frame:Up to approximately 25 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:Up to approximately 25 months
Safety Issue:
Description: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).
Measure:Overall Survival (OS)
Time Frame:Up to approximately 25 months
Safety Issue:
Description:OS is defined as the time from the start of treatment to death due to any cause.
Measure:Adverse Events (AEs)
Time Frame:Up to 30 days after last dose of study treatment (Up to approximately 26 months)
Safety Issue:
Description:Percentage of participants who experienced one or more AEs.
Measure:Discontinuations from Study Drug Due to an Adverse Event
Time Frame:Up to approximately 25 months
Safety Issue:
Description:Percentage of participants discontinuing study treatment(s) due to an AE.

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 Cell Death Ligand 1
  • PDL1
  • PD-L1

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