Details

Details

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

IRB MRK1516

CC 16-1153

Hospital Main Campus

Stage Advanced/Metastatic

Phase Phase 3

Disease Lung - NSCLC (Non-small cell lung cancer)

Drug Pembrolizumab, Pemetrexed

Description

Description

Primary Objective
  • Progression Free Survival (PFS) per RECIST 1.1 as assessed by blinded central imaging vendor.
Secondary Objective
  1. Overall response rate (ORR) and response duration (DOR) per RECIST 1.1 by central imaging vendor review
  2. Overall Survival (OS)
  3. In subjects with PD-L1 TPS ≥1%, PFS per RECIST 1.1 as assessed by blinded central imaging vendor
  4. Progression Free Survival (PFS) per investigator assessed irRECIST response criteria
  5. Safety and tolerability profile of pembrolizumab combined with platinum-pemetrexed chemotherapy in subjects with 1L metastatic non-squamous NSCLC.
Exploratory Objectives
  1. ORR and DOR per investigator-assessed irRECIST response criteria
  2. To investigate the relationship between pembrolizumab treatment and biomarkers predicting response (e.g., PD-L1, genetic variation, serum sPDL1) utilizing newly obtained or archival FFPE tumor tissue and blood, including serum and plasma.
  3. To evaluate changes in health-related quality-of-life assessments from baseline in the biomarker-positive strata and in the overall study population using the EORTC QLQ-C30 and EORTC QLQ-LC13.
  4. To characterize utilities in subjects treated with pembrolizumab and chemotherapy compared to saline placebo and chemotherapy using the EuroQoL(EQ)-5D.
  5. To characterize the pharmacokinetic characteristics of pemetrexed, platinum treatment, and pembrolizumab.
  6. To explore the relationship between genomic variation and response to the treatment(s) administered. Variation across the human genome (germline and tumor) will be analyzed for association with clinical data collected in this study.
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Inclusion Criteria

Inclusion Criteria

  1. Have a histologically-confirmed or cytologically confirmed diagnosis of stage IV (M1a or M1b- AJCC 7th edition) non-squamous NSCLC.
  2. Have confirmation that EGFR or ALK-directed therapy is not indicated (documentation of absence of tumor activating EGFR mutations AND absence of ALK gene rearrangements OR presence of a K-Ras mutation).
  3. Have 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.
  4. Have not received prior systemic treatment for their advanced/metastatic NSCLC. Subjects 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.
  5. Have provided tumor tissue from locations not radiated prior to biopsy; formalinfixed specimens after the subject has been diagnosed with metastatic disease will be preferred for determination of PD-L1 status prior to randomization. Biopsies obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible.
  6. Be ≥18 years of age on day of signing informed consent.
  7. Have a life expectancy of at least 3 months.
  8. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
  9. Have adequate organ function as indicated by the following laboratory values (Table 1):
    • Absolute neutrophil count (ANC) ≥1,500 /mcL
    • Platelets ≥100,000 / mcL
    • Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L- 4 weeks without transfusions
    • Calculated creatinine clearance (CrCl)a ≥50 mL/min
    • Serum total bilirubin ≤1.5xULN OR Direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5xULN
    • AST (SGOT) and ALT (SGPT) ≤2.5xULN OR ≤5xULN for subjects with liver metastases
    • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless the subject is receiving anticoagulant therapy
    • Activated Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT) ≤1.5 X ULN unless the subject is receiving anticoagulant therapy
  10. If female of childbearing potential (Section 5.7.2), have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  11. If female of childbearing potential (Section 5.7.2), be willing to use an adequate method of contraception as outlined in Section 5.7.2-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 as specified in the protocol. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  12. If male subject with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception as outlined in Section 5.7.2-Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy or through 180 days after last dose of chemotherapeutic agents as specified in the protocol. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  13. Subject has voluntarily agreed to participate by giving written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
Exclusion Criteria

Exclusion Criteria

  1. Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the subject is ineligible.
  2. 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.
  3. Before the first dose of trial treatment:
    • Has received prior systemic cytotoxic chemotherapy for metastatic disease
    • Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib, cetuximab)
    • Had major surgery (<3 weeks prior to first dose)
  4. Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment.
  5. Completed palliative radiotherapy within 7 days of the first dose of trial treatment.
  6. Is expected to require any other form of antineoplastic therapy while on study.
  7. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
  8. Has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis.
  9. Has a known history of prior malignancy except if the subject has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy. Note: The time requirement for no evidence of disease for 5 years does not apply to the NSCLC tumor for which a subject is enrolled in the study. The time requirement also does not apply to subjects who underwent 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
  10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 2 weeks and, have no evidence of new or enlarging brain metastases and also are off steroids 3 days prior to dosing with study medication. Stable brain metastases by this definition should be established prior to the first dose of study medication. Subjects with asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of the brain as a site of disease.
  11. Previously had a severe hypersensitivity reaction to treatment with another mAb.
  12. Has a known sensitivity to any component of cisplatin, carboplatin or pemetrexed
  13. 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). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  14. Is on chronic systemic steroids. Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
  15. 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).
  16. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
  17. Had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms. Has participated in any other MK-3475 trial and has been treated with MK-3475. Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR
  18. Has an active infection requiring therapy.
  19. Has known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive).
  20. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
  21. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
  22. Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
  23. Is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
  24. Has symptomatic ascites or pleural effusion. A subject who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
  25. Has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
  26. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.