Evaluation of the Effect of Time of Administration on the Activity on First Line of Pembrolizumab in Association With Carboplatin-pemetrexed in Metastatic Non-squamous Lung Cancer. A Randomised Multicenter Phase III Trial

Prior treatment

• 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
• 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.
• 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.
• 15. 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.
• 16. 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 longacting agents, such as piroxicam).
• 18. 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

Other illness

• 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
• 14. 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.
• 19. Has an active infection requiring therapy.
• 20. Has known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive).
• 21. 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.
• 23. Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
• 24. 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.

Lab values

• 22. 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.
• Secondary exclusion criterion: If female of childbearing potential, have a positive 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.

Other

• The patient will not be included in the trial if he or she:
• 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.
• 8. Has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis.
• 12. Has a known sensitivity to any component of carboplatin or pemetrexed
• 13. Contraindication to investigational medicinal products or to auxiliary medicinal products
• 17. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
• 25. Is pregnant or breastfeeding, or expecting to conceive or father children with in the projected duration of the study
• 26. Patients under AME
• 27. Adults subject to a legal measure protection (guardianship, curatorship and safeguard of justice)
• 28. Patients deprived of their liberty by a judicial or administrative decision

• 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; formalin fixed specimens after the subject has been diagnosed with metastatic disease will be preferred for determination of PD-L1 status prior to randomisation. 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 the 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 :
  • Hematological Absolute neutrophil count (ANC) ≥ 1,500 /mcL
  • Platelets Hemoglobin (4 weeks without transfusions) ≥ 100,000 / mcL ≥ 9.0 g/dL or ≥ 5.6 mmol/L
  • Renal calculated creatinine clearance (CrCl)a ≥ 50 mL/min
  • Hepatic Serum total bilirubin ≥ 50 mL/min ≤ 1.5xULN 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
  • Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) / Activated Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT) ≤ 1.5xULN unless the subject is receiving anticoagulant therapy
  • Creatinine Clearance should be calculated using the Cockcroft-Gault Method
• 10. If female of childbearing potential*, be willing to use an adequate method of 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.
• 11. If male subject with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception. 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.
• 12. Subject has voluntarily agreed to participate by giving written informed consent/assent for the trial. The subject may also provide consent/assent for exploratory studies. However, the subject may participate in the main trial without participating in exploratory studies.
• 13. Affiliation to French social security system
  • A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.