Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open-Label Randomized Phase III Trial of BMS-936558 (Nivolumab) Versus Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NSCLC)
Brief Summary: The purpose of the study is to compare the overall survival of BMS-936558 as compared with Docetaxel in subjects with squamous cell non-small cell lung cancer (NSCLC), after failure of prior platinum-based chemotherapy.


Options:
A: Inclusion Criteria:

1. Patients must be \>=18 years of age.
2. Non-squamous NSCLC (adenocarcinoma or large cell carcinoma). Mixed tumors with small cell anaplastic elements are not eligible. Mixed tumors with squamous histology are acceptable as long as the squamous element is not the dominant histology.
3. Unresectable stage IIIB or stage IV disease. Stage IIIB disease should be ineligible for combined modality therapy (i.e., pleural effusions, pericardial effusions).
4. ECOG performance status of 2.
5. No prior systemic therapy for stage IIIB or stage IV lung cancer.
6. Life expectancy of at least 12 weeks.
7. Patients must have measurable disease per RECIST version 1.1 (see Section 8).
8. Laboratory values as follows:

   * Absolute neutrophil count (ANC) ≥1500/μL
   * Hemoglobin (Hgb) ≥10 g/dL
   * Platelets ≥100,000/μL (≤7 days prior to treatment)
   * AST or ALT and alkaline phosphatase (ALP) must be \<2.5 x ULN, or \<5 x ULN in patients with liver metastases.
   * Total bilirubin \<1.5 x the institutional ULN
   * Calculated creatinine clearance ≥45 mL/min
9. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol.
10. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately.
11. Patient must be accessible for treatment and follow-up.
12. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry.

Exclusion Criteria:

1. Squamous cell histology. Mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient will be ineligible; sputum cytology alone is unacceptable.
2. Patients with active brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if there is no evidence of central nervous system (CNS) disease progression, and at least 2 weeks have elapsed since treatment. Ideally, patients should not still require use of seizure medication or steroids.
3. Patients who have had major surgical procedure (not including mediastinoscopy), open biopsy, or significant traumatic injury within 4 weeks of beginning treatment; or, the anticipation of the need for major surgical procedure during the course of the study.
4. Women who are pregnant or lactating.
5. Minor surgical procedures (with the exception of the placement of portacath or other central venous access) must be completed at least 7 days prior to beginning protocol treatment.
6. History of hypersensitivity to active or inactive excipients of any component of treatment (pemetrexed, bevacizumab, and/or carboplatin).
7. Pulmonary carcinoid tumors.
8. Patients with proteinuria at screening as demonstrated by either:

   * urine protein creatinine (UPC) ratio ≥1.0 at screening OR
   * urine dipstick for proteinuria ≥2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection, and must demonstrate ≤1 g of protein/24 hours to be eligible) (see Appendix B)
9. Patients with a serious non healing wound, active ulcer, or untreated bone fracture.
10. Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
11. Patients with history of hematemesis or hemoptysis (defined as having bright red blood of ½ teaspoon or more per episode) within 1 month prior to study enrollment.
12. History of myocardial infarction or unstable angina within 6 months of beginning treatment.
13. Inadequately controlled hypertension (defined as systolic blood pressure \>150 mmHg and /or diastolic blood pressure \>100 mmHg while on antihypertensive medications).
14. New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF) (see Appendix C).
15. Serious cardiac arrhythmia requiring medication.
16. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of treatment.
17. History of stroke or transient ischemic attack ≤ 6 months prior to beginning treatment.
18. Any prior history of hypertensive crisis or hypertensive encephalopathy.
19. History of abdominal fistula or gastrointestinal perforation ≤ 6 months prior to Day 1 of beginning treatment.
20. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
21. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
22. Use of any non-approved or investigational agent ≤ 30 days of administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
23. Past or current history of neoplasm other than the entry diagnosis with the exception of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a DFS ≥5 years.
B: Inclusion Criteria:

* Men \& women ≥18 years of age
* Subjects with histologically or cytologically-documented non-squamous cell NSCLC who present with Stage IIIB/IV disease or recurrent or progressive disease following multimodal therapy (radiation therapy, surgical resection, or definitive chemoradiation therapy for locally advanced disease) and who will receive study therapy as second or third line of treatment for advanced disease
* Disease recurrence or progression during/after one prior platinum doublet-based chemotherapy regimen for advanced or metastatic disease
* Measurable disease by Computed tomography (CT)/Magnetic resonance imaging (MRI) per RECIST 1.1 criteria
* Eastern Cooperative Oncology Group (ECOG) performance status ≤1
* A formalin fixed, paraffin-embedded (FFPE) tumor tissue block or unstained slides of tumor sample (archival or recent) must be available for biomarker evaluation. Specimens must be received by the central lab prior to randomization. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is insufficient

Exclusion Criteria:

* Subjects with untreated central nervous system (CNS) metastases are excluded. Subjects are eligible if CNS metastases are asymptomatic or treated and subjects are neurologically returned to baseline for at least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤10mg daily prednisone (or equivalent)
* Subjects with carcinomatous meningitis
* Subjects with active or recent history of known or suspected autoimmune disease. Subjects with Type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, or skin disorders (vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll
* Subjects with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of randomization
* Prior therapy with anti-programmed death-1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), anti-programmed cell death ligand 2 (anti-PD-L2), anti-cluster of differentiation 137 (anti-CD137), or anti-Cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) antibody (including Ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
* Prior treatment with Docetaxel
* Treatment with any investigational agent within 14 days of first administration of study treatment

Other protocol-defined inclusion/exclusion criteria apply
C: Core Inclusion Criteria:

* Histologically confirmed PD-L1 status defined NSCLC. Biopsy must be within 70 days of first treatment with pembrolizumab.
* Eastern Cooperative Oncology Group (ECOG) performance status 2.
* Life expectancy \> 12 weeks.
* Uni-dimensionally measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1
* Computerised Tomography (CT) scan of chest and abdomen within 28 days of starting pembrolizumab.
* Adequate haematological function:

  * Platelet count ≥100 x 109 /L.
  * Neutrophils ≥1.5 x 109/L.
  * Haemoglobin ≥ 90 g/L.
* Adequate hepatic function:

  * Serum bilirubin ≤1.5 x upper limit of normal (ULN).
  * Serum transaminases ≤2.5 x ULN.
* Adequate renal function: Creatinine clearance \<1.5 times ULN concurrent with creatinine clearance \>50 ml/min.
* Provision of signed and dated, written informed consent prior to any trial specific procedures, sampling and analyses.

Core Exclusion Criteria:

* Patients who do not meet the criteria of performance status = 2 on the ECOG Performance scale.
* Untreated symptomatic brain or leptomeningeal metastatic disease.
* Medical or psychiatric conditions compromising informed consent.
* Any medical condition which in the opinion of the investigator would compromise the ability of the patient to participate in the trial or which would jeopardise compliance with the protocol.
* Radiotherapy within 28 days of trial treatment.
* Active autoimmune disease that has required systemic treatment in past 2 years
* Chronic usage of steroids or other immunosuppressant medication.
* Previous history of pneumonitis.
* Any evidence of clinical autoimmunity.
D: Inclusion Criteria:

* Men and women ≥18 years of age
* Subjects with histologically or cytologically-documented squamous cell NSCLC who present with Stage IIIB/IV disease or with recurrent or progressive disease following multimodal therapy (radiation therapy, surgical resection or definitive chemoradiation therapy for locally advanced disease)
* Disease recurrence or progression during/after one prior platinum doublet-based chemotherapy regimen for advanced or metastatic disease
* Measurable disease by computed tomography (CT)/Magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
* Eastern Cooperative Oncology Group (ECOG) performance status ≤1
* A formalin fixed, paraffin-embedded (FFPE) tumor tissue block or unstained slides of tumor sample (archival or recent) must be available for biomarker evaluation. Specimens must be received by the central lab prior to randomization. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is insufficient

Exclusion Criteria:

* Subjects with untreated central nervous system (CNS) metastases are excluded. Subjects are eligible if CNS metastases are treated and subjects are neurologically returned to baseline for at least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent)
* Subjects with carcinomatous meningitis
* Subjects with active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
* Subjects with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of randomization
* Prior therapy with anti-Programmed death-1 (PD-1), anti-Programmed cell death ligand 1 (PD-L1), anti-Programmed cell death ligand 2 (PD-L2), anti-CD137, or anti-Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
* Prior treatment on the first line study CA184104 first line NSCLC study
* Prior treatment with Docetaxel
* Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
* Treatment with any investigational agent within 14 days of first administration of study treatment

Answer: D