Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase III Trial of Single-Agent Pemetrexed (Alimta®) Versus the Combination of Carboplatin and Pemetrexed in Patients With Advanced Non-small-cell Lung Cancer and Performance Status of 2
Brief Summary: Optimal management of patients with advanced NSCLC and with PS 2 remains controversial and underrepresented in clinical trials, typically accounting for 5 to 10% of enrolled patients. Patient PS 2 proportion in population-based studies is considerably higher than that included in clinical trials. Management of patients with PS of 2 in clinical practice is empirical and inconsistent. Patients have median overall survival of 3 to 5 months in randomized trials, and treatment options include best supportive care, single-agent and combination chemotherapy. Retrospective studies have suggested that patients PS 2 may benefit from first-line chemotherapy in terms of symptom improvement and overall survival. In many of these studies, single-agent chemotherapy was compared with best supportive care alone. Data on the role of cisplatin-based combinations for patients with PS 2 is more scant, with one study questioning its benefit, and another interrupting accrual because of undue toxicity. With regards to carboplatin, the Cancer and Leukemia Group B (CALGB) study 9730 compared paclitaxel plus carboplatin versus paclitaxel alone in a subgroup of 107 patients with PS 2; the median overall survival was significantly longer in group treated with combination chemotherapy (4.7 versus 2.4 months). Combination chemotherapy with carboplatin and paclitaxel also produced a statistically significantly higher incidence of severe hematological and non-hematological toxicities. On the basis of aforementioned results, a recent European panel stated that carboplatin-based or low-dose cisplatin-based doublets might represent alternative options to single-agent chemoterapy in patients PS 2. Outside clinical trials, single-agent chemotherapy with a 3rd generation agent remains valid option for patients PS2. Results demonstrate that pemetrexed is an agent with established single-agent activity in NSCLC, and suggest it is a potential candidate for combinations with platinum and other agents currently utilized for patients with advanced NSCLC. Favorable toxicity profile of pemetrexed suggests that this agent is an ideal candidate for single agent testing and in combination among patients with PS 2. Substantial doubt remains in the comparative benefit from monotherapy versus combination. Starting dose and schedule of pemetrexed were set for this study based on its current labeling in the 2nd line treatment of metastatic NSCLC and 1st line treatment of malignant pleural mesothelioma.


Options:
A: Inclusion Criteria:

* Histologic or cytologic new diagnosis of NSCLC, Stage IIIB with a cytologically positive pleural or pericardial effusion or Stage IV.
* No prior chemotherapy, including adjuvant or neoadjuvant therapy, for the treatment of NSCLC.
* ECOG Performance Status of 2 .
* Patients must be at least 3 weeks since major surgery. Patients must be at least 1 week since surgery, such as mediastinoscopy, pleuroscopy, or thoracostomy.
* Patients must have measurable disease, defined as lesions that can be accurately measured in at least 1 dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than 10 mm with spiral CT scan.

Exclusion Criteria:

* Any prior radiation therapy to the thoracic area.
* Active and ongoing systemic infection.
* Prior radiation to greater than 25% of the bone marrow.
* ECOG PS other than 2
* Patients with a known hypersensitivity to gemcitabine and carboplatin.
B: Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of advanced non small cell lung cancer, not amenable to surgical or curative radiation therapy (stage IIIB or IV);
* No prior or concomitant chemotherapy (adjuvant/neoadjuvant chemotherapy permitted if concluded at least one year prior to enrollment);
* ECOG performance status 2;
* Age: \> or = 18 and \< 70 years;
* Life expectancy at least 4 weeks;
* Normal bone marrow, hepatic and renal function defined as: neutrophils \> or = 2000/mm3, PLT \> or = 100,000/mm3, Hb \> or = 10.0 g/dl, Bilirubin \> or = 1.5 times the upper normal limit (UNL), AST and ALT \< or = 3 times the UNL (5 times in the presence of liver metastases), creatinine within normal limits;
* Signed informed consent.

Exclusion Criteria:

* Active systemic infections;
* Severe concomitant illness (congestive heart failure, angina pectoris, myocardial infarction within previous 6 months, cardiac arrhythmias under treatment, severe arterial hypertension, severe or uncontrolled diabetes mellitus);
* Inadequate hepatic or renal function;
* Radiation therapy ongoing or concluded within two weeks prior to enrollment;
* Symptomatic cerebral metastases;
* Previous chemotherapy for advanced disease;
* Any condition that would, in the investigator's opinion, limit the patients ability to provide informed consent or to comply with study procedures;
* Pregnant or nursing females;
* Any malignancy within the past 5 years (except for adequately treated carcinoma in situ of the cervix or non melanoma skin cancer)
C: 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
D: Inclusion Criteria:

* Newly diagnosed NSCLC in stage IIIB (with a cytologically positive pleural or pericardial effusion) or stage IV, according to the sixth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual37;
* Age \> 18 years;
* No prior chemotherapy, including adjuvant or neoadjuvant therapy, for the treatment of NSCLC;
* Histological confirmation of any non-squamous histological type of NSCLC, given the recent findings of treatment benefit in this population44;
* ECOG performance status of 2;
* At least 3 weeks must have elapsed since major surgery, and at least 1 week since mediastinoscopy, pleuroscopy, or thoracostomy;
* Patients must have measurable disease, defined as lesions that can be accurately measured in at least 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques (computed tomography \[CT\] or magnetic resonance imaging \[MRI\] scan) or as ≥ 10 mm with spiral CT scan;
* Adequate organ function as indicated by the following:

  * White blood cell (WBC) count ≥ 3500/mm3
  * Absolute neutrophil count (ANC) ≥1500/mm3
  * Hemoglobin ≥ 9.0 g/dL
  * Platelet count ≥ 100,000/ mm3
  * Total bilirubin ≤ 2 times the upper limit of normal (ULN)
  * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the ULN, unless liver metastases present, in which case AST and ALT have to be ≤ 5 times the ULN
  * Estimated glomerular filtration rate (GFR) ≥ 45 mL/min
* Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to registration;
* Fertile patients (male or female) must agree to use an acceptable method of contraception to avoid pregnancy for the duration of the study and for 3 months thereafter;
* Patients must sign an Informed Consent Form;
* Have the ability to take folic acid, Vitamin B12, and dexamethasone according to protocol requirements;

Exclusion Criteria:

* ECOG performance status other than 2;
* Prior chemotherapy for the treatment of NSCLC;
* Lesions that have been irradiated cannot be included as sites of measurable disease. If the only measurable lesion was previously irradiated the patient cannot be included;
* Symptomatic central nervous system (CNS) metastases. Prior CNS metastases are allowed if the patient is neurologically stable and not receiving corticosteroids;
* Serious uncontrolled intercurrent medical or psychiatric illness;
* Active and ongoing systemic infection;
* Second primary malignancy (except in situ carcinoma of the cervix, in situ carcinoma of the bladder, adequately treated basal-cell carcinoma of the skin, adequately treated squamous-cell carcinoma of the skin, T1 vocal cord cancer in remission, or prior malignancy treated more than 5 years prior to enrollment and without recurrence);
* Known hypersensitivity to pemetrexed;
* known hypersensitivity to carboplatin;
* Pregnancy or lactation;
* Use of any investigational agent within 30 days prior to enrollment into the study;
* Unable to discontinue administration of non-steroidal anti-inflammatory (NSAIDSs) agents for 2 days before, the day of and 2 days after the dose of pemetrexed, in the case of NSAIDs with short half-life, such as ibuprofen (total of 5 days), in patients with a GFR between 45 and 79 mL/min; and for 5 days before, the day of and 2 days after the dose of pemetrexed, in the case of NSAIDs with long half-life (total of 8 days, see 7.4.2) in all patients; patients with a GFR ≥ 80 mL/min may receive concomitant study treatment and ibuprofen or aspirin (≤ 1.3 g/day);
* Inability to comply with requirements and procedures of study.

Answer: D