Alimta® Versus Its Combination With Carboplatin in Advanced Non-small-cell Lung Cancer in Patients Performance Status 2

This is a Phase III, open label, randomized study to enroll 228 patients with advanced in a 1:1 ratio at the time of registration. Patients in Arm A will receive pemetrexed, 500 mg/m2, with appropriate vitamin supplementation; patients in Arm B will receive the same dose and schedule of pemetrexed as in Arm A, in combination with carboplatin, AUC of 5. For the purpose of the study, treatment (Arm A or Arm B) will consist of up to four cycles of therapy (repeated every 21 days). Primary endpoint of the study is overall survival; secondary endpoints include toxicity, response rate, and progression-free survival. At the time of analysis, patients will be stratified according to age (≥ 70 versus < 70 years), disease stage (IIIB versus IV), site, and weight loss (≥ 5 Kg versus < 5 Kg).

The dose of carboplatin will be determined according to the formula developed by Calvert et al., which is shown in equation [1] below and uses the estimated creatinine clearance according to the method of Cockcroft and Gault for estimation of the glomerular filtration rate (GFR) (equation [2] below):

• Dose of carboplatin (mg) = Target AUC x (GFR + 25)
• GFR = (140 - Age) x Weight/(72 x serum creatinine) (multiply by 0.85 in women) Sample Size and Expected Accrual In the CALGB 9730 study of advanced NSCLC, first-line treatment with paclitaxel plus carboplatin resulted in a median overall survival of 4.7 months among patients with a performance status of 2. In the ECOG 1594 study, the median overall survival of patients with a performance status of 2 who were treated with platinum-based doublets was 4.1 months. Approximately 208 eligible patients are needed to provide 80% power to detect a difference between the two treatment arms with a two-sided type I error of 0.05, assuming that pemetrexed plus carboplatin will result in a median survival of at least 4.3 months, and pemetrexed alone 2.9 months. An additional 20 patients will be accrued to account for an early dropout rate of 10%, for a total of 228 patients. It is anticipated that the accrual time will be approximately 22 months and patients will be followed for 1 year after completion of treatment; therefore, 2 years and 10 months will be needed to complete the study.

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.