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About
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.
Full description
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):
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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:
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;
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228 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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