| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with histological or cytological diagnosis of NSCLC with locally advanced or metastatic disease. Patients must have failed only one prior chemotherapy regimen and must be considered eligible for further chemotherapy following progression of their disease. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the proportion of patients who experience any drug-related Grade 3 or 4 toxicity on a simplified vitamin and steroid schedule plus pemetrexed versus the standard vitamin and steroid schedule plus pemetrexed in patients with advanced NSCLC who have been previously treated with chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare tumor response rate between patients receiving a simplified vitamin and steroid schedule plus pemetrexed and those receiving the standard vitamin and steroid schedule plus pemetrexed. To compare overall survival and progression-free survival between patients receiving the two vitamin/steroid schedules. To compare the following between patients: o time to first drug-related Grade 3/4 toxicity o time to first treatment-emergent Grade 3/4 toxicity o time to first drug-related Grade 3/4 hematologic toxicity o time to first treatment-emergent Grade 3/4 hematologic toxicity o time to first drug-related Grade 3/4 nonhematologic toxicity o time to first treatment-emergent grade 3/4 nonhematologic toxicity o time to first appearance of treatment-emergent Grade 3/4 rash. To assess the relationship between patient toxicity and possible predictors (i.e., folate status, type of first-line chemotherapy received, response to first-line chemotherapy). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1] Histologic or cytologic diagnosis of NSCLC with locally advanced or metastatic disease (Stage IIIA, IIIB, or IV), as defined by the American Joint Committee on Cancer Staging Criteria for NSCLC (Fleming et al. 1997, Mountain 1997). (See Protocol Attachment S111.1). [2] Patients must have failed only one prior chemotherapy regime and must be considered eligible for further chemotherapy following progression of their disease. The first chemotherapy regime may be administered as neoadjuvant, adjuvant, concurrent with radiotherapy, or palliatively in advanced disease. Chemotherapy must be completed at least 2 weeks prior to randomization and the patient must have recovered from the acute toxic effects of the regimen (except alopecia). [3] Disease status must be that of measurable disease as defined by RECIST criteria (Therasse et al. 2000). [4] Prior radiation therapy is allowed, but should be limited to <25% of the bone marrow (Cristy and Eckerman 1987). Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 2 weeks prior to randomization. Patients must have recovered from the acute toxic effects of the treatment prior to randomization. [5] Prior surgery is allowed, but should be completed at least 4 weeks prior to randomization, and, in the opinion of the investigator, the patient must have recovered from the surgery. Patients who, in the opinion of the investigator, have fully recovered from surgery in less than 4 weeks may also be considered for the study. [6] Performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) Scale. (See Protocol Attachment S111.2) [7] Estimated life expectancy of at least 8 weeks. [8] Patient compliance and geographic proximity that allow adequate follow-up. [9] Adequate organ function including the following: Adequate bone marrow reserve: Absolute neutrophil (segmented and bands) count (ANC) ≥1.5 x 109/L, platelets ≥100 x 109/L, and hemoglobin ≥9 g/dL. Hepatic: Bilirubin ≤1.5 x upper limit of normal (ULN), alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤3 x ULN (AP, AST and ALT ≤5 x ULN is acceptable if liver has tumor involvement). Renal: Calculated creatinine clearance (CrCl) ≥45 mL/min based on the standard Cockcroft and Gault formula (Protocol Attachment S111.3) [10] Males or females at least 18 years of age. [11] Signed informed consent from patient. [12] Male and female patients with reproductive potential must use an approved contraceptive method if appropriate (e.g., intrauterine device [IUD], birth control pills, or barrier device) during and for 3 months after the study. Females with childbearing potential must have a negative serum pregnancy test within 7 days prior to study randomization and must not be breast-feeding. |
|
| E.4 | Principal exclusion criteria |
| [13] Brain metastasis. Patients who are symptomatic for brain metastasis must have a pretreatment computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain. A patient with documented brain metastasis at the time of randomization will be excluded. Treated, stable central nervous system metastases are allowed, however, the patient must be stable after radiotherapy for ≥2 weeks and off all corticosteroids or on a stable dose for ≥1 week. [14] Prior exposure to agents directed at pemetrexed molecular targets (such as thymidylate synthase or dihydrofolate reductase inhibitors). [15] Concurrent administration of any other antitumor therapy. [16] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. [17] Active infection that in the opinion of the investigator would compromise the patient’s ability to tolerate therapy. [18] Serious concomitant disorders that would compromise the safety of the patient or compromise the patient’s ability to complete the study, at the discretion of the investigator. [19] Pregnancy or breast-feeding. [20] Have had a prior malignancy other than NSCLC, carcinoma in situ of the cervix or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. Patients with a history of low grade (Gleason score <6) localized prostate cancer will be eligible even if diagnosed less than 5 years previously. [21] Inability to interrupt aspirin or other non-steroidal anti-inflammatory agents, other than aspirin doses ≤1.3 grams per day, for a 5-day period (8-day period for long-acting agents such as piroxicam). [22] Presence of clinically relevant (by physical exam) third-space fluid collections (e.g., ascites or pleural effusions) that cannot be controlled by drainage or other procedures prior to study entry. [23] Inability or unwillingness to take folic acid or vitamin B12 supplementation or dexamethasone (or equivalent). [24] Significant weight loss (i.e., ≥10%) over the 6 weeks before study entry. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the proportion of patients who experience any treatment-emergent Grade 3 or 4 toxicity over the course of the study and will be based on the Qualified ITT population. Patients will be rated for toxicity before each cycle using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (CTEP 2003). Noninferiority of the simplified schedule will be claimed if the difference between the simplified schedule retains at least some of the benefit of the standard supplementation schedule, that is, the difference in proportions is at least smaller than 14%. The primary test of noninferiority will be conducted at a one-sided alpha level of 0.025. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| schema semplificato di acido folico e desametaso |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| I pazienti possono ricevere un massimo di 6 cicli di trattamento. I pazienti saranno seguiti per la sopravvivenza per 12 mesi dopo l'interruzione dello studio o il completamento dei 6 cicli di terapia. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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