| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with histological or cytological diagnosis of nonsquamous 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 | 10029520 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIA |
|
| 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 | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
|
| 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 an erlotinib-pemetrexed combination with pemetrexed alone, and erlotinib alone, in terms of progression-free survival (PFS) in non-smoker patients with locally advanced or metastatic (Stage IIIA, IIIB, or IV) nonsquamous NSCLC who have failed first-line chemotherapy treatment. |
|
| E.2.2 | Secondary objectives of the trial |
• to compare the erlotinib-pemetrexed combination with pemetrexed alone, and erlotinib alone, in non-smoker patients with locally advanced or metastatic (Stage IIIA, IIIB, or IV) nonsquamous(NS) NSCLC who have failed 1st-line chemotherapy treatment in terms of:
o tumor response rate
o disease control rate
o overall survival
o safety and adverse events profile
o association between EGFR and MTAP genotype, and clinical outcome to treatment
o time-to-worsening of symptoms using the Lung Cancer Symptom Scale (LCSS)
• to compare pemetrexed alone with erlotinib alone in non-smoker patients with locally advanced or metastatic (Stage IIIA, IIIB, or IV) NS NSCLC who have failed 1st-line chemotherapy treatment in terms of:
o progression-free survival
o tumor response rate
o disease control rate
o overall survival
o safety and adverse events profile
o association between EGFR and MTAP genotype, and clinical outcome to treatment
o time-to-worsening of symptoms using LCSS
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Histological or cytological 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 Lung Cancer, that is of nonsquamous histology and not amenable to curative therapy (Protocol Attachment S103.1). Nonsquamous histology includes adenocarcinoma, large cell carcinoma & other NSCLC histologies(that is, those that do not clearly qualify as adenocarcinoma, large cell carcinoma or squamous cell carcinoma.
[2] Patients must be non-smokers (defined as having smoked <100 cigarettes [or equivalent] during his/her lifetime; Pham et al. 2006).
One cigarette contains approximately 1 gram of tobacco. Other products should be converted to cigarette equivalents based on grams of tobacco content (eg. a pipe contains approximately 5 grams of tobacco [Srivastava and Kreiger 2004]; cigars approximately 5-17 grams, depending on the size [NCI 2000]; and one bidi contains approximately 0.25 grams [Gajalakshmi et al. 2003]).
[3] At least one unidimensionally measurable lesion meeting Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (Protocol Attachment S103.2). Positron emission tomography scans and ultrasound are not allowed as methods of measurement.
[4] Patients must have failed only one prior chemotherapy regimen and must be considered eligible for further chemotherapy following progression of their 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.
[5] 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.
Lesions that have been irradiated cannot be included as sites of measurable disease unless clear tumor progression has been documented in this lesion since the end of radiation therapy.
[6] 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.
[7] Performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) Scale (Protocol Attachment S103.3).
[8] Estimated life expectancy of at least 8 weeks.
[9] Patient compliance and geographic proximity that allow adequate follow-up.
[10] 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 S103.4) and serum creatinine <1.5 x ULN.
[11] Signed informed consent from patient.
[12] Males or females at least 18 years of age.
[13] For women: Must be surgically sterile, postmenopausal, or compliant with a medically approved contraceptive regimen during and for 6 months after the treatment period; must have a negative serum or urine pregnancy test within 7 days prior to randomization, and must not be breast-feeding.
For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 6 months after the treatment period.
|
|
| E.4 | Principal exclusion criteria |
[14] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of randomization.
[15] Prior exposure to agents directed at the human epidermal growth factor receptor axis (for example, gefitinib, erlotinib, cetuximab, or trastuzumab).
[16] Prior exposure to agents directed at pemetrexed ď€ molecular targets (such as thymidylate synthase or dihydrofolate reductase inhibitors).
[17] Any known significant ophthalmologic abnormalities of the surface of the eye. The use of contact lenses is not recommended during the study.
[18] Have a history of severe hypersensitivity reaction to erlotinib or pemetrexed or to any other ingredient used in the formulation.
[19] Recent (within 30 days of randomization) or concurrent yellow fever vaccination.
[20] Patients who cannot take oral medication, who require intravenous alimentation, have had prior surgical procedures affecting absorption, or have active peptic ulcer disease.
[21] Patients under therapy with warfarin or coumarin derivatives.
[22] Pregnancy or breast-feeding.
[23] Have a serious concomitant systemic disorder (e.g., active infection including human immunodeficiency virus, or unstable cardiovascular disease) that, in the opinion of the Investigator, would compromise the patient’s ability to adhere to the protocol.
Unstable cardiovascular disease is defined as congestive heart failure (New York Heart Association class III or worse), unstable angina, myocardial infarction, or coronary revascularization procedure within 6 months prior to randomization.
[24] 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.
[25] Inability to interrupt aspirin or other non-steroidal anti-inflammatory agents, other than an aspirin doses ≤1.3 grams per day, for a 5-day period (8-day period for long-acting agents such as piroxicam).
[26] 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 ≥1week.
[27] Presence of clinically significant (by physical exam) third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to randomization.
[28] Concurrent administration of any other antitumor therapy.
[29] Inability or unwillingness to take folic acid, dexamethasone (or equivalent) or vitamin B12 supplementation.
[30] Significant weight loss (i.e., ≥10%) over the previous 6 weeks before
study entry. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is progression-free survival (PFS) and will be based on the ITT population. The primary objective is to compare the erlotinib-pemetrexed combination (Arm A) with erlotinib alone (Arm B), and pemetrexed alone (Arm C), in terms of PFS. Primary analysis will be conducted following a sequential approach. A global comparison of PFS across the three treatment groups will be performed using Cox proportional hazards modeling (Cox 1972), with pairwise comparisons made between treatments using contrasts within the model (ie. A vs B, and A vs C). |
|
| 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 | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 | Yes |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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