| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage IB-IIIA Non-small Cell Lung Carcinoma with EGFR-positive tumors |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
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| 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 |
The primary objectives of this study are to assess the efficacy of single agent, oral, once daily, Tarceva (150 mg/day) at increasing the DFS following complete surgical resection with or without adjuvant chemotherapy in the following patient populations:
· Overall Population: Patients who have EGFR-positive tumor tissue (by IHC and/or FISH);
· Selected Subset Population:
For regulatory submission in the US: Patients who have EGFR-positive tumor tissue by FISH.
For regulatory submission in Rest of World (ROW): The subset population will be prospectively defined in the Statistical Analysis Plan before the first interim analysis. The reason for delaying the definition of the subset population until that time is that more information on which biomarkers are most suitable for identifying the subgroups of patients benefiting most from Tarceva therapy will become available from currently ongoing studies at that time. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives, to be analyzed for both patient populations, are to:
· Compare the OS by study arm;
· Evaluate the safety of Tarceva;
· Explore the prognostic and predictive value of EGFR-related biomarkers and other biomarkers that may be associated with clinical outcomes following treatment with Tarceva;
· For regulatory submission in the US: If the subset population defined for the ROW submission is different than the subset population defined for the US submission, that population will be analyzed as a secondary endpoint;
· For regulatory submission in the ROW: If the subset population defined for the ROW submission is different than the subset population defined for the US submission, the population of FISH-positive patients will be analyzed as a secondary endpoint.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for participation in the Screening portion of this study, patients must meet all of the following inclusion criteria:
A. Histologically confirmed diagnosis of stage IB-IIIA NSCLC.
- Patients with bronchoalveolar carcinoma that presents as a single, solitary, discrete nodule or mass may be included;
- Patients with preoperative radiological evidence of N2 disease by either PET or CT scan (ie, radiological evidence of metastasis to ipsilateral mediastinal and subcarinal lymph nodes) that is confirmed as N2 disease histologically are excluded. However, patients determined to have microscopic N2 disease, that was not radiologically obvious preoperatively, can be included;
- Patients with histologically confirmed intralobar satellites (T4) are not eligible for this study.
B. Patients must have had a complete surgical resection defined as the appropriate
pulmonary parenchymal resection including lobectomy, bilobectomy, sleeve
lobectomy, and pneumonectomy with histologically confirmed negative bronchial
margins. Patients treated by a segmentectomy or wedge resection are not eligible for this study. Additionally, patients must have had a nodal dissection of 2 separate mediastinal nodal stations or nodal sampling of 2 separate mediastinal nodal stations (levels 4, 7, and 9 for right-sided tumors and levels 5, 6, 7, and 9 for left sided tumors are strongly suggested)
C. Age greater than or equal to 18 years;
D. Written informed consent to participate in the Screening portion of the study.
To be eligible for participation in the On-treatment portion of this study, patients must continue to meet all of the Screening inclusion criteria as well as all of the following Treatment inclusion criteria:
1. Primary tumor tissue from patient’s surgical resection must be analyzed by the central laboratory and determined to be EGFR-positive by IHC and/or FISH. This is a mandatory requirement for entry;
2. Patients may have completed up to a total of 4 cycles of adjuvant chemotherapy using a standard (non-investigational), 2-drug, platinum-based regimen OR may not have received adjuvant chemotherapy for NSCLC. Patients who have received adjuvant chemotherapy must have recovered from the acute side effects before randomization;
3. Ability to be randomized within the following timelines: 6 months (less than or equal to 180 days) from the day of surgical resection for patients who receive adjuvant chemotherapy and 3 months (less than or equal to 90 days) from the day of surgical resection for patients who do not receive adjuvant chemotherapy;
4. Ability to take oral medications;
5. An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 – 2
6. Patients with reproductive potential (ie, pre-menopausal females, females who have been menopausal for < 1 year and not surgically sterilized, or males not surgically sterilized) must practice effective contraceptive measures for the duration of study drug therapy and for at least 30 days after completion of study drug therapy. Female patients of child-bearing potential must provide a negative pregnancy test (serum) less than or equal to 14 days before randomization;
7. Adequate hematopoietic, renal and hepatic functions as defined by the following required laboratory values obtained less than or equal to 14 days before randomization:
ANC Greater than or equal to 1.0 x 10 9/L
Platelet count Greater than or equal to 75 x 10 9/L
Serum creatinine Less than or equal to 1.5 times the ULN (Less than or equal to 3.0 times the ULN if due to platinum adjuvant chemotherapy)
Total bilirubin Less than or equal to 1.5 times the ULN
ALT (SGPT) Less than or equal to 2.5 times the ULN
8. Written informed consent to participate in the On-treatment portion of the study;
9. Patients must be accessible for continued treatment and follow-up.
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| E.4 | Principal exclusion criteria |
Patients who meet any of the following exclusion criteria are not eligible to be screened for this study:
A. Patients with mixed histology of small cell and non-small cell carcinoma, or pulmonary
carcinoid tumors, or large cell carcinoma with evidence of neuroendocrine features.
Tumors with mixed adenocarcinoma and squamous cell carcinoma histology are
eligible;
B. Patients with preoperative radiological evidence of N2 disease by either PET or CT scan (ie, radiological evidence of metastasis to ipsilateral mediastinal and subcarinal lymph nodes) that is confirmed as N2 disease histologically are excluded. In addition, patients who have histologically confirmed positive bronchial margins are also excluded;
C. History of prior radiotherapy for NSCLC either as neoadjuvant or adjuvant therapy;
D. Patients who received neoadjuvant chemotherapy for NSCLC;
E. History of significant cardiac disease, (eg, uncontrolled high blood pressure, unstable angina, uncontrolled congestive heart failure, myocardial infarction) or uncontrolled cardiac arrhythmias within the previous year;
F. History of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (eg, Crohn’s disease, ulcerative colitis, etc.);
G. History of other prior malignancy except for adequately treated basal cell or squamous cell skin cancer or in-situ cervical cancer. Patients with other malignancies are eligible if they have remained disease free for at least 5 years;
H. History of a neurologic or psychiatric condition that might impair the patient’s ability to understand or to comply with the requirements of the study or to provide informed consent;
I. Prior treatment with any EGFR inhibitor.
Patients who meet any of the Screening exclusion criteria or any of the following Treatment exclusion criteria are not eligible to be randomized for this study:
1. Tumor tissue from the patient’s surgical resection determined to be EGFR-negative by both IHC and FISH. If an individual tissue test result is inconclusive (unable to be determined), it will be considered negative for study eligibility purposes
2. Active or uncontrolled infections or serious illnesses or medical conditions that could interfere with the patient’s ongoing participation in the study;
3. Ocular inflammatory or infectious conditions that have not been completely resolved before randomization;
4. Pregnant or breast-feeding females;
5. Participation in another investigational drug trial while on-study;
6. Hypersensitivity to erlotinib or to any of the excipients contained in the study drug.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Disease Free Survival (DFS) will be defined as time from the date of randomization until the first day NSCLC relapse is documented by radiological examination and/or biopsy, or until death in the absence of relapse. The investigator-determined date of relapse will be used for analysis of DFS. Patients who do not relapse will be censored on the last radiological assessment/biopsy date. Patients who receive other therapy for NSCLC before documented disease relapse (eg, radiotherapy or other chemotherapy) will be censored the day this subsequent therapy started. |
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| 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 | No |
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
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| 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
|
| Approximately 6 months after the date when at least 500 total disease relapse events have occurred. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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