Surgery for Early Lung Cancer With Preoperative Erlotinib (Tarceva): A Clinical Phase II Trial (SELECT) (SELECT)
2.5 Rationale for preoperative erlotinib therapy
Erlotinib is the only EFGR tyrosine kinase inhibitor to demonstrate a survival advantage and symptom improvement in a large phase III trial after failure of chemotherapy in advanced non-small cell lung cancer (Shepherd, Rodrigues Pereira et al. 2005). Although the potential utility of erlotinib in earlier stage NSCLC is unclear, given its activity in advanced disease and its minimal toxicity profile, there is likely a subset of patients who may benefit and potentially be cured by adjuvant erlotinib therapy. Erlotinib may also have greater antitumour activity in earlier stage disease. Therefore, we propose a phase II study to assess erlotinib pre-operatively in clinical stage 1 and 2 NSCLC, and downstream effects on signal transduction pathways and possible markers of treatment resistance and sensitivity.
The proposed study involves administering oral erlotinib for four weeks (28 days) preoperatively in early stage (1A/B, 2A/B) NSCLC. Current waiting times for surgical resection of early stage NSCLC at UHN ranges from 4 to 6 weeks (Hui, Johnston et al. 2004), thus patients would not experience significant delay in time to surgery through this trial design. This study provides the opportunity to explore the impact of erlotinib on early stage NSCLC in humans, with pharmacodynamic assessment expected in 100% of patients post-treatment, in addition to correlative imaging. This study will evaluate the feasibility of preoperative therapy with erlotinib, and may facilitate the identification of predictive markers for response to erlotinib in early stage NSCLC. This may help further define the subset of patients who would benefit from adjuvant EGFR tyrosine kinase inhibitors, and those who may require other adjuvant approaches including chemotherapy and further clinical trials.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Surgery for Early Lung Cancer With Preoperative Erlotinib (Tarceva): A Clinical Phase II Trial|
- changes in tumor cell proliferation measured by a 75% reduction of Ki67 Immunohistochemistry (ICH) expression comparing pre and postoperative lung cancer [ Time Frame: Before surgery and after surgery ] [ Designated as safety issue: No ]
- response rate, stable disease rate evaluated by RECIST criteria, median overall and disease-free survival time, 1-year overall and disease-free survival rate, toxicity and time to disease progression [ Time Frame: Baseline, 2weeks, 4weeks and 30 days after surgery ] [ Designated as safety issue: Yes ]
|Study Start Date:||May 2006|
|Study Completion Date:||February 2012|
|Primary Completion Date:||January 2012 (Final data collection date for primary outcome measure)|
Active Comparator: Erlotinib
Erlotinib 150mg once a day p.o
150mg once a day for 28 days
Other Name: TarcevaDrug: Erlotinib
28 days of Erlotinib before surgery in patients with stage I-IIb NSCLC
Treatment will be administered on an outpatient basis. Patients may be identified by thoracic surgeons, respirologists and/or interventional chest radiologists for study participation upon clinical and radiographic assessment.
4.2 Diagnostic biopsy, Pretreatment Investigations
If patients have already had a core or FNA biopsy before referral, this material will be sought from the original pathologist for review and inclusion in the study with appropriate consent sought. If a patient does not have a biopsy upon presentation to the thoracic surgeon, and consents to inclusion in the trial, a percutaneous biopsy will be mandated as part of entry into the study. The order of test will be up to the treating thoracic surgeon. As part of this procedure a large localizing needle is inserted into the tumour. In collaboration with pathology, a fine needle is passed through the outer needle and an immediate diagnosis will be made at the time of fine needle aspiration biopsy. After a pathologic diagnosis of cancer is confirmed, additional biopsies to obtain material for correlative studies will be performed through the standard localizing needle, assuming no complications or technical difficulties have arisen. These studies will be done in collaboration with thoracic interventional radiologists from Diagnostic Imaging, who perform the lung fine needle aspirates and biopsies.
All patients will undergo pre-study assessments for symptoms, performance status, radiographic assessment and blood tests (complete blood count, electrolytes, liver and renal function tests). Blood samples before treatment and post treatment with erlotinib will be banked for future serum proteomic analysis. Assessment of response will occur after the 4-week treatment period. Toxicity will be assessed continuously, with patient assessment weekly on treatment, repeat blood tests at 2 weeks and imaging of measurable disease at 4 weeks. All subjects will be invited to have their initial diagnostic biopsy and subsequent surgical tumor specimen examined as part of the laboratory correlate component of the study. Patients will be considered evaluable for pharmacodynamic assessment if they complete at least 21 of the planned 28 days of therapy.
Patients will have PET-CT scan study done pre- and post-treatment (see section 7). If the enrolment PET-CT imaging reveals mediastinal disease (IIIA or IIIB) or extensive disease and this is pathologically confirmed the patient will not be enrolled in the study.
Once the diagnosis is established and assessment completed, oral erlotinib will be administered at a dose of 150 mg (1 pill) daily for 28 days prior to the planned mediastinoscopy and/or surgery. Tablets should be taken preferably in the morning with up to 200 mL of water at least 1 hour before or 2 hours after meals. If the patient forgets to take a dose, they should take the last missed dose as soon as they remember, as long as it is at least 12 hours before the next dose is due. If patient vomits after taking the dose, the dose may be retaken if the tablet is seen in the emesis. The last dose of erlotinib will be administered early in the morning of the mediastinoscopy or surgery.
If the mediastinoscopy reveals the presence of Stage III disease, the patient's mediastinoscopy samples may still be analyzed as part of the correlative study. Patients will be followed for 90 days or as long as required after the last dose of erlotinib to ensure resolution of any erlotinib-related toxicities. However these patients will be offered standard therapy for stage III disease off study protocol, for example a combination of chemotherapy, radiation with or without surgical resection. If these patients do proceed to thoracotomy post-chemotherapy and/or radiotherapy, their resection specimen will not be eligible for this correlative protocol.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00462995
|Toronto General Hospital|
|Toronto, Ontario, Canada, M5G 2C4|
|Princess Margaret Hospital|
|Toronto, Ontario, Canada, M5G 2M9|
|Principal Investigator:||Natasha Leighl, MD FRCPC||University Health Network, Toronto|
|Principal Investigator:||Thomas Waddell, MD FRCSC||University Health Network, Toronto|