Surgery for Early Lung Cancer With Preoperative Erlotinib (Tarceva): A Clinical Phase II Trial (SELECT)

• Status: Completed
• Trial end date: 2012-02-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University Health Network, Toronto
• Collaborator: Hoffmann-La Roche
• Treatments: Erlotinib Hydrochloride

Criteria

Inclusion Criteria:

• Patients must have cytology or biopsy-proven non-small cell lung carcinoma (NSCLC);

• Preoperative clinical stage must be 1A (T1N0), 1B(T2N0), 2A (T1N1) and 2B (T2N1) by radiographic criteria;

• Patients must be deemed appropriate candidates for resection by the treating surgeon and surgical assessment team;

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan;

• Age ³ 18 years;

• ECOG performance status £ 2 (Karnofsky ³ 60%; see Appendix A);

• Patients must have normal organ and marrow function as defined below:

• absolute neutrophil count ³1,500/uL

• platelets ³100,000/uL

• total bilirubin £1.5 times institutional upper limit of normal

• AST(SGOT)/ALT(SGPT) £2 times institutional upper limit of normal

• creatinine £1.5 times institutional upper limit of normal , or creatinine clearance³50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal;

• The effects of erlotinib on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (abstinence, hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately;

• Patients on warfarin are not excluded from the trial but are required to have their INR measured intensively during the initial stages of starting the study drug as alterations in INR have been noted. This intensive monitoring should entail measurements (3 X week for the first week then twice weekly for the remainder of the trial);

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients clinically T2N1 (2B), and/or T3N0 (2B) requiring a sleeve lobectomy, and/or chest wall resection; and tumors with higher staging;

• Patients who have received prior anticancer treatment with chemotherapy, radiotherapy or EGFR inhibitor therapy;

• Patients who have had a previous diagnosis of cancer within 5 years are excluded except adequately treated non-melanoma skin cancer, and carcinoma in situ of the cervix or breast;

• Patients may not be receiving any other investigational or anticancer agents while on study;

• History of allergic reactions to erlotinib;

• Pre-existing diarrhea ³ NCI CTC Grade 2 (4 to 6 loose stools per day) not controlled on standard therapy;

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure or evidence of cardiac dysfunction, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease, poorly controlled diabetes mellitus, clinically significant or untreated ophthalmologic (e.g. Sjogrens etc.) or gastrointestinal conditions (e.g. Crohn's disease, ulcerative colitis) or psychiatric illness/social situations that would limit compliance with study requirements.

• Pregnant women are excluded from this study, as the effects of erlotinib on a developing fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with erlotinib, breastfeeding should be discontinued if the mother is treated with this combination.

• HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with erlotinib.

• Active malignancy at any other site including combined small cell and non-small cell carcinomas or a pulmonary carcinoid tumor;

• Because drugs that induce CYP3A4 enzymes have been shown to significantly reduce plasma concentrations of erlotinib, patients with ongoing use of phenytoin, rifampicin, carbamazepine, barbiturates, rifampicin, or St John's Wort are excluded;

• Incomplete healing from previous surgery;

• Use of any agent that decreases gastric pH, including proton pump inhibitors, histamine-2 receptor blockers or sodium bicarbonate. Use of calcium or magnesium based elixirs are not included;

• Concomitant use of CYP3A4 inhibitors, e.g. itraconazole, may result in increased levels of erlotinib (TARCEVA®). This increase may be clinically relevant since adverse experiences are related to dose and exposure.