Erlotinib and Cetuximab in Treating Patients With Advanced Solid Tumors With Emphasis on Non-Small Cell Lung Cancer

Phase I/II Study of Erlotinib (TARCEVA) and Cetuximab (ERBITUX) in Advanced Solid Tumors, With Emphasis on Non Small Cell Lung Cancer (NSCLC)

RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving erlotinib together with cetuximab may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of erlotinib and cetuximab and to see how well they work in treating patients with advanced solid tumors or progressive or recurrent stage III or stage IV non-small cell lung cancer.

OBJECTIVES:

Primary

• Determine the safety and feasibility of erlotinib hydrochloride and cetuximab in patients with advanced solid tumors. (Phase I)
• Determine the efficacy of this regimen, in terms of objective tumor response rate, in patients with advanced non-small cell lung cancer (NSCLC) pre-treated with platinum. (Phase II)

Secondary

• Determine the maximum tolerated dose of this regimen in these patients. (Phase I)
• Determine the efficacy of this regimen, in terms of response rate, in these patients. (Phase I)
• Determine the progression-free and overall survival of patients treated with this regimen. (Phase II)
• Determine the frequency and severity of toxicities of this regimen in these patients. (Phase II)
• Determine epidermal growth factor receptor (EGFR) and K-RAS mutation status. (Phase II)
• Evaluate EGFR protein expression and protein expression of downstream markers (e.g., pMAPK, pAKT, p27, and Ki-67). (Phase II)
• Evaluate the levels of marker proteins (e.g., pMAPK, pAKT, p27, and Ki-67) in buccal cells. (Phase II)
• Determine gene copy number by EGFR fluorescent in situ hybridization (FISH). (Phase II)
• Identify EGFR polymorphisms by analysis of genomic DNA from peripheral blood mononuclear cells. (Phase II)
• Determine if the continued presence or absence of mutant K-RAS tumor DNA correlates with response and/or outcome. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by an open-label, phase II study.

• Phase I: Patients receive oral erlotinib hydrochloride once daily on days 1-28 and cetuximab IV over 1-2 hours on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride and cetuximab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which ≥ 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

• Phase II: Patients receive erlotinib hydrochloride and cetuximab at the MTD determined in phase I.

Blood and buccal samples are acquired from patients at baseline and prior to courses 2 and 3. Samples are examined by fluorescent in situ hybridization (FISH), immunohistochemistry, polymorphism analysis, and protein expression assays to assess molecular markers (epidermal growth factor receptor, K-RAS, pMAPK, pAKT, p27 and Ki-67) for biologic effects and predictive response.

After completion of phase I treatment, patients are followed for 30 days or until all toxicities resolve. After completion of phase II treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 62 patients will be accrued for this study

Inclusion criteria

• For the phase I portion of the study (completed 10/05/08), patients must have cytologically or histologically proven advanced solid tumors for which there is no standard effective therapy available.
• Any number of prior chemotherapy regimens are allowed for the both the Phase I and Phase II portions
• For the phase II portion patients must have cytologically or histologically proven selected stage IIIB (pleural effusion) or IV NSCLC. Patients with NSCLC that have progressed or recurred after first-line therapy for stage IIIA or IIIB may also be considered.
• Patients must have measurable disease by RECIST criteria for the Phase II portion. Disease in previously irradiated sites is considered measurable if there is clear disease progression following radiation therapy. Patients with evaluable disease (bone metastases, pleural fluid, ascites, etc.) may be included in the phase I portion of the trial (completed 10/08/08).
• Must be 18 years of age or older.
• Patients must have a performance status of 0 -2.
• Patients must have an estimated survival of at least 3 months.
• Any prior chemotherapy must have been completed at least 4 weeks prior to start of treatment. For prior mitomycin chemotherapy a 6-week interval is required. Prior radiation must have been completed at least 2 weeks prior to start of therapy. Patients must have recovered from acute reversible medically significant side effects of prior chemotherapy regimens or radiotherapy to NCI-CTC < grade 1 (excluding alopecia). Prior herceptin is allowed.
• Patients must have adequate renal function as documented by a serum creatinine < 1.5 mg/dl or a calculated creatinine clearance of > 45 ml/min (see protocol Appendix D for formula for calculating creatinine clearance).
• Patients must have adequate liver function as documented by serum bilirubin < 1.5 x ULN. AST must be < 2.5 x institutional upper limit of normal.
• Patients must have a pretreatment granulocyte count of >1500/mm3 and platelet count of >100 000/mm3.
• Patients with asymptomatic treated brain metastasis (surgical resection or radiotherapy) may be included if they are neurologically stable and have been off steroids and anticonvulsants for at least 2 weeks.
• All patients must give voluntary written informed consent.
• Patients must be able to take and retain oral medication.
• Documentation of a negative serum pregnancy test.
• Patients on coumadin should have their INR monitored at least once per week or more frequently depending on the investigator's judgment. There have been some case reports of increased INR when coumadin is co-administered with erlotinib.

Exclusion criteria

• Patients who have received erlotinib, cetuximab, or any other EGFR-directed therapy (excluding herceptin).
• Patients with symptomatic brain metastasis or still requiring steroids and anti-convulsants may not be included.
• For the phase II portion of the study, no other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, and any other cancer from which the patient has been disease-free for over five years
• Patients with acute hepatitis or known HIV.
• Patients with active or uncontrolled infection.
• Patients with significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction.
• Patients with prior severe infusion reaction to a monoclonal antibody.
• Any concurrent chemotherapy not indicated in the study protocol or any other investigational agent(s).
• Pregnant or breastfeeding females as the effects of these drugs on the unborn fetus are unknown.