Pharmocokinetic/Pharmacodynamic (PK/PD) Study of the Combination Cetuximab/Gefitinib

Phase 1 Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of the Combination of Cetuximab (C-225), a Chimeric Monoclonal Antibody Against the Epidermal Growth Factor Receptor (EGFR), and Gefitinib (ZD1839), a Selective EGFR Tyrosine Kinase Inhibitor, in Patients With Advanced Cancer

This is an open-label, phase 1, non-randomised, non-controlled trial, carried out in two centres on patients with advanced cancer expressing EGFR. Primary objective is the determination of the maximum tolerated dose (MTD) and recommended dose (RD) of the combination of intravenous Cetuximab and oral Gefitinib.

Between 36 and 66 patients will be enrolled depending on the number of dose levels which can be completed. Patients will have histologically confirmed EFGR-expressing solid malignant tumours (colorectal cancer, head and neck cancer and NSCLC), which did not respond to standard therapy or for which no suitable therapy exists.

Inclusion Criteria:

• Written informed consent prior to inclusion
• Confirmed histological diagnosis of non-resectable, solid, malignant, EGFR expressing tumours of the following types: colorectal cancer, head and neck cancer and non-small cell lung cancer (NSCLC). Advanced clinical stage III/IV which did not respond to standard therapy or for which no suitable therapy exists
• Patients with at least one evaluable lesion (evaluable disease) by the RECIST criteria
• Availability of tumour tissue, whether from primary tumour or metastasis to determine EGFR expression
• Viability of establishing outpatient treatment
• Effective contraception for patients of both sexes if there is a risk of conception
• Karnofsky performance status greater than 70 %
• Life expectancy > 12 weeks
• Adequate renal function (creatinine < 1.5 x UNL), liver function (bilirubin < 1.5 x UNL, ALT/AST < 2.5 x UNL o <5 x UNL if hepatic metastasis) and adequate bone marrow (leucocytes > 3000/µl, absolute neutrophil count > 1500/µl, platelets > 100,000/µl, haemoglobin > 9 g/dl)
• Patients must not have undergone chemotherapy, radiotherapy or major surgery during the 3 weeks before the beginning of the study, and they must have recovered from the relevant secondary effects of previous treatments
• Patients agree to have a new biopsy after two weeks.

Exclusion Criteria:

• Patients with any symptom of bowel obstruction and/or inflammatory bowel disease
• Previous therapy with anti-EGFR drugs
• Patients with known cerebral metastasis
• Patients with known active and uncontrolled infections
• Severe uncontrolled organic dysfunctions or metabolic disorders
• Patients unable to give informed consent
• Patients who do not wish to or who cannot undergo the specific study treatments and the study procedures
• Pregnancy or breastfeeding
• Patient participation in another clinical trial during the previous 30 days
• Patients with known drug and/or alcohol abuse
• Known hypersensitivity to chimeric MoAbs or pretreatment with MoAbs
• Any other malignant tumour in the last two years or previously diagnosed malignant tumour if there is no guarantee that it is under complete control, except for suitably treated in situ cervical carcinoma or basocellular carcinoma
• Known severe hypersensitivity to ZD1839 or any of the excipients of this product
• Any evidence of clinically active interstitial lung disease (patients with chronic, stable, radiographic changes who are asymptomatic need not to be excluded)
• Any unresolved chronic toxicity greater than common toxicity criteria (CTC) grade 2 from previous anticancer therapy
• Concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, or St John's Wort