Part 1 Inclusion Criteria:
- Histologically or cytologically confirmed solid tumour refractory to standard therapy or for whom no established therapy exists
- Age >= 18 years
- Karnofsky performance status of >= 70%
- Life expectancy of >= 3 months
- Absolute neutrophil count of >= 1.5 × 109/l, platelet count of ³ 100 × 109/l, haemoglobin level of ³ 10 g/dl (>= 6.2 mmol/l) (prior transfusion is permitted)
- Normal hepatic and renal function as defined by serum bilirubin £ 1.5 times the upper limit of normal, ALT and AST £ 2.5 times the upper limit of normal (£ 5 times the upper limit of normal in the presence of hepatic metastases), creatinine clearance ³ 50 ml/min (by Cockroft-Gault formula)
- Male and female patients
- Written informed consent to participate in the study
Part 1 Exclusion Criteria:
- More than two previous courses of documented myelosuppresive chemotherapy (epidermal growth factor targeted therapy does not constitute a course of chemotherapy)
- CNS metastases (a CT or MRI scan should be done if there is a clinical suspicion of CNS metastases)
- Major surgery, chemotherapy or radiation therapy (except palliative) within 4 weeks of treatment start
- Previous investigational cytotoxic treatment for malignant disease within 30 days before the start of the study
- Any treatment with non-oncological investigational drugs within 30 days before the start of the study
- Pregnancy or breast feeding (all women of childbearing potential must have a pregnancy test before inclusion in the study; post-menopausal women must be amenorrhoeic for at least 12 months). Female patients must use adequate contraceptive protection.
- Fertile males not willing to use contraception or whose female partners are not using adequate contraceptive protection
- Uncontrolled infections
- Clinically significant cardiac impairment or unstable ischaemic heart disease including a myocardial infarction within three months of study entry
- History of alcoholism, drug addiction, or any psychiatric or psychological condition which in the opinion of the investigator would impair study compliance
- History of hypersensitivity to sulphonamides
- Prior severe or unexpected reaction to fluoropyrimidine therapy (which may be explained by dihydropyrimidine dehydrogenase deficiency or hypersensitivity to 5-FU)
- Malabsorption syndrome or other condition which may affect absorption of drug
- Concurrent or previous malignancy of a different tumour type within five years of starting the study except for adequately treated non-melanoma skin cancer or cervical intraepithelial neoplasia
- Treatment within two weeks before the start of the study with any of the following: coumarin anti-coagulants, terfenadine, cisapride, cyclosporin, tacrolimus, theophylline, diazepam, sulphonylurea hypoglycaemics, phenytoin, or carbamazepine
- Legal incapacity
Part 2 Inclusion Criteria:
- Ambulant patients with progressive metastatic CRC who have received prior treatment with 5 FU and irinotecan and/or oxaliplatin either as single agents or in combination. Either 5 FU and/or irinotecan and/or oxaliplatin may have been administered in the adjuvant setting or for the treatment of metastatic disease. Patients who have received both 5-FU and irinotecan or oxaliplatin in the adjuvant setting only must have experienced disease recurrence within one year of starting chemotherapy.
- At least one unidimensionally measurable lesion according to the RECIST criteria
- Age ³ 18 years
- Karnofsky performance status of ³ 70%
- Life expectancy of ³ 3 months
- Absolute neutrophil count of ³ 1.5 × 109/l, platelet count of ³ 100 × 109/l, haemoglobin level of ³ 10 g/dl (³ 6.2 mmol/l) (prior transfusion is permitted)
- Normal hepatic and renal function as defined by serum bilirubin £ 1.5 times the upper limit of normal, ALT and AST £ 2.5 times the upper limit of normal (£ 5 times the upper limit of normal in the presence of hepatic metastases), creatinine clearance ³ 50 ml/min (by Cockroft-Gault formula)
- Male and female patients
- Written informed consent to participate in the study
Part 2 Exclusion Criteria:
- Prior chemotherapy other than 5-FU, irinotecan and/or oxaliplatin
- CNS metastases (a CT or MRI scan should be done if there is a clinical suspicion of CNS metastases)
- Major surgery, chemotherapy or radiation therapy (except palliative) within 4 weeks of treatment start
- Previous investigational cytotoxic treatment for malignant disease within 30 days before the start of the study
- Any treatment with non-oncological investigational drugs within 30 days before the start of the study
- Pregnancy or breast feeding (all women of childbearing potential must have a negative pregnancy test before inclusion in the study; post-menopausal women must be amenorrhoeic for at least 12 months). Female patients must use adequate contraceptive protection.
- Fertile males not willing to use contraception or whose female partners are not using adequate contraceptive protection
- Uncontrolled infections
- Clinically significant cardiac impairment or unstable ischaemic heart disease including a myocardial infarction within three months of study start
- History of alcoholism, drug addiction, or any psychiatric or psychological condition which in the opinion of the investigator would impair study compliance
- History of hypersensitivity to sulphonamides
- Prior severe or unexpected reaction to fluoropyrimidine therapy (which may be explained by dihydropyrimidine dehydrogenase deficiency or hypersensitivity to 5-FU)
- Malabsorption syndrome or other condition which may affect absorption of drug
- Concurrent or previous malignancy of a different tumour type within five years of starting the study except for adequately treated non-melanoma skin cancer or cervical intraepithelial neoplasia
- Treatment within two weeks before the start of the study with any of the following: coumarin anti-coagulants, terfenadine, cisapride, cyclosporin, tacrolimus, theophylline, diazepam, sulphonylurea hypoglycaemics, phenytoin, or carbamazepine
- Legal incapacity
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