Patient selection
All patients had a baseline history and full physical examination with radiologic and laboratory evaluation. Patients with measurable or clinically assessable histologically confirmed advanced solid tumours who hade failed to response to standard therapy or for whom no standard therapy was available were elegible for this study. An age between 18 and 80 years, an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 and a life expectance > 3 months were required. Bone marrow function requirements included an absolute neutrophil count ≥ 1500/mm3, a platelet count ≥ 100000/mm3 and hemoglobin ≥ 10.0 g/100 ml. Preserved renal function (serum creatinine ≤ 1.6 mg/dL, normal creatinine clearance), hepatic function (total bilirubin ≤ 1.5 mg/dL, AST and ALT ≤ 2,5 times normal without hepatic metastasis and ≤ 4 times normal with hepatic metastasis; serum alkaline phosphatase < 2.5 times the upper limit of normal or < five times the upper limit of normal if liver metastases were present or < 10 times the upper limit of normal if bone metastases were present) and cardiac function were required.
Major exclusion criteria included cytotoxic or radiotherapy treatment within the previous 4 weeks (6 weeks if the previous therapy included a nitrosourea or mitomycin). Concomitant use of amiodarone, ketoconazole, itraconazole, diltiazem, verapamil, barbiturates, warfarin was not permitted. Pregnant or breast feeding woman or patients with uncontrolled severe disease were excluded. Patients with significant stomach, small intestine, liver, or kidney disease likely to affect drug absorption or metabolism were excluded from the study. Patients with history of coagulopathy or with nervous central system tumour or metastasis were excluded too. All patients were required to provide written informed consent prior to initiation of treatment, after a complete and opportune explanation. Local ethics committee approval was obtained. Women in fertile age had to be informed about risks incurring in case of pregnancy. The trial was conducted in accordance with the declaration of Helsinki. Patients were excluded if adequate follow-up was not possible (environmental or geographic difficulties, no compliance to undergo necessary clinical-instrumental investigations, etc.). The institution that granted ethical approval for the study was University Campus Bio-Medico of Rome. A specific informed consent was obtained from each participant before study entry.
Study design
This is an open-label, single-center, nonrandomized, dose-escalating phase I study. All laboratory tests required to assess eligibility had to be completed within 7 days before start of treatment.
Capecitabine was administered orally according to following schedule: 1/4 of dose at 8:00 a.m.; 1/4 of dose at 6:00 p.m. and 1/2 of dose at 11:00 p.m. each day for 14 consecutive days (Days 1–14), followed by a 7-day rest period. Each treatment cycle is repeated every 21 days. Capecitabine was supplied as film-coated Xeloda tablets in two dosages strengths, 150-mg and 500-mg tablets administered not in fasting conditions, swallowed with water. No specific pre-medication for nausea and/or vomiting was provided (anticipated). A preventive protonic pump inhibitor (PPI) was advised to gastro-protective aim.
Dose-escalation and definition of study end points
In phase I study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer, Mackean et al [17] used a starting dose level of 502 to 3,514 mg/mq daily, following a modified Fibonacci scheme. Since 3,000 mg/mq daily was not tolerated, they defined 2,510 mg/mq daily as the dose for phase II studies. Considering these results, the starting dose level in our phase I trial was 1750 mg/mq daily. The subsequent dose levels foreseen were: 2,000, 2,250, 2,500, 2,750, 3,000 mg/mq daily. In the absence of dose-limiting toxicities, only three patients were to be treated at the first two dose levels. At the third and subsequent dose levels, it was planned to treat at least six patients because it was anticipated that these dose levels may be therapeutic or associated with toxicity. Patients were seen weekly and toxicity was assessed by the National Cancer Institute of Canada Common Toxicity Criteria (NCI-CTC). For purposes of determining the MTD, only DLTs occurring during the first two cycles of therapy were considered. The MTD was defined as the dose level at which no more than one out of six patients experienced a DLT. Once this dose level was established, additional patients will be enrolled (maximum of 12) to gain additional experience with the combination. The MTD represents the dose recommended for further studies. DLTs were defined as any of the following: grade 4 neutropenia lasting at least 3 days or grade 3 or 4 neutropenia associated with fever ≥ 38.1°C; grade 4 thrombocytopenia lasting at least 3 days, grade 4 anemia; any grade 3 or 4 nonhematologic toxicity except alopecia, gastrointestinal toxicity, and palmar-plantar erythrodysesthesia (hand-foot syndrome); grade 3 or 4 nausea, vomiting, or mucositis; grade 3 and 4 diarrhea or a second occurrence of grade 2 diarrhea; grade 2 or 3 hand-foot syndrome not reduced to grade 1 before the start of cycle 2; delay of ≥ 14 days in initiating the second or the third cycle of therapy because of persistent toxicity of grade 2 or higher.
Dose modifications
The capecitabine dose was interrupted or modified in spite of observed toxicity. There was no dose modification for grade 1 toxicity. For grade 2 toxicity that persisted despite symptomatic treatment, capecitabine was withheld until resolution to grade 0 or 1 and then restarted at the same dose. If the grade 2 toxicity recurred or any grade 3 toxicity, capecitabine was withheld until resolution to grade 0 or 1 and then restarted at the preceding dose. For grade 4 toxicity, capecitabine was discontinued unless considered by the investigator to be in patient's best interest, e.g. a responding patient, to continue at a lower dose level. In any case, patients who experienced DLT could be continued on treatment at a modified dose at the discretion of the treating physician if they seemed to be benefiting from the therapy.
Pretreatment and follow-up studies
All patients had a baseline history and full physical examination with radiologic and laboratory evaluations. History, physical examination, and laboratory tests were repeated on day 1 of each cycle of therapy. Assessment of toxicity and hematology tests were performed weekly during each cycle of therapy [during and after the study period]. Response was assessed after two cycles of treatment (day 43) according to RECIST response criteria [20]. Responding patients or those with stable disease could continue treatment for a further four cycles of intermittent chronomodulated therapy with assessment of tumor response after four and six cycles (day 85 and 127, respectively). Patients who responded or had stable disease after six cycles could continue treatment at the discretion of the investigator.