MILAN, ITALY-In a dosefinding and pharmacokinetic phase I study, a team of French and Italian researchers has found combination therapy with oral vinorelbine (Navelbine) and capecitabine(Drug information on capecitabine) (Xeloda) to be active and well tolerated in women with metastatic breast cancer (MBC), with no mutual pharmacokinetic interaction seen when both drugs were coadministered. The study adds to a growing body of literature supporting use of the vinorelbine/ capecitabine combination in the MBC setting, and the oral availability of both drugs offers the benefit of convenient administration and improved patient comfort, Franco Nolé, MD, of the European Institute of Oncology, Milan, Italy, and colleagues reported (abstract 666). Although oral vinorelbine and capecitabine have distinct mechanisms of action-vinorelbine interacts with tubulin and capecitabine acts through antimetabolite properties of fluorouracil(Drug information on fluorouracil) (5-FU)-the agents share common metabolic pathways, with carboxylesterases involved in their biotransformation and elimination from the body, he explained. Because both can be administered orally, the combination is an attractive one for this very ill patient population, he added. Patient Characteristics and Dosing Regimens The primary objective of the study, Dr. Nolé said, was to determine the maximum tolerated dose (MTD) of the combination of oral vinorelbine with capecitabine in patients with MBC. Secondary objectives were to determine the recommended dose and the optimal schedule (days 1 and 8 or days 1, 8, and 15); to define the safety profile and dose-limiting toxicities; and to investigate putative pharmacokinetic interactions between oral vinorelbine and capecitabine. A total of 44 women with first-line (n = 35) or second-line (n = 9) MBC entered the study. Their median age was about 54 years (range, 31 to 73 years), the majority (about 60%) were premenopausal, and they had a Karnofsky performance status of 90% or 100%. Most (86%) had received prior chemotherapy, with about two-thirds having received prior (neo)adjuvant chemotherapy. About three-fourths of the patients had visceral involvement and two-thirds had involvement of two or more organs. The women were distributed into seven different groups differentiated by dose level and number of cycles. A total of 323 cycles were given, and the median number of cycles was 7 (range 1 to 17). Dr. Nolé and colleagues tested three schedules:

• Oral vinorelbine on days 1 and 8, with capecitabine given on days 1 to 14 every 3 weeks;
• Oral vinorelbine weekly, with capecitabine given on days 1 to 14 every 3 weeks;
• Oral vinorelbine on days 1 and 8, with capecitabine given on days 1 to 14 every 4 weeks.
• Oral vinorelbine was given at a dose of 60 mg/m² or 80 mg/m², and the capecitabine dose ranged from 1,650 to 2,500 mg/m² in divided doses per day.

Toxicity and Pharmacokinetic Assessments Toxicity was graded using National Cancer Institute criteria. The MTD was determined to have been reached when at least two of three or two of six patients (depending on the dose level) experienced dose-limiting toxicities (DLTs). The DLT was defined during the first cycle as any one of the following toxicities:

• Grade 4 neutropenia lasting 7 days or longer;
• Febrile neutropenia;
• Neutropenic infection (grade 3 or 4 infection (concomitant with neutropenia of grade 3 or higher);
• Grade 3 thrombocytopenia;
• Grade 3 or higher nonhematologic toxicity (excluding asthenia; inadequately treated nausea, vomiting, or diarrhea; and grade 3 or higher increase in total serum bilirubin level);
• Delay of 1 week in starting the next cycle because of toxicity.

For the pharmacokinetic assessment, oral vinorelbine was evaluated on day 1, when it was coadministered with capecitabine, using a population pharmacokinetic approach (NONMEM). Capecitabine was evaluated on day 1 (in combination with capecitabine) and on day 7 (capecitabine only) using a noncompartmental approach. Good Tolerability, Responses The investigators analyzed all 323 cycles of chemotherapy. They reported that DLTs consisted of neutropenia resulting in a 1-week delay in starting cycle 2 in nine patients and febrile neutropenia in two patients. Grade 3 neutropenia occurred in 14 patients (about 32%) and about 6% of cycles, Dr. Nolé said, and grade 4 neutropenia was seen in 12 patients (about 27%) and about 4% of cycles. Complications were rare, he added, with only three episodes of febrile neutropenia occurring. No grade 4 nonhematologic toxicity was seen. Grade 3 diarrhea occurred in two patients (4.5%) and 0.6% of cycles, and grade 2 hand-foot syndrome occurred in two patients (4.5%) and 1.2% of cycles. No grade 3 hand-foot syndrome was seen. A total of 18 responses were observed (3 complete and 15 partial responses), for a response rate of about 41% (95% confidence interval [CI]: 26.3% to 56.8%) in the intent-to-treat population. Half of the patients (n = 22) had disease control, which the investigators defined as a complete or partial response or no change in the disease state for at least 6 months. Six patients progressed during the study, and two were unevaluable. In the 44 patients, progression-free survival time (according to investigator assessment) was 7.7 months (95% CI: 5.0 to 11.6). Dosages Established With the every-3-week schedule, the investigators established two recommended dosages: oral vinorelbine at 60 mg/m² weekly plus capecitabine at 2,000 mg/m² per day (divided doses) on days 1 to 14 every 3 weeks; and oral vinorelbine at 60 mg/m² on days 1 and 8 plus capecitabine at 2,250 mg/m² per day (divided doses) on days 1 to 14 every 3 weeks. For the every-4-week schedule, the recommended dosage was oral vinorelbine at 80 mg/m² on days 1 and 8 plus capecitabine at 2,000 mg/m² per day on days 1 to 14 every 4 weeks; Dr. Nolé pointed out that none of the q4wk dose levels reached the criteria for MTD, therefore the regimen chosen simply reflects the highest dose intensities for both oral vinorelbine and capecitabine. No drug-drug pharmacokinetic interaction was seen when the drugs were coadministered. In conclusion, Dr. Nolé noted that "the combination of oral vinorelbine and capecitabine is safe and easy to administer in an outpatient setting" and that "this all-oral combination regimen may offer a good alternative to the intravenous route for patients with MBC. Based on these promising results, a phase II study has been initiated using oral vinorelbine at 60 mg/m² week with capecitabine at 2,000 mg/m² per day on days 1 to 14 every 3 weeks as first-line chemotherapy in women with MBC." (See sidebar on page 37 discussing the status of oral vinorelbine in the United States.)