All-Oral Vinorelbine/Capecitabine Regimen Is Active and Safe in Metastatic Breast Cancer

August 1, 2005

MILAN, ITALY-In a dosefindingand pharmacokinetic phase Istudy, a team of French and Italianresearchers has found combinationtherapy with oral vinorelbine (Navelbine)and capecitabine (Xeloda) to be

MILAN, ITALY-In a dosefindingand pharmacokinetic phase Istudy, a team of French and Italianresearchers has found combinationtherapy with oral vinorelbine (Navelbine)and capecitabine (Xeloda) to beactive and well tolerated in womenwith metastatic breast cancer (MBC),with no mutual pharmacokinetic interactionseen when both drugs werecoadministered.The study adds to a growing bodyof literature supporting use of the vinorelbine/capecitabine combinationin the MBC setting, and the oral availabilityof both drugs offers the benefitof convenient administration and improvedpatient comfort, Franco Nol,MD, of the European Institute of Oncology,Milan, Italy, and colleaguesreported (abstract 666).Although oral vinorelbine andcapecitabine have distinct mechanismsof action-vinorelbine interacts withtubulin and capecitabine acts throughantimetabolite properties of fluorouracil(5-FU)-the agents share commonmetabolic pathways, with carboxylesterasesinvolved in theirbiotransformation and eliminationfrom the body, he explained. Becauseboth can be administered orally, thecombination is an attractive one forthis very ill patient population, headded.Patient Characteristics andDosing RegimensThe primary objective of the study,Dr. Nol said, was to determine themaximum tolerated dose (MTD) ofthe combination of oral vinorelbinewith capecitabine in patients withMBC. Secondary objectives were todetermine the recommended dose andthe optimal schedule (days 1 and 8 ordays 1, 8, and 15); to define the safetyprofile and dose-limiting toxicities;and to investigate putative pharmacokineticinteractions between oral vinorelbineand capecitabine.A total of 44 women with first-line(n = 35) or second-line (n = 9) MBCentered the study. Their median agewas about 54 years (range, 31 to 73years), the majority (about 60%) werepremenopausal, and they had a Karnofskyperformance status of 90% or100%. Most (86%) had received priorchemotherapy, with about two-thirdshaving received prior (neo)adjuvantchemotherapy. About three-fourths ofthe patients had visceral involvementand two-thirds had involvement oftwo or more organs.The women were distributed intoseven different groups differentiatedby dose level and number of cycles. Atotal of 323 cycles were given, and themedian number of cycles was 7 (range1 to 17). Dr. Nol and colleagues testedthree schedules:

  • Oral vinorelbine on days 1 and8, with capecitabine given on days 1 to14 every 3 weeks;
  • Oral vinorelbine weekly, withcapecitabine given on days 1 to 14every 3 weeks;
  • Oral vinorelbine on days 1 and8, with capecitabine given on days 1 to14 every 4 weeks.
  • Oral vinorelbine was given at a doseof 60 mg/m2 or 80 mg/m2, and thecapecitabine dose ranged from 1,650to 2,500 mg/m2 in divided doses perday.

Toxicity andPharmacokinetic Assessments

Toxicity was graded using NationalCancer Institute criteria. The MTDwas determined to have been reachedwhen at least two of three or two of sixpatients (depending on the dose level)experienced dose-limiting toxicities(DLTs). The DLT was defined duringthe first cycle as any one of the followingtoxicities:

  • Grade 4 neutropenia lasting 7days or longer;
  • Febrile neutropenia;
  • Neutropenic infection (grade 3or 4 infection (concomitant with neutropeniaof grade 3 or higher);
  • Grade 3 thrombocytopenia;
  • Grade 3 or higher nonhematologictoxicity (excluding asthenia; inadequatelytreated nausea, vomiting,or diarrhea; and grade 3 or higher increasein total serum bilirubin level);
  • Delay of 1 week in starting thenext cycle because of toxicity.

For the pharmacokinetic assessment,oral vinorelbine was evaluatedon day 1, when it was coadministeredwith capecitabine, using a populationpharmacokinetic approach (NONMEM).Capecitabine was evaluated onday 1 (in combination with capecitabine)and on day 7 (capecitabine only)using a noncompartmental approach.

Good Tolerability, Responses

The investigators analyzed all 323cycles of chemotherapy. They reportedthat DLTs consisted of neutropenia resultingin a 1-week delay in startingcycle 2 in nine patients and febrile neutropeniain two patients. Grade 3 neutropeniaoccurred in 14 patients (about32%) and about 6% of cycles, Dr. Nolsaid, and grade 4 neutropenia was seenin 12 patients (about 27%) and about4% of cycles. Complications were rare,he added, with only three episodes offebrile neutropenia occurring. No grade4 nonhematologic toxicity was seen.Grade 3 diarrhea occurred in two patients(4.5%) and 0.6% of cycles, andgrade 2 hand-foot syndrome occurredin two patients (4.5%) and 1.2% ofcycles. No grade 3 hand-foot syndromewas seen.A total of 18 responses were observed(3 complete and 15 partialresponses), for a response rate of about41% (95% confidence interval [CI]:26.3% to 56.8%) in the intent-to-treatpopulation. Half of the patients (n =22) had disease control, which theinvestigators defined as a complete orpartial response or no change in thedisease state for at least 6 months.Six patients progressed during thestudy, and two were unevaluable. Inthe 44 patients, progression-free survivaltime (according to investigatorassessment) was 7.7 months (95% CI:5.0 to 11.6).

Dosages Established

With the every-3-week schedule,the investigators established two recommendeddosages: oral vinorelbineat 60 mg/m


weekly plus capecitabineat 2,000 mg/m


per day (divided doses)on days 1 to 14 every 3 weeks; andoral vinorelbine at 60 mg/m


on days1 and 8 plus capecitabine at 2,250mg/m


per day (divided doses) ondays 1 to 14 every 3 weeks. For theevery-4-week schedule, the recommendeddosage was oral vinorelbineat 80 mg/m


on days 1 and 8 pluscapecitabine at 2,000 mg/m


per dayon days 1 to 14 every 4 weeks; Dr.Nol pointed out that none of theq4wk dose levels reached the criteriafor MTD, therefore the regimen chosensimply reflects the highest doseintensities for both oral vinorelbineand capecitabine. No drug-drug pharmacokineticinteraction was seenwhen the drugs were coadministered.In conclusion, Dr. Nol noted that"the combination of oral vinorelbineand capecitabine is safe and easy toadminister in an outpatient setting"and that "this all-oral combinationregimen may offer a good alternativeto the intravenous route for patientswith MBC. Based on these promisingresults, a phase II study has been initiatedusing oral vinorelbine at 60mg/m


week with capecitabine at2,000 mg/m


per day on days 1 to 14every 3 weeks as first-line chemotherapyin women with MBC." (Seesidebar on page 37 discussing the statusof oral vinorelbine in the UnitedStates.)