ANN ARBOR, MichiganGiving oral capecitabine (Xeloda) plus IV
vinorelbine (Navelbine) in flat doses unadjusted for body surface area (BSA) is
a feasible, convenient strategy that has good activity in previously treated
metastatic breast cancer, according to results of a phase I/II study. The
findings lay the groundwork for investigating a potential flat-dosed, all-oral
regimen, according to Anne F. Schott, MD, assistant professor of internal
medicine with the University of Michigan Comprehensive Cancer Center at Ann
"Right now, we know what the maximum tolerated dose (MTD) is,
we know this is safe and effective, and we know that this is a potential
all-oral regimen, but we will have to repeat the study using oral vinorelbine,"
Dr. Schott said.
A parallel study is looking at the variable expression of
enzymes associated with drug metabolism, and investigators hope to correlate
that data with pharmacokinetic findings of a breath test that can serve as a
surrogate measure of drug clearance.
Flat Dosing Scheme
Body surface area is used to calculate dose escalation in many
phase I chemotherapy studies, even though clearance of many agents such as
capecitabine and vinorelbine does not correlate well with BSA, Dr. Schott
noted. Furthermore, calculating BSA can introduce prescribing errors, and may
be difficult to do with oral formulations of drugs.
Accordingly, investigators evaluated a fixed dose of
capecitabine (1,500 mg twice daily for 14 days, every 3 weeks) with a dose
escalation of vinorelbine using a flat dosing scheme (starting at 20 mg IV on
days 1 and 8, every 3 weeks) as second-line or third-line treatment in 23
Caucasian women with metastatic breast cancer (mean age 50, range 28 to 72).
Of 16 women with measurable disease, there were two complete
responses and five partial responses, for an overall response rate of 43.8%.
Generally Well Tolerated
Treatment was generally well tolerated, according to Dr.
Schott. Grade 4 neutropenia occurred at the highest vinorelbine dose level (50
mg IV days 1 and 8), while febrile neutropenia occurred in four patients at
differing dose levels. Grade 3 nonhematologic toxicity included peripheral
neuropathy in one patient and elevations in hepatic aminotransferases in
another patient. The only nonhematologic Grade 4 toxicity was thromboembolism,
which occurred in two patients.
Investigators determined the MTD to be vinorelbine 40 mg IV on
days 1 and 8 in combination with capecitabine 1,500 mg twice daily every 14
Investigators will continue to strive for an all-oral
combination chemotherapy as a step up for patient convenience, particularly for
patients who must travel a long way to receive treatment. "There may even be a
role, if this is highly active, to use an all-oral regimen as adjuvant therapy,
which I think would be terrific," Dr. Schott said.
Dr. Schott and colleagues also analyzed patients for genetic
polymorphisms in metabolizing enzymes including CYP3A5, which is
polymorphically expressed in Caucasians. Specifically, single-nucleotide
polymorphisms in CYP3A5*3 and CYP3A5*6 alleles can result in absence of CYP3A5
in tissue (Kuehl P et al: Nat Genet 27: 383-91, 2001).
None of the patients studied had wild-type CYP3A5 at both
alleles. "We are waiting for pharmacokinetics data to see if there are any
correlations with drug clearance and genotype," Dr. Schott said.
Vinorelbine pharmacokinetics were performed for all patients.
Investigators modeled area under the concentration-time curve (AUC) of
vinorelbine against CYP3A4 metabolism as measured by an erythromycin breath
test. This breath test predicts steady state trough blood levels of drugs that
are CYP3A4 substrates, and can serve as a surrogate measure of CYP3A4 drug
metabolism. Previously, Dr. Schott and colleagues demonstrated that an
erythromycin breath test could predict docetaxel (Taxotere) metabolism.