Trial Lays Groundwork for All-Oral Capecitabine/Vinorelbine

ANN ARBOR, Michigan—Giving 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 Arbor.

"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 days.

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.

Pharmacokinetics Data

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.