Vinorelbine/Paclitaxel Combination Studied in Treatment of Metastatic Breast Cancer Patients

June 1, 1995

The combination of vinorelbine tartrate (Navelbine) and paclitaxel (Taxol) appears promising for the treatment of patients with metastatic breast cancer, including some patients who had previously receivedanthracycline-based adjuvant therapy,

The combination of vinorelbine tartrate (Navelbine) and paclitaxel(Taxol) appears promising for the treatment of patients with metastaticbreast cancer, including some patients who had previously receivedanthracycline-basedadjuvant therapy, according to researchers at the M. D. AndersonCancer Center in Houston. Preliminary results of the phase I studywere recently reported at the annual meeting of the American Associationof Cancer Research (AACR).

The phase I study, the first to combine these two drugs to treatadvanced breast cancer, was conducted to evaluate dosing and thecombined effect of vinorelbine and paclitaxel on 25 patients untreatedfor metastatic breast cancer. In previous preclinical studies,the two drugs, when added simultaneously to breast and lung cancertissue cultures, had synergistic antitumor effects, despite exhibitingdifferent mechanisms of action on the cell division process.

"This is a progress report for a combination that has greatpotential as an effective treatment option for advanced breastcancer, especially as an alternative for patients that are resistantto standard therapy such as doxorubicin or the combination ofCytoxan, methotrexate, and fluorouracil (CMF)," said leadinvestigator Gabriel Hortobagyi, MD, Department of Breast andGynecologic Medical Oncology at M. D. Anderson. "Individually,both Navelbine and Taxol are exciting in treating breast cancer.We are hopeful this combination will improve the treatment ofthese patients substantially," Dr. Hortobagyi added.

The agents were given simultaneously by 3-hour infusion on thefirst day of treatment and repeated every 21 days, with dosesstarting at 36 mg/m² for vinorelbine, 175 mg/m² forpaclitaxel. The maximum tolerated dose was 25 mg/m² for vinorelbineand 150 mg/m² for paclitaxel. At this dose and schedule,the combination therapy was moderately well-tolerated. Neutropenicfever was encountered during 19 of the 115 courses (16%). Twopatients experienced reversible grade 3 pelvic floor pain, andgrade 3 paresthesia of the hands and feet was reported in fivepatients. Granulocyte colony-stimulating factor (G-CSF) supportwas not given prophylactically with the initial treatment.

"As a first step, the combination at this dosage and scheduleis reasonably well-tolerated and effective," said Dr. Hortobagyi."As we continue its evaluation, our next step is to developa schedule that will enable us to intensify treatment and increaseefficacy while maintaining its safety profile."

Researchers also determined the combination's maximum-tolerateddose when combined with G-CSF:vinorelbine at 36mg/m2 and paclitaxelat 150mg/m2 when given every 3 weeks.

Evaluation is ongoing to determine the flexibility of this dosagegiven on a 2-week schedule.

Vinorelbine is a semi-synthetic vinca alkaloid. In December 1994,the FDA approved vinorelbine for marketing as a first-line treatmentfor ambulatory patients with unresectable, advanced non-small-celllung cancer. Paclitaxel is a chemotherapeutic agent in the taxaneclass.

Granulocytopenia, a reversible decrease in the white blood cellcount, is the dose-limiting toxicity for both drugs. As with othercancer drugs that suppress white blood cell counts, vinorelbineand paclitaxel are associated with an increased risk of infection,which may require hospitalization and can sometimes be fatal.

In previous clinical studies with vinorelbine as a single agent,granulocytopenia is the most commonly reported and important sideeffect, and is usually manageable with patient monitoring andreductions or delays in dosing.

Overall, vinorelbine has been found to have a favorable side effectprofile in clinical trials. Side effects often considered to beof greatest importance and concern to patients, such as nausea,vomiting, and alopecia, were reported as mild to moderate in intensity.Other clinical studies are also ongoing in lung, breast, ovarian,and prostate cancer.