Docetaxel Combined With Vinorelbine: Phase I Results and New Study Designs

June 1, 1997

This was a phase I dose-finding and pharmacokinetic study of vinorelbine (Navelbine) and docetaxel (Taxotere) as first-line chemotherapy for metastatic breast cancer. Vinorelbine dose, 20 or 22.5 mg/m², on days 1 and 5, was followed on day 1 by docetaxel every 21 days, in doses increasing from 60 to 100 mg/m².

ABSTRACT: This was a phase I dose-finding and pharmacokinetic study of vinorelbine (Navelbine) and docetaxel (Taxotere) as first-line chemotherapy for metastatic breast cancer. Vinorelbine dose, 20 or 22.5 mg/m², on days 1 and 5, was followed on day 1 by docetaxel every 21 days, in doses increasing from 60 to 100 mg/m². Two maximum tolerated doses were reached, the first at 75 mg/m² of docetaxel and 22.5 mg/m² of vinorelbine, and the second at 100 mg/m² of docetaxel and 20 mg/m² of vinorelbine. Symptomatic peripheral neuropathy was not observed. The recommended doses for phase II studies are 75 to 85 mg/m² of docetaxel on day 1 and 20 mg/m² of vinorelbine on days 1 and 5, every 3 weeks. The treatment regimen, which included 3-day corticosteroid prophylaxis, resulted in only mild fluid retention. Responses were seen at all dose levels, with an 80% overall response rate at the higher recommended dose; the overall response rate for patients at all dose levels was 66%. A high rate of response, including a complete response, was observed in patients with liver metastases. [ONCOLOGY 11(Suppl 6):29-31, 1997]

Introduction

The large number of patients with metastatic breast cancer resistantto anthracyclines suggests a need to develop nonanthracycline combinationchemotherapies. The differing mechanisms of action of docetaxel (Taxotere)and vinorelbine (Navelbine) suggest a rationale for their use in combination.Docetaxel promotes tubulin polymerization and stabilizes the formed microtubules.[1]In contrast, vinorelbine inhibits the polymerization of tubulin into microtubules.[2]Both compounds have demonstrated high antitumor activity as first-linechemotherapy in metastatic breast cancer, with overall response rates of61% for docetaxel and 41% to 50% for vinorelbine.

In addition, preclinical research has shown a therapeutic synergy betweenthe two drugs in mice bearing subcutaneous transplantable tumors.[3] Moreover,the combination toxicity index was between 1.8 and 1.55, indicating thatapproximately 78% to 90% of the maximum tolerated dose of the two drugscould be administered together without additional toxicity.

These observations led to a phase I dose-finding study of the combinationof docetaxel and vinorelbine, conducted at Centre René Gauducheau,Nantes, France.[4] Ongoing and future research will compare the docetaxel/vinorelbinecombination with other regimens routinely used as first-line therapy forpatients with advanced breast cancer or as second-line therapy after thefailure of anthracycline treatment.

Objectives

The objectives of this phase I study were to determine the dose-limitingtoxicities and the recommended dose for further phase II trials. A secondaryobjective was to define the major pharmacokinetic parameters in order toassess potential interactions between the two drugs when administered incombination.

Patients and Study Procedures

Patients

All patients had evaluable and/or measurable metastatic breast cancer,with no prior chemotherapy for advanced disease. Previous adjuvant chemotherapywas allowed, provided that there was a 1-year interval between the endof adjuvant chemotherapy and entry into the study. Performance status onthe Eastern Cooperative Oncology Group (ECOG) scale was 2 or less, withnormal hematologic, liver, and renal function. All patients gave writtenconsent.

Treatment

Vinorelbine was administered as a 20-minute intravenous infusion ondays 1 and 5, followed by docetaxel as a 1-hour infusion on day 1, repeatedevery 3 weeks. Vinorelbine doses were 20 or 22.5 mg/m², while docetaxeldoses increased from 60 to 100 mg/m². At least three patients wereaccrued at each dose level (Table 1).

Patients received 3 days of corticosteroid premedication (8 mg of oraldexamethasone every 6 hours, starting the day before therapy and continuingthrough the day after). They also received 500 mg of diosime (Daflon),2 g/d, starting the day before the first infusion and continuing throughthe entire course of therapy. (Diosime is a flavonoid approved in Franceas a "vascular tonic" to stabilize capillary endothelium.)

Assessments

Dose-limiting toxicities were defined as grade 4 absolute neutrophilcount for more than 7 days, febrile neutropenia for more than 3 days, grade3 or 4 infection, grade 4 thrombocytopenia, and/or any other grade 3 or4 adverse event, except anemia or alopecia. The maximum tolerated dosewas defined as the dose at which a dose-limiting toxicity occurred in twoor more of three patients entered, or in three or more of six patientsentered.

Neurologic function was evaluated prospectively by the same neurologistat baseline, every two cycles during the study, and at the end of the study.This included a clinical examination and measurement of nerve conductionvelocities.

Results

Patient Characteristics

Over 1 year, 29 patients were enrolled in the study. The majority ofpatients had visceral disease, mainly liver involvement.

Safety

Table 1 summarizes the overall safetyresults. The incidence of grade 4 neutropenia was high at all dose levels,with febrile neutropenia highest at level III. Grade 3 or 4 mucositis occurredin two patients at level III and in one patient each at levels IV and V.Symptomatic peripheral neuropathy was not observed. Neurologic adverseevents were no higher than grade 1. The treatment regimen, which includedcorticosteroid prophylaxis, resulted in only mild fluid retention.

Table 2 summarizes the dose-limitingtoxicities, which were first observed at level III. At level III, three(75%) of the four patients had dose-limiting toxicities. Dose-limitingtoxicities were also high at level V (four of six patients; 67%).

Two maximum tolerated doses were reached. The first, at 75 mg/m²of docetaxel and 22.5 mg/m² of vinorelbine, included the dose-limitingtoxicities of febrile neutropenia plus mucositis (two patients) or febrileneutropenia alone (one patient). The second maximum tolerated dose wasreached at 100 mg/m² of docetaxel and 20 mg/m² of vinorelbine;dose-limiting toxicities were febrile neutropenia, febrile neutropeniaplus mucositis, febrile neutropenia plus sepsis, or grade 4 mucositis (onepatient each).

From these results, the recommended doses for phase II studies weredetermined to be 75 to 85 mg/m² of docetaxel on day 1 and 20 mg/m²of vinorelbine on days 1 and 5, every 3 weeks (level IV); at these doses,only one dose-limiting toxicity occurred in 10 patients.

Pharmacokinetics and Efficacy

Based on the maximum concentration, bioavailability, and clearance data,the pharmacokinetics of docetaxel and vinorelbine were not altered by combiningthem at the doses and schedule studied. The data indicate that under theseconditions the two drugs can be administered together without any relevantdrug interactions.

The responses observed were promising, with an 80% overall responserate at the higher recommended dose, 85 mg/m² of docetaxel on day1 and 20 mg/m² of vinorelbine on days 1 and 5, and a 67% overall responserate at 75 mg/m²of docetaxel and 20 mg/m² of vinorelbine at thesame schedule. At all dose levels, the overall response rate was 66%. Itis noteworthy that in the 11 patients with evaluable liver metastases,the overall response rate was 82%, with one complete response.

Discussion

These results correlate well with the preclinical data. Bissery et al[2,3]performed three experiments in mice: one in the MA/16 model and two withMA 13/C to determine the mean combination toxicity index; ie, the sum ofthe percentages of the highest nontoxic doses of each of the agents usedin the combination. They found a mean combination toxicity index of 1.79for docetaxel/vinorelbine.

When considering the recommended dose in humans--ie, 75 to 85 mg/m²of docetaxel on day 1 and 20 mg/m² of vinorelbine on days 1 and 5of a 21-day course--the combined dosages correspond to 87% of the actualdose intensity of docetaxel (98 mg/m² every 3 weeks) and 95% of theactual dose intensity of vinorelbine (21 mg/m²/wk). This correspondsto an overall combined toxicity index of 1.82, which correlates well withthe preclinical data.

Future study designs will continue to investigate the combination ofdocetaxel and vinorelbine, as first-line therapy for patients with advancedbreast cancer, and as second-line therapy after the failure of an anthracycline-containingtreatment.

Future investigations may attempt to raise the rate of complete responsesby increasing the dose density to every 14 days, dosing with additionalgranulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) orby administering several therapies alternately or sequentially.

Conclusions

Based on the results of this trial, the recommended dosage regimen forthe docetaxel/vinorelbine combination in phase II studies is docetaxel,75 to 85 mg/m²on day 1, and vinorelbine, 20 mg/m² on days 1 and5, every 3 weeks. This combination will play an important role in the treatmentof patients with advanced breast cancer.

References:

1. Gelmon K: The taxoids: Paclitaxel and docetaxel. Lancet 344:1267-1272,1994.

2. Bissery MC, Azli N, Fumoleau P, et al: Docetaxel in combination withvinorelbine: preclinical-clinical correlation (abstract). Proc Am Soc ClinOncol 15:487 1550, 1996.

3. Bissery MC, Vrignaud P, Bayssas M, et al: Docetaxel (RP 56976, docetaxel)efficacy as a single agent or in combination against mammary tumors inmice (abstract 1946). Proc Am Assoc Cancer Res 35:327, 1994.

4. Fumoleau P, Delecroix V, Perrocheau G, et al: Final results of aphase I dose finding and pharmacokinetic (P.K.) study of docetaxel in combinationwith vinorelbine in metastatic breast cancer (abstract 606P). Ann Oncol7(suppl 5):126, 1996.