Docetaxel in Combination With Doxorubicin: A Phase I Dose-Finding Study

June 1, 1997

This phase I dose-finding study examined the effects of the combination of doxorubicin and docetaxel (Taxotere) in 42 women with metastatic breast cancer. The combination was studied at six different dosing levels. The maximum tolerated doses were defined as doxorubicin, 50 mg/m², and docetaxel, 85 mg/m², with sepsis as the dose-limiting toxicity.

ABSTRACT: This phase I dose-finding study examined the effects of the combination of doxorubicin and docetaxel (Taxotere) in 42 women with metastatic breast cancer. The combination was studied at six different dosing levels. The maximum tolerated doses were defined as doxorubicin, 50 mg/m², and docetaxel, 85 mg/m², with sepsis as the dose-limiting toxicity. Activity was observed at all dose levels, especially at the highest dose levels (50/60, 50/75, 50/85, and 60/60 mg/m²), with a response rate of 81% (95%; confidence interval, 62.5% to 92.5%) in patients treated at these dose levels. The response rate in patients with visceral disease was 74%, and 82% in patients with liver metastasis. Adjuvant chemotherapy with or without anthracyclines did not affect the response rate. The recommended doses were doxorubicin, 50 mg/m², and docetaxel, 75 mg/m², or 60 mg/m² of both drugs, administered on day 1 every 3 weeks, without granulocyte-colony stimulating factor (G-CSF, filgrastim [Neupogen]) support. Neutropenia was the only grade 3 or 4 adverse event. There were no cases of congestive heart failure, a significant decrease in left-ventricular ejection fraction, or interruption of treatment because of fluid retention. [ONCOLOGY 11(Suppl 6):17-20, 1997]

Introduction

Doxorubicin has long been recognized as one of the most effective singleagents in the treatment of metastatic breast cancer, and doxorubicin combinationsare among the most active in advanced or metastatic disease.[1] Docetaxel(Taxotere) is highly active as a first- or second-line agent in the samesetting.[2] Moreover, there is no clinical cross-resistance between thetwo drugs.[3]

These observations were the rationale for a feasibility study usingthe two drugs in combination.[4,5] The objectives of the study were toascertain the dose-limiting toxicity, the maximum tolerated doses of thesedrugs in combination, and the recommended doses for future phase II andIII trials, and to establish a safety profile of this combination therapy.

Patients and Methods

Patients

To be eligible, patients had to have metastatic breast cancer with measurableand/or evaluable disease. Other criteria included no prior chemotherapyfor metastatic disease and a World Health Organization performance status2 or less. Prior chemotherapy was allowed only if it occurred at the adjuvantstage, at least 1 year before entry into the study, with a cumulative doseof less than 300 mg/m² of doxorubicin, less than 500 mg/m² ofepirubicin, or less than 500 of mg/m² pirarubicin. Patients were requiredto have normal baseline left-ventricular ejection fraction; during thetrial, ejection fraction was monitored every two cycles, and then everycycle after a cumulative dose of anthracycline 400 or more mg/m² wasreached.

Treatment

Every 3 weeks, doxorubicin was administered to outpatients as an intravenousbolus over 15 minutes, followed after 1 hour by docetaxel as a 1-hour infusion.No prophylactic supporting granulocyte colony-stimulating factor (G-CSF,filgrastim [Neupogen]) was used.

Doxorubicin doses increased from 40 mg/m² at levels I and II, to50 mg/m² at levels III through V, and to 60 mg/m² at level VI(Table 1). Docetaxel doses increased from50 mg/m² at level I, to 60 mg/m² at levels II and III, 75 mg/m²at level IV, 85 mg/m² at level V, and dropped to 60 mg/m² atlevel VI. Cumulative doses were monitored, and doxorubicin administrationwas stopped at a cumulative dose of 550 mg/m².

To avoid hypersensitivity reactions, patients received prophylacticpremedication consisting of dexamethasone, cetirizine (an H1-blocker),ranitidine, and Tanakan (ginkgo-biloba extracts) beginning on the day offirst infusion, and continuing throughout treatment until the first symptomsof fluid retention appeared.

At least three patients were included at each dose level and followedfor a minimum of 3 weeks before escalation to the next dose level. If adose-limiting toxicity was noted in a patient, three more patients wereincluded at that level, and the average maximum tolerated dose was determined.Maximum tolerated dose was defined if a dose-limiting toxicity was observedin 2 of 3 or 3 of 6 patients.

Assessments

Dose-limiting toxicity was defined as grade 4 neutropenia lasting morethan 7 days, febrile neutropenia lasting more than 3 days, grade 4 thrombocytopenia,grade 3 or 4 infection, and any grade 3 or 4 adverse event except anemia.The recommended dose for the phase II study is the highest dose that canbe safely administered to a patient. Usually it is chosen as the dose levelbelow the maximum tolerated dose.

Results

Patient Characteristics

A total 42 patients were entered into the study. Patients were characterizedby a high prevalence of visceral involvement (79%). The majority of thepatients (60%) had had prior adjuvant chemotherapy, with 52% receivingan anthracycline-containing regimen. The prior median cumulative dose ofanthracycline was 152 mg/m² (range, 82 to 287 mg/m²).

Hematologic Adverse Events

The most frequent grade 3 and 4 toxicity was neutropenia. With the exceptionof the lowest dose level, grade 4 neutropenia occurred in more than 70%of cycles, with a median duration of 5 days (Table1).

Febrile neutropenia occurred in less than 10% of cycles (30/314 cycles).One patient at level IV and two patients at level V developed a grade 3or 4 infection (sepsis; Table 2). Themaximum tolerated doses were defined as doxorubicin, 50 mg/m², anddocetaxel, 85 mg/m², with sepsis as the dose-limiting toxicity occurringin 3 of 42 patients. The recommended doses were defined as 50 mg/m²of doxorubicin and 75 mg/m² of docetaxel, or 60 mg/m² on bothdrugs on day 1 every 3 weeks, without G-CSF support.

Nonhematologic Adverse Events

Nonhematologic toxicity was mild, with no grade 3 or 4 adverse events.There were no cases of severe fluid retention, although the median cumulativedose of docetaxel was 610 mg/m² (range, 199 to 1,010 mg/m²).

Patients were carefully monitored for cardiotoxicity. At a median of18.4 months of follow-up, only four patients had abnormal grade 1 cardiacfunction, but all were asymptomatic; no congestive heart failure was observed,although 23 patients needed a cumulative dose of doxorubicin more than360 mg/m². No patient had to leave the study because of cardiac toxicity.

Efficacy

Although this was a phase I study, all 42 patients were evaluable forresponse. Responses were observed at all dose levels. Response rates werehigher at dose levels III to V (80% to 90%). Response rates were also highin patients whose disease had metastasized to the liver (82%). The medianfollow-up of 18.4 months (range, 9.0 to 28.3 months) was not sufficientto assess median duration of response or time to progression. Median survivalhas not been reached, but 9 patients (21.4%) have died, and 33 patients(78.6%) survive.

Discussion

The results of five phase I studies of paclitaxel (Taxol)/doxorubicincombination therapy in a total of 122 patients with advanced breast cancerare summarized in Table 3. In the firstthree studies, paclitaxel was administered by a prolonged (72- or 24-hour)infusion, while doxorubicin dosing varied from a bolus to a 48- or 72-hourinfusion.[1-3,6] Administering paclitaxel as a 24-hour infusion beforedoxorubicin resulted in sequence-dependent toxicity, consisting of an increasedincidence of severe mucositis and neutropenia. Similarly, giving both drugssimultaneously in a 72-hour infusion caused a high, schedule-dependentincidence of thrombocytopenia and typhlitis.

The response rates to these regimens were high, from 42% to 94% overall.However, the complete response rate was less than 10%. Two of the studiesdemonstrated that using shorter administration (3-hour) periods for bothdrugs permitted higher dose intensity, with paclitaxel doses as high as200 mg/m² and doxorubicin at 60 mg/m².[1,6,7] This resulted invery good response rates. The 94% overall response rate of Gianni et alincluded 40% complete responses in a chemotherapy-naive patient population.[6]However, these higher dosages were accompanied by an increase in cardiomyopathy,which occurred in as many as 20% of patients.

In the current study, the maximum tolerated doses were defined as 50mg/m² of doxorubicin and 85 mg/m² of doctaxel. The dose-limitingtoxicity was sepsis, occurring in two of five patients. The only grade3 or 4 adverse event was neutropenia. There was no congestive heart failure,significant decrease in left-ventricular ejection fraction, or discontinuationof treatment because of fluid retention.

This study did not use G-CSF; an increase in dose intensity of thiscombination might be possible if G-CSF were added to the regimen to controlfebrile neutropenia. The recommended doses were defined as 75 mg/m²of docetaxel and 50 mg/m² of doxorubicin, or 60 mg/m² of bothdrugs on day 1 every 3 weeks, without G-CSF support. Responses were observedat all dose levels.

The recommended doses used in this study demonstrated an acceptablesafety profile; ie, an acceptable incidence and severity of febrile neutropenia,with no grade 3 or 4 toxicity or severe infection. A phase II trial isunderway, and an ongoing phase III study is investigating whether the doxorubicin/docetaxelcombination is more effective than doxorubicin/cyclophosphamide (Cytoxan,Neosar).

References:

1. Fisherman JS, McCabe M, Noone M, et al: Phase I study of Taxol, doxorubicin,plus granulocyte-colony stimulating factor in patients with metastaticbreast cancer. Monogr Natl Cancer Inst 15:189-194, 1993.

2. Holmes FA, Frye D, Valero V, et al: Phase I study of Taxol (T) anddoxorubicin (D) with G-CSF in patients (pts) without prior chemotherapy(CT) for metastatic breast cancer (MBC) (abstract). Proc Annu Meet Am SocClin Oncol 11:A66, 1992.

3. Sledge GW Jr, Robert B, Sparano JA, et al: Paclitaxel (Taxol)/doxorubicincombinations in advanced breast cancer: The Eastern Cooperative OncologyGroup experience. Semin Oncol 21(5; suppl 8):15-18, 1994.

4. Gruia G, Misset S, Giachetti S, et al: A phase I-II study of Taxotere(TXTR) in combination with adriamycin (AD) as first line chemotherapy (CT)in patients with metastatic breast cancer (MBC) (abstract 258). Proc AmSoc Clin Oncol 14:140, 1995.

5. Kalla S, Bourgeois H, Gruia G, et al: Docetaxel (D) in combinationwith doxorubicin (Dx) as 1st line CT of metastatic breast cancer (MBC):A Phase I dose finding study-final results (abstract 5990). Ann Oncol 7(suppl5):124-125, 1996.

6. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusionin combination with bolus doxorubicin in women with untreated metastaticbreast cancer: High antitumor efficacy and cardiac effects in a dose-findingand sequence-finding study. J Clin Oncol 13:2688-2699, 1995.

7. Dombernowsky P, Gehl J, Boesgaard M, et al: Treatment of metastaticbreast cancer with paclitaxel and doxorubicin. Semin Oncol 22(6: suppl15):13-17, 1995.