Combination Docetaxel/Cyclophosphamide in Patients With Advanced Solid Tumors

ABSTRACT: Preclinical studies showthat docetaxel (Taxotere) and cyclophosphamide (Cytoxan, Neosar) are synergisticagainst MA 13/C mammary adenocarcinoma. Both agents are highly active asmonotherapy in a number of tumors, including metastatic breast cancer.Therefore, we performed a phase I dose-finding study to determine the maximumtolerated dose of this combination regimen in patients with advanced solidtumors. A total of 45 patients were enrolled and received cyclophosphamidefollowed by docetaxel, both administered as 1-hour intravenous infusionsonce every 3 weeks. The dose levels of cyclophosphamide/docetaxel were600/60 mg/m² (group 0), 600/75 mg/m² (group 1), 700/75 mg/m²(group 2), 800/75 mg/m² (group 3), 800/85 mg/m² (group 4), 800/75mg/m² (group 5), and 800/85 mg/m² (group 6). Patients with dose-limitingneutropenia in groups 5 and 6 received 300 µg of granulocyte colony-stimulatingfactor (G-CSF) (filgrastim [Neupogen]) support on days 2 through 9 duringsubsequent cycles of chemotherapy. All patients received premedicationwith 8 mg of dexamethasone twice daily for 5 days, beginning 1 day priorto chemotherapy. The dose-limiting toxicity was neutropenic fever. Therecommended dose for phase II studies of cyclophosphamide/docetaxel is700/75 mg/m² in previously treated patients and 800/75 mg/m²in previously untreated patients. G-CSF support did not allow for furtherdose escalation. Preliminary results from this phase I trial indicate thatthe combination of docetaxel and cyclophosphamide produced an objectiveresponse rate of 69% in 32 patients with metastatic breast cancer (including3 patients who achieved complete responses). [ONCOLOGY 11(Suppl 8):34-36,1997]

Introduction

Docetaxel (Taxotere) is a semisynthetic taxane that promotes tubulinassembly into microtubules, stabilizing microtubules and inhibiting depolymerizationto free tubulin, thereby blocking cells in the M phase of the cell cycle.[1,2]In preclinical studies, the broad spectrum of in vitro and in vivo antitumoractivity of docetaxel has translated into clinical efficacy in a varietyof cancers, including breast, lung, ovarian, and others.[3] The primarytoxicity of docetaxel is neutropenia, which generally resolves within 1week.[4] The incidence of thrombocytopenia and anemia associated with docetaxelis low, occurring in less than 8% of patients.[4]

Following hepatic transformation to active alkylating metabolites, cyclophosphamide(Cytoxan, Neosar) produces predominately interstrand DNA cross-links, aneffect that is thought to be cell-cycle nonspecific.[5] The combinationof docetaxel and cyclophosphamide is attractive for a number of reasons.Both agents have been highly active in a wide range of solid tumors. Inaddition, preclinical data demonstrate that docetaxel and cyclophosphamidehave synergistic effects against MA 13/C mammary adenocarcinoma.[6,7] Inpreclinical combination studies, 60% to 70% of the maximum tolerated doseof each agent could be administered safely.[6,7] Thus, the use of granulocytecolony-stimulating factor (G-CSF) (filgrastim [Neupogen]) support may beuseful in ameliorating neutropenic events or enabling dose-escalation beforedose-limiting toxicities occur.

Determining the Maximum Tolerated Dose

Our group performed a phase I trial of docetaxel and cyclophosphamidein 45 patients with advanced solid tumors to determine the maximum tolerateddose in patients who had prior therapy for metastatic disease, and in patientswith untreated metastatic disease (with and without G-CSF support), aswell as to characterize the toxicity of this combination regimen.[8]

The working definition of maximum tolerated dose in this trial was 1dose level below the dose that produces a dose-limiting toxicity in 3 ormore patients during the first cycle. A dose-limiting toxicity was categorizedas grade 4 or greater nonhematologic toxicity, except nausea/vomiting;grade 4 neutropenia of at least 8 days' duration; grade 4 neutropenia plusfever, with or without infection; or grade 4 thrombocytopenia.

Eligibility criteria for study participation included patients witha life expectancy of at least 3 months and with a Karnofsky performancestatus of at least 60%. Patients were to have histologically confirmedsolid malignancies with bidimensionally measurable or evaluable disease.Moreover, patients were to have adequate hematopoietic, renal, and hepaticfunction. In addition, patients were to have no prior chemotherapy or radiationtherapy within 4 weeks of the study.

The treatment plan consisted of patients receiving cyclophosphamideimmediately followed by docetaxel, both administered over 1-hour as anintravenous infusion, once every 3 weeks. The dose levels of cyclophosphamide/docetaxelwere 600/60 mg/m² (group 0), 600/75 mg/m² (group 1), 700/75 mg/m²(group 2), 800/75 mg/m² (group 3), 800/85 mg/m² (group 4), 800/75mg/m² (group 5), and 800/85 mg/m² (group 6).

Patients with dose-limiting neutropenia in groups 5 and 6 received 300µg of G-CSF support on days 2 through 9 during subsequent cyclesof chemotherapy. All patients received premedication with 8 mg of dexamethasonetwice daily for 5 days beginning 1 day prior to chemotherapy.

Demographics

Included in the analysis were 45 patients with a median age of 53 years(range: 29 to 73 years) and a median Karnofsky performance status of 90%(range: 60% to 90%). The tumor types among the 45 patients included metastaticbreast cancer (32 patients), sarcoma (6 patients), colon (3 patients),and others, including lung and head/neck cancers (4 patients). The mediannumber of sites involved was 3 (range: 1 to 4).

Antitumor Activity

The preliminary response rate for all tumor types was 51%, consistingof 3 complete and 20 partial responses (Table1). A total of 9 patients had stable disease, and the other 13 patientsexperienced progression. When the data were analyzed for the 32 patientswith metastatic breast cancer, an objective response rate of 69% was noted,with 3 patients achieving a complete response and 19 achieving partialresponses.

Tolerability

The combination of docetaxel and cyclophosphamide produced complicatedneutropenia in approximately 51% of the patients and 16% of the cycles.Febrile neutropenia occurred in 20% of patients and 6% of cycles administered.Similarly, grade 3 to 4 infections plus neutropenia were noted in 31% ofpatients and only 8% of cycles.

In general, nonhematologic toxicities were mild in severity. Mucositiswas the most common gastrointestinal toxicity, occurring in 38% of patientsand 14% of cycles administered. Other common gastrointestinal toxicitiesof grade 2 severity or higher were nausea in 27% and diarrhea in 20% ofthe patients, respectively.

Subacute nonhematologic toxicities included moderate-to-severe fatigue(75% of patients), myalgia (47%), mild peripheral neuropathy (22%), andskin abnormalities (20%). Moderate-to-severe fluid retention occurred inonly 15% of patients, with no cases of significant pleural effusions.

Conclusions

The preliminary results from this phase I study are encouraging. Thecombination of docetaxel and cyclophosphamide is potentially beneficialfor the palliation and adjuvant management of many neoplasias, includingbreast cancer, non-small-cell lung cancer, non-Hodgkin's lymphoma, ovariancancer, and others. The initial objective response rate seen in patientswith metastatic breast cancer was 69%, with 3 patients achieving a completeresponse. In addition, the combination of docetaxel and cyclophosphamidein this phase I trial was well tolerated with no unexpected toxicities.The dose-limiting toxicity was neutropenic fever. The addition of G-CSFdid not allow for additional dose escalation.

Based on these results, the recommended dose for phase II studies withoutG-CSF support) is 700 mg/m² of cyclophosphamide followed by 75 mg/m²of docetaxel, both given as 1-hour intravenous infusions, once every 3weeks, for previously treated patients. For previously untreated patients,cyclophosphamide can be given at a dose of 800 mg/m² followed by 75mg/m² of docetaxel.

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