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Combination Docetaxel/Cyclophosphamide in Patients With Advanced Solid Tumors

Combination Docetaxel/Cyclophosphamide in Patients With Advanced Solid Tumors

ABSTRACT: Preclinical studies show that docetaxel (Taxotere) and cyclophosphamide (Cytoxan, Neosar) are synergistic against MA 13/C mammary adenocarcinoma. Both agents are highly active as monotherapy in a number of tumors, including metastatic breast cancer. Therefore, we performed a phase I dose-finding study to determine the maximum tolerated dose of this combination regimen in patients with advanced solid tumors. A total of 45 patients were enrolled and received cyclophosphamide followed by docetaxel, both administered as 1-hour intravenous infusions once every 3 weeks. The dose levels of cyclophosphamide/docetaxel were 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), 800/75 mg/m² (group 5), and 800/85 mg/m² (group 6). Patients with dose-limiting neutropenia in groups 5 and 6 received 300 µg of granulocyte colony-stimulating factor (G-CSF) (filgrastim [Neupogen]) support on days 2 through 9 during subsequent cycles of chemotherapy. All patients received premedication with 8 mg of dexamethasone twice daily for 5 days, beginning 1 day prior to chemotherapy. The dose-limiting toxicity was neutropenic fever. The recommended dose for phase II studies of cyclophosphamide/docetaxel is 700/75 mg/m² in previously treated patients and 800/75 mg/m² in previously untreated patients. G-CSF support did not allow for further dose escalation. Preliminary results from this phase I trial indicate that the combination of docetaxel and cyclophosphamide produced an objective response rate of 69% in 32 patients with metastatic breast cancer (including 3 patients who achieved complete responses). [ONCOLOGY 11(Suppl 8):34-36, 1997]

Introduction

Docetaxel (Taxotere) is a semisynthetic taxane that promotes tubulin assembly into microtubules, stabilizing microtubules and inhibiting depolymerization to 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 antitumor activity of docetaxel has translated into clinical efficacy in a variety of cancers, including breast, lung, ovarian, and others.[3] The primary toxicity of docetaxel is neutropenia, which generally resolves within 1 week.[4] The incidence of thrombocytopenia and anemia associated with docetaxel is 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, an effect that is thought to be cell-cycle nonspecific.[5] The combination of docetaxel and cyclophosphamide is attractive for a number of reasons. Both agents have been highly active in a wide range of solid tumors. In addition, preclinical data demonstrate that docetaxel and cyclophosphamide have synergistic effects against MA 13/C mammary adenocarcinoma.[6,7] In preclinical combination studies, 60% to 70% of the maximum tolerated dose of each agent could be administered safely.[6,7] Thus, the use of granulocyte colony-stimulating factor (G-CSF) (filgrastim [Neupogen]) support may be useful in ameliorating neutropenic events or enabling dose-escalation before dose-limiting toxicities occur.

Determining the Maximum Tolerated Dose

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

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

Eligibility criteria for study participation included patients with a life expectancy of at least 3 months and with a Karnofsky performance status of at least 60%. Patients were to have histologically confirmed solid malignancies with bidimensionally measurable or evaluable disease. Moreover, patients were to have adequate hematopoietic, renal, and hepatic function. In addition, patients were to have no prior chemotherapy or radiation therapy within 4 weeks of the study.

The treatment plan consisted of patients receiving cyclophosphamide immediately followed by docetaxel, both administered over 1-hour as an intravenous infusion, once every 3 weeks. The dose levels of cyclophosphamide/docetaxel were 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), 800/75 mg/m² (group 5), and 800/85 mg/m² (group 6).

Patients with dose-limiting neutropenia in groups 5 and 6 received 300 µg of G-CSF support on days 2 through 9 during subsequent cycles of chemotherapy. All patients received premedication with 8 mg of dexamethasone twice 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 metastatic breast cancer (32 patients), sarcoma (6 patients), colon (3 patients), and others, including lung and head/neck cancers (4 patients). The median number of sites involved was 3 (range: 1 to 4).

Antitumor Activity

The preliminary response rate for all tumor types was 51%, consisting of 3 complete and 20 partial responses (Table 1). A total of 9 patients had stable disease, and the other 13 patients experienced progression. When the data were analyzed for the 32 patients with metastatic breast cancer, an objective response rate of 69% was noted, with 3 patients achieving a complete response and 19 achieving partial responses.

Tolerability

The combination of docetaxel and cyclophosphamide produced complicated neutropenia 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% of patients and only 8% of cycles.

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

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

Conclusions

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

Based on these results, the recommended dose for phase II studies without G-CSF support) is 700 mg/m² of cyclophosphamide followed by 75 mg/m² of docetaxel, both given as 1-hour intravenous infusions, once every 3 weeks, for previously treated patients. For previously untreated patients, cyclophosphamide can be given at a dose of 800 mg/m² followed by 75 mg/m² of docetaxel.

References

1. Gueritte-Voegelein F, Guenard D, Lavelle F, et al: Relationships between the structure of Taxol analogues and their antimitotic activity. J Med Chem 34:992-998, 1991.

2. Ringel I, Horwitz SB: Studies with RP 56976 (Taxotere): A semisynthetic analogue of taxol. J Natl Cancer Inst 83:288-291, 1991.

3. Kaye SB: Docetaxel (Taxotere) in the treatment of solid tumors other than breast and lung cancer. Semin Oncol 22(suppl 4):30-33, 1995.

4. Cortes JE, Pazdur R: Docetaxel. J Clin Oncol 13:2643-2655, 1995.

5. Hengstler JG, Hengst A, Fuchs J, et al: Induction of DNA crosslinks and DNA strand lesions by cyclophosphamide after activation by cytochrome P450 2B1. Mutat Res 373:215-223, 1997.

6. Bissery MC, Vrignaud P, Bayssas M, et al: Taxotere synergistic combination with cyclophosphamide, etoposide, and 5-fluorouracil in mouse tumor models (abstract). Proc Am Assoc Cancer Res 34:1782, 1993.

7. Bissery MC, Vrignaud P, Lavelle F: Preclinical profile of docetaxel (Taxotere): Efficacy as a single agent and in combination. Semin Oncol 22(suppl 13):3-16, 1995.

8. Valero V, Esparza-Guerra L, Rahman Z, et al: Phase I study of docetaxel (Taxotere) and cyclophosphamide without and with G- CSF in previously treated and untreated solid neoplasms (abstract 772). Proc Am Soc Clin Oncol 16, 1997.

 
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