A PHASE-I DOSE-ESCALATION TRIAL OF CONTINUOUS-INFUSION PACLITAXEL TO AUGMENT HIGH-DOSE CYCLOPHOSPHAMIDE AND THIOTEPA PLUS STEM-CELL RESCUE FOR THE TREATMENT OF PATIENTS WITH ADVANCED BREAST-CARCINOMA

BACKGROUND. Paclitaxel, an effective chemotherapeutic agent in the man agement of breast carcinoma, may have activity in women whose disease has recurred after high dose chemotherapy. With this is mind the autho rs explored the addition of a 120-hour continuous infusion of paclitax el to a previously reported regimen comprised of high dose cyclophosph amide and thiotepa. METHODS. Thirty-one women with advanced breast car cinoma (30 patients with Stage IV disease and 1 patient with Stage III B disease) underwent harvest and cryopreservation of bone marrow and/o r peripheral blood progenitor cells. High dose cyclophosphamide (2.5 g /m(2)) and thiotepa (225 mg/m(2)) were administered intravenously on D ays -7, -5, and -3. Paclitaxel was administered as a 120-hour continuo us infusion starting on Day -7. RESULTS. Three patients were treated a t the initial cohort dose of 50 mg/m(2) (over 120 hours), 6 patients a t 100 mg/m(2), 6 patients at 125 mg/m(2), 6 patients at 150 mg/m(2), 6 patients at 180 mg/m(2), and 4 patients at 210 mg/m(2). All patients completed the treatment protocol as planned with no associated transpl ant-related deaths. Mucositis as evidenced by either stomatitis or non infectious diarrhea was experienced by all patients and was determined to be the dose-limiting toxicity at the 210 mg/m(2) dose level. One p atient with dose-limiting mucositis required intubation for airway pro tection and also experienced Grade 3 (according to the Cancer and Leuk emia Group B common toxicity grading scale) pulmonary and neurologic t oxicity. Only one Grade 3 toxicity was encountered below the maximum t olerated dose in a patient who developed diffuse alveolar hemorrhage a t a dose of 125 mg/m(2). No allergic reactions or clinical evidence of peripheral neuropathies were encountered. Cardiac, hepatic, and renal toxicities were minimal. Response rates in this previously treated pa tient population were difficult to assess in light of the high inciden ce of bone metastases; an overall response rate of 24% was obtained. C ONCLUSIONS. Paclitaxel at a dose of 180 mg/m(2) as a 120-hour continuo us infusion may be added safely to high dose cyclophosphamide and thio tepa with autologous stem cell rescue. Further studies are ongoing to evaluate the efficacy and further define the toxicity of this recommen ded Phase II dose. Cancer 1998;83:1540-5. (C) 1998 American Cancer Soc iety.