Phase I clinical and pharmacokinetic studies of the taxoid derivative RPR 109881A administered as a 1-hour or a 3-hour infusion in patients with advanced solid tumors.

PURPOSE: To define the maximum tolerated dose (MTD), the recommended phase II dose, the optimal infusion duration and pharmacokinetics of the semisynthetic taxoid derivative RPR 109881A, given as a 1-h or 3-h infusion every 3 weeks. PATIENTS AND METHODS: RPR109881A was administered as a 1-h i.v. infusion to 34 patients (study 1) with oral steroids as pre-medication. In a subsequent study, 29 patients were treated at the recommended dose or at the dose immediately below (study 2); the first 14 patients received RPR 109881A as a 3-h infusion, while the subsequent 15 were randomized to receive the drug as a 1-h or 3-h infusion. The pharmacokinetics of RPR109881A was studied in plasma and urine and for selected patients in some biological fluids (cerebrospinal fluid, pleural effusion, ascitis). RESULTS: In study 1, the dose was escalated from 15 to 105 mg/m(2), at which dose two of five patients presented dose-limiting toxicities with febrile neutropenia (FN) after the first cycle, thus defining the MTD. The dose of 90 mg/m(2), at which grade 3/4 neutropenia was almost universal with FN in 18%, was recommended for phase II. At 90 mg/m(2) the incidence of diarrhea, fatigue and alopecia were 59, 29 and 70%, respectively. The results of study 2 were comparable to those of study 1, thus recommending the 1-h infusion duration for phase II evaluation. RPR 109881A exhibited a high total body clearance, a large distribution volume and long terminal half-life of 20 h. RPR 109881A was detected in cerebrospinal fluid shortly after the end of 1-h infusion. Three objective responses were observed in non-small-cell lung cancer (NSCLC) patients, including a patient with brain metastases. CONCLUSIONS: The antitumor activity in NSCLC, the reproducible profile of toxicity and above all the ability to cross the blood-brain barrier make RPR 109881A worthy of further disease-oriented clinical development.

Docetaxel in combination with 5-fluorouracil in patients with metastatic breast cancer previously treated with anthracycline-based chemotherapy: a phase I, dose-finding study.

This phase I study evaluated the maximum tolerated dose, dose-limiting toxicity and recommended dose of docetaxel in combination with 5-fluorouracil (5-FU) in patients with metastatic breast cancer previously treated with anthracycline-based chemotherapy. 32 patients received docetaxel at 60, 75, 85 or 100 mg/m(2) by 1-h intravenous (i.v.) infusion, followed, after a 1-h interval, by 5-FU at 250, 350, 500 or 750 mg/m(2)/day by continuous infusion over 5 days every 3 weeks. Dose-limiting stomatitis defined the maximum tolerated dose at a docetaxel dose of 100 mg/m(2) with 5-FU 750 mg/m(2)/day. None of 5 patients treated at the previous dose level (docetaxel 85 mg/m(2) with 5-FU 750 mg/m(2)/day) had a dose-limiting toxicity in the first cycle, and this was, therefore, considered the recommended dose. The combination was generally well tolerated. Grade 4 neutropenia was common (29 patients; 91%), but no patient experienced febrile neutropenia of duration >3 days requiring i.v. antibiotics. An objective response was achieved by 18 patients overall (56%), and in 4 out of 5 patients treated with the determined recommended dose. No pharmacokinetic interaction between docetaxel and 5-fluorouracil was apparent. The activity of docetaxel 85 mg/m(2) with 5-fluorouracil 750 mg/m(2)/day will be explored more extensively in phase II studies of patients with metastatic breast cancer previously treated with anthracycline-based chemotherapy.

Cauda equina syndrome with pagetic vertebral fusion. Clinical recovery under calcium-vitamin D supplementation plus clodronate after apparent failure of pamidronate and acquired resistance to etidronate.

A patient with an osteolytic L2-L3 pagetic block and pagetic lesions of L1 and the sacrum seen only as increased radionuclide activity became resistant to etidronate after the fifth course (5 mg/kg/d six months per year) and developed severe cauda equina syndrome (reduction in walking distance to 30 m and sphincter dysfunction) due primarily to vertebral hypertrophy. Five months after a ten-day course of intravenous pamidronate (22.5 mg/d), the clinical symptoms were unchanged, although the alkaline phosphatase level was down 50%. Oral clodronate (1,600 mg/day for six months per year) in combination with calcium and vitamin D supplementation dramatically improved the walking distance and sphincter disorders. Resolution of the neurological manifestations was complete after the second clodronate course. At last follow-up nine months after the fourth clodronate course, there was no evidence of a relapse and the alkaline phosphatase level was normal. The time course of events in this patient does not allow to affirm that pamidronate was ineffective and suggests that calcium and vitamin D supplementation improved mineralization of the pagetic block and enhanced the effect of bisphosphonate therapy.