bms184476 and Neoplasms

BMS-184476 is a taxane analog under development by Bristol-Myers Squibb for the potential treatment of solid tumors. By February 2001, it had entered phase II trials and, as of May 2002, phase II studies had been carried out in patients with a number of tumor types, including breast, ovarian and non-small-cell lung cancer.

Topics: Animals; Clinical Trials, Phase II as Topic; Drugs, Investigational; Humans; Neoplasms; Paclitaxel; Taxoids; Technology, Pharmaceutical

The aim of this study was to define the maximum tolerated dose (MTD) and the pharmacological profile of the paclitaxel analogue BMS-184476 given once every 3 weeks, or on days 1 and 8 every 3 weeks (d1&8), in combination with a fixed dose of 50 mg/m(2) of Doxorubicin (Doxo) administered on day 1 of a 21-day cycle. Adult patients with advanced solid malignancies received escalating doses of BMS-184476 infused over 1 h after bolus Doxo. Pharmacokinetics (PK) of BMS-184476, Doxo and metabolites were investigated. The effect of BMS-184476 on doxorubicinol formation was studied in the cytosol from human myocardium. The MTD of 3-weekly BMS-184476 was 30 mg/m(2). The MTD/recommended Phase II dose was 35 mg/m(2)/week (70 mg/m(2) per cycle) in the d1&8 schedule. The dose-limiting toxicity was neutropenia for both schedules. Other toxicities were loss of appetite, asthenia, and mild, cumulative peripheral neuropathy. The objective response rate in 17 previously untreated or minimally pretreated patients with breast cancer treated at 35 mg/m(2)/week of BMS-184476 was 59% (95% Confidence Interval (CI): 33-82%). Two of the 7 patients not responding to the study regimen later responded to Doxo and paclitaxel. Plasma disposition of BMS-184476 at 30, 35 and 40 mg/m(2) was linear without evidence of a PK interaction with Doxo. In studies with cytosol from human myocardium, the formation of cardiotoxic doxorubicinol was not enhanced by BMS-184476. Dosing of BMS-184476 for 2 consecutive weeks allowed the administration of larger doses of the taxane with a promising antitumour activity in patients with untreated or minimally pretreated breast cancer. The higher than expected myelotoxicity of the 3-weekly schedule is unexplained by the investigated interactions. Lack of enhanced doxorubicinol formation in human myocardium is consistent with the cardiac safety of the regimen.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Heart; Humans; Maximum Tolerated Dose; Middle Aged; Myocardium; Neoplasms; Taxoids

The aim of the study was to determine the maximum-tolerated dose and dose-limiting toxicities for BMS-184476, in combination with carboplatin, in patients with advanced solid tumours and to describe any preliminary antitumour activity associated with this regimen. Patients received combination therapy with BMS-184476 given intravenously over 1 h followed by carboplatin administered over 30 min on day 1 of a 21-day cycle. In all, 28 patients received 146 cycles of BMS-184476 and carboplatin. Patients were enrolled at four dose levels: BMS-184476 (mg m(-2))/carboplatin (mg min ml(-1)): 40/5, 50/5, 50/6 and 60/6. Dose-limiting toxicity at 60/6 was neutropenia. Among 27 evaluable patients, 11 demonstrated stable disease for a median of 8.5 cycles. In 22 patients, the pharmacokinetics of BMS-184476 appeared independent of dose of BMS-184476. The mean+/-s.e.m. values for clearance (Cl), volume of distribution at steady state and apparent terminal half-life of BMS-184476 in the four dose groups during cycle 1 were 192+/-25 ml min m(-2), 377+/-69 l m(-2) and 33.7+/-5.9 h, respectively. An increase in the dose of carboplatin from 5 to 6 mg min ml(-1) may have decreased Cl of BMS-184476. BMS-184476 in combination with carboplatin was well tolerated at a dose of 50/6 and shows evidence of antitumour activity in a pretreated population.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Taxoids

The study was designed to establish the maximum administered dose and maximum tolerated dose (MTD) of BMS-184476, an analogue of paclitaxel, given weekly for 3 consecutive weeks every 28 days, later amended to a regimen of weekly administration for 2 consecutive weeks every 21 days.. Adult patients with solid tumors received BMS-184476 i.v. on days 1, 8, and 15 without premedication. The trial followed a modified accelerated titration design. Doses of 7, 14, 28, 40, 50, and 60 mg/m(2)/wk were investigated. Pharmacokinetics of BMS-184476 in plasma and urine were investigated by high-performance liquid chromatography assay.. Fifty-three patients were treated; the maximum administered dose was 60 mg/m(2)/wk, and the MTD was 50 mg/m(2)/wk. Dose-limiting neutropenia was the main toxicity. Neutropenia at the higher dose levels frequently prevented administration of the day 15 dose, and a modified schedule at MTD dosing on days 1 and 8 every 21 days was evaluated and found more feasible for Phase II studies. Diarrhea was the main nonhematological toxicity; other toxicities were vomiting, cumulative fatigue, and loss of appetite. Two patients died of neutropenia-related complications. Antitumor activity was observed in patients with breast and non-small cell lung cancer, with confirmed partial responses in 22% of patients. BMS-184476 was the main species found in the plasma with <5% present as paclitaxel or sulfoxide metabolites. The PKs of BMS-184476 appeared to be linear in the dose range of 7-60 mg/m(2).. The recommended dose and schedule of weekly BMS-184476 is 50 mg/m(2) on days 1 and 8 every 21 days.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Molecular Structure; Neoplasms; Neutropenia; Paclitaxel; Remission Induction; Taxoids

To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks.. Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474.. Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively.. The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Bone Marrow; Female; Humans; Male; Middle Aged; Neoplasms; Paclitaxel; Solubility; Taxoids