TY - JOUR
T1 - Phase I and pharmacokinetic study of LU79553, a DNA intercalating bisnaphthalimide, in patients with solid malignancies
AU - Villalona-Calero, M. A.
AU - Eder, J. P.
AU - Toppmeyer, D. L.
AU - Allen, L. F.
AU - Fram, R.
AU - Velagapudi, R.
AU - Myers, M.
AU - Amato, A.
AU - Kagen-Hallet, K.
AU - Razvillas, B.
AU - Kufe, D. W.
AU - Von Hoff, D. D.
AU - Rowinsky, E. K.
PY - 2001/2/1
Y1 - 2001/2/1
N2 - Purpose: To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks. Patients and Methods: Patients with advanced solid malignancies received escalating doses of LU79553. Plasma sampling and urine collections were performed on both days 1 and 5 of the first course. Results: Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m2/d. Proximal myopathy, erectile dysfunction, and myelo-suppression precluded the administration of multiple courses at doses above 18 mg/m2/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m2/d dose level. At the 18-mg/m2/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electro-physiologic, histopathologic, and ultrastructural studies supported a drug-induced primary myopathic process. A patient with a platinum- and taxane-resistant papillary serous carcinoma of the peritoneum experienced a partial response lasting 22 months. Pharmacokinetics were dose-independent, optimally described by a three-compartment model, and there was modest drug accumulation over the 5 days of treatment. Conclusion: Although no dose-limiting events were noted in the first two courses of LU79553, cumulative muscular toxicity precluded repetitive treatment with LU79553 at doses above 18 mg/m2/d, which is the recommended dose for subsequent disease-directed evaluations. The preliminary antitumor activity noted is encouraging, but the qualitative and cumulative nature of the principal toxicities, as well as the relatively small number of patients treated repetitively, mandate that rigorous and long-term toxicologic monitoring be performed in subsequent evaluations of this unique agent.
AB - Purpose: To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks. Patients and Methods: Patients with advanced solid malignancies received escalating doses of LU79553. Plasma sampling and urine collections were performed on both days 1 and 5 of the first course. Results: Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m2/d. Proximal myopathy, erectile dysfunction, and myelo-suppression precluded the administration of multiple courses at doses above 18 mg/m2/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m2/d dose level. At the 18-mg/m2/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electro-physiologic, histopathologic, and ultrastructural studies supported a drug-induced primary myopathic process. A patient with a platinum- and taxane-resistant papillary serous carcinoma of the peritoneum experienced a partial response lasting 22 months. Pharmacokinetics were dose-independent, optimally described by a three-compartment model, and there was modest drug accumulation over the 5 days of treatment. Conclusion: Although no dose-limiting events were noted in the first two courses of LU79553, cumulative muscular toxicity precluded repetitive treatment with LU79553 at doses above 18 mg/m2/d, which is the recommended dose for subsequent disease-directed evaluations. The preliminary antitumor activity noted is encouraging, but the qualitative and cumulative nature of the principal toxicities, as well as the relatively small number of patients treated repetitively, mandate that rigorous and long-term toxicologic monitoring be performed in subsequent evaluations of this unique agent.
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U2 - 10.1200/JCO.2001.19.3.857
DO - 10.1200/JCO.2001.19.3.857
M3 - Article
C2 - 11157040
AN - SCOPUS:0035253372
SN - 0732-183X
VL - 19
SP - 857
EP - 869
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 3
ER -