TY - JOUR
T1 - Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors
AU - O'Reilly, S.
AU - Grochow, L. B.
AU - Donehower, R. C.
AU - Chen, T. L.
AU - Bowling, K.
AU - Hartman, N. R.
AU - Struck, R. F.
AU - Rowinsky, E. K.
PY - 1997/5
Y1 - 1997/5
N2 - Purpose: To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. Patients and Methods: Penclomedine (45 to 550 mg/m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. Results: On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. Conclusion: Neurotoxicity was the dose-limiting toxicity (DLT) penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated.
AB - Purpose: To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. Patients and Methods: Penclomedine (45 to 550 mg/m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. Results: On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. Conclusion: Neurotoxicity was the dose-limiting toxicity (DLT) penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated.
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U2 - 10.1200/JCO.1997.15.5.1974
DO - 10.1200/JCO.1997.15.5.1974
M3 - Article
C2 - 9164209
AN - SCOPUS:0030906399
SN - 0732-183X
VL - 15
SP - 1974
EP - 1984
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 5
ER -