Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors

S. O'Reilly, L. B. Grochow, Ross C Donehower, T. L. Chen, K. Bowling, N. R. Hartman, R. F. Struck, E. K. Rowinsky

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1974-1984
Number of pages11
JournalJournal of Clinical Oncology
Volume15
Issue number5
StatePublished - May 1997

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penclomedine
Alkylating Agents
Ataxia
Neoplasms
Appointments and Schedules
Vertigo
Dizziness
Broca Aphasia
Cerebellar Diseases
Maximum Tolerated Dose
Aphasia
Intravenous Infusions
Nervous System
Signs and Symptoms
Breast Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

O'Reilly, S., Grochow, L. B., Donehower, R. C., Chen, T. L., Bowling, K., Hartman, N. R., ... Rowinsky, E. K. (1997). Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors. Journal of Clinical Oncology, 15(5), 1974-1984.

Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors. / O'Reilly, S.; Grochow, L. B.; Donehower, Ross C; Chen, T. L.; Bowling, K.; Hartman, N. R.; Struck, R. F.; Rowinsky, E. K.

In: Journal of Clinical Oncology, Vol. 15, No. 5, 05.1997, p. 1974-1984.

Research output: Contribution to journalArticle

O'Reilly, S, Grochow, LB, Donehower, RC, Chen, TL, Bowling, K, Hartman, NR, Struck, RF & Rowinsky, EK 1997, 'Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors', Journal of Clinical Oncology, vol. 15, no. 5, pp. 1974-1984.
O'Reilly, S. ; Grochow, L. B. ; Donehower, Ross C ; Chen, T. L. ; Bowling, K. ; Hartman, N. R. ; Struck, R. F. ; Rowinsky, E. K. / Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors. In: Journal of Clinical Oncology. 1997 ; Vol. 15, No. 5. pp. 1974-1984.
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