Phase I Clinical Trial of Pyrazoloacridine NSC366140 (PD115934)

Patricia Lorusso, Brenda J. Foster, Elizabeth Poplin, Julie McCormick, Michael Kraut, Lawrence Flaherty, Lance K. Heilbrun, Manuel Valdivieso, Laurence Baker

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

The pyrazoloacridine (PZA) analogue NSC366140 (PD115934) entered clinical trial based on unique preclinical characteristics including solid tumor selectivity in vitro, marked antitumor activity in vivo against murine solid tumors, selectivity against noncycling cells, and activity against multidrug-resistant tumor cells. After identification of the preclinical efficacy and an acceptable toxicity profile, a Phase I study of PZA was carried out. A total of 28 patients was entered and received a total of 67 treatment courses. The drug was administered via a 1-h infusion every 21 days. The starting dose was 30 mg/m2 with 2-fold dose escalations through 480 mg/m2. The next dose escalation was 50%, to 720 mg/m2. Grade I through grade IV toxicities were observed. Since no dose-limiting toxicities were observed at 480 mg/m2, and up to grade IV toxicities were observed at 720 mg/m2, an intermediate dose, 600 mg/m2, was evaluated. Dose-limiting toxicities at 720 mg/m2 were hematological (grade III and IV neutropenia) in four of six patients and neurological (up to grade III cerebral toxicities, including restlessness, dizziness, agitation/anxiety, personality changes, and nightmares, as well as myoclonus) in three of six patients treated. The pharmacokinetic parameters which helped predict these toxicities included area under the curve and peak plasma level. Pharmacokinetic studies showed interpatient variations in all parameters studied. The mean area under the curve levels of PZA at the highest two dose levels in patients were near the level detected in mice at their maximum tolerated total dose. The recommended starting dose for Phase II trials using this schedule is 600 mg/m2.

Original languageEnglish (US)
Pages (from-to)1487-1493
Number of pages7
JournalClinical Cancer Research
Volume1
Issue number12
StatePublished - Aug 1 1995
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Phase I Clinical Trial of Pyrazoloacridine NSC366140 (PD115934)'. Together they form a unique fingerprint.

Cite this