Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules

Eric K. Rowinsky, Dennis A. Noe, Louise B. Grochow, Susan E. Sartorious, M. Kathy Bowling, Tian Ling Chen, Barbara G. Lubejko, Scott H Kaufmann, Ross C. Donehower

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Purpose: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacologic behavior of pyrazoloacridine (PZA), a novel DNA intercalator with a unique mechanism of action, on single- and multiple- dosing schedules. Patients and Methods: PZA was administered on a single- dosing schedule as a 1- to 3-hour infusion and on a multiple-dosing schedule as a 1-hour infusion daily for 5 days to cancer patients at doses ranging from 400 to 935 mg/m2 and 40 to 180 mg/m2/d every 3 weeks, respectively. Results: On the single-dosing 1-hour schedule, CNS toxicity, characterized by neuropsychiatric and neuromotor effects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures resulted in lower incidence of CNS toxicity. Neutropenia was the principal toxicity and precluded dose escalation to levels greater than 750 mg/m2 on the single-dosing (3-hour) schedule and 150 mg/m2/d x 5 (total dose, 750 mg/m2) on the multiple-dosing schedule. Thrombocytopenia, anemia, and nonhematologic effects occurred less frequently. Responses were observed in several patients with platinum- and taxane-refractory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and troughs was observed in the pharmacologic studies. The maximal PZA concentrations achieved in both studies exceeded drug concentrations associated with significant cytotoxicity in preclinical studies and correlated with the occurrence of CNS toxicity. Conclusion: Neutropenia is the dose-limiting toxicity on both schedules and 750 mg/m2 and 150 mg/m2/d are the recommended starting doses of PZA on single-and multiple-dosing schedules, respectively, for minimally pretreated patients in phase II studies; slightly lower doses are recommended for more heavily pretreated subjects. The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase II evaluations of this agent.

Original languageEnglish (US)
Pages (from-to)1975-1984
Number of pages10
JournalJournal of Clinical Oncology
Volume13
Issue number8
StatePublished - Aug 1995
Externally publishedYes

Fingerprint

NSC 366140
Intercalating Agents
Appointments and Schedules
DNA
Neutropenia
Maximum Tolerated Dose
Platinum
Thrombocytopenia
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Rowinsky, E. K., Noe, D. A., Grochow, L. B., Sartorious, S. E., Bowling, M. K., Chen, T. L., ... Donehower, R. C. (1995). Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules. Journal of Clinical Oncology, 13(8), 1975-1984.

Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules. / Rowinsky, Eric K.; Noe, Dennis A.; Grochow, Louise B.; Sartorious, Susan E.; Bowling, M. Kathy; Chen, Tian Ling; Lubejko, Barbara G.; Kaufmann, Scott H; Donehower, Ross C.

In: Journal of Clinical Oncology, Vol. 13, No. 8, 08.1995, p. 1975-1984.

Research output: Contribution to journalArticle

Rowinsky, EK, Noe, DA, Grochow, LB, Sartorious, SE, Bowling, MK, Chen, TL, Lubejko, BG, Kaufmann, SH & Donehower, RC 1995, 'Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules', Journal of Clinical Oncology, vol. 13, no. 8, pp. 1975-1984.
Rowinsky, Eric K. ; Noe, Dennis A. ; Grochow, Louise B. ; Sartorious, Susan E. ; Bowling, M. Kathy ; Chen, Tian Ling ; Lubejko, Barbara G. ; Kaufmann, Scott H ; Donehower, Ross C. / Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules. In: Journal of Clinical Oncology. 1995 ; Vol. 13, No. 8. pp. 1975-1984.
@article{97cd55b95d6b43f29f9a19c9ad28b02b,
title = "Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules",
abstract = "Purpose: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacologic behavior of pyrazoloacridine (PZA), a novel DNA intercalator with a unique mechanism of action, on single- and multiple- dosing schedules. Patients and Methods: PZA was administered on a single- dosing schedule as a 1- to 3-hour infusion and on a multiple-dosing schedule as a 1-hour infusion daily for 5 days to cancer patients at doses ranging from 400 to 935 mg/m2 and 40 to 180 mg/m2/d every 3 weeks, respectively. Results: On the single-dosing 1-hour schedule, CNS toxicity, characterized by neuropsychiatric and neuromotor effects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures resulted in lower incidence of CNS toxicity. Neutropenia was the principal toxicity and precluded dose escalation to levels greater than 750 mg/m2 on the single-dosing (3-hour) schedule and 150 mg/m2/d x 5 (total dose, 750 mg/m2) on the multiple-dosing schedule. Thrombocytopenia, anemia, and nonhematologic effects occurred less frequently. Responses were observed in several patients with platinum- and taxane-refractory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and troughs was observed in the pharmacologic studies. The maximal PZA concentrations achieved in both studies exceeded drug concentrations associated with significant cytotoxicity in preclinical studies and correlated with the occurrence of CNS toxicity. Conclusion: Neutropenia is the dose-limiting toxicity on both schedules and 750 mg/m2 and 150 mg/m2/d are the recommended starting doses of PZA on single-and multiple-dosing schedules, respectively, for minimally pretreated patients in phase II studies; slightly lower doses are recommended for more heavily pretreated subjects. The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase II evaluations of this agent.",
author = "Rowinsky, {Eric K.} and Noe, {Dennis A.} and Grochow, {Louise B.} and Sartorious, {Susan E.} and Bowling, {M. Kathy} and Chen, {Tian Ling} and Lubejko, {Barbara G.} and Kaufmann, {Scott H} and Donehower, {Ross C.}",
year = "1995",
month = "8",
language = "English (US)",
volume = "13",
pages = "1975--1984",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "8",

}

TY - JOUR

T1 - Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules

AU - Rowinsky, Eric K.

AU - Noe, Dennis A.

AU - Grochow, Louise B.

AU - Sartorious, Susan E.

AU - Bowling, M. Kathy

AU - Chen, Tian Ling

AU - Lubejko, Barbara G.

AU - Kaufmann, Scott H

AU - Donehower, Ross C.

PY - 1995/8

Y1 - 1995/8

N2 - Purpose: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacologic behavior of pyrazoloacridine (PZA), a novel DNA intercalator with a unique mechanism of action, on single- and multiple- dosing schedules. Patients and Methods: PZA was administered on a single- dosing schedule as a 1- to 3-hour infusion and on a multiple-dosing schedule as a 1-hour infusion daily for 5 days to cancer patients at doses ranging from 400 to 935 mg/m2 and 40 to 180 mg/m2/d every 3 weeks, respectively. Results: On the single-dosing 1-hour schedule, CNS toxicity, characterized by neuropsychiatric and neuromotor effects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures resulted in lower incidence of CNS toxicity. Neutropenia was the principal toxicity and precluded dose escalation to levels greater than 750 mg/m2 on the single-dosing (3-hour) schedule and 150 mg/m2/d x 5 (total dose, 750 mg/m2) on the multiple-dosing schedule. Thrombocytopenia, anemia, and nonhematologic effects occurred less frequently. Responses were observed in several patients with platinum- and taxane-refractory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and troughs was observed in the pharmacologic studies. The maximal PZA concentrations achieved in both studies exceeded drug concentrations associated with significant cytotoxicity in preclinical studies and correlated with the occurrence of CNS toxicity. Conclusion: Neutropenia is the dose-limiting toxicity on both schedules and 750 mg/m2 and 150 mg/m2/d are the recommended starting doses of PZA on single-and multiple-dosing schedules, respectively, for minimally pretreated patients in phase II studies; slightly lower doses are recommended for more heavily pretreated subjects. The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase II evaluations of this agent.

AB - Purpose: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacologic behavior of pyrazoloacridine (PZA), a novel DNA intercalator with a unique mechanism of action, on single- and multiple- dosing schedules. Patients and Methods: PZA was administered on a single- dosing schedule as a 1- to 3-hour infusion and on a multiple-dosing schedule as a 1-hour infusion daily for 5 days to cancer patients at doses ranging from 400 to 935 mg/m2 and 40 to 180 mg/m2/d every 3 weeks, respectively. Results: On the single-dosing 1-hour schedule, CNS toxicity, characterized by neuropsychiatric and neuromotor effects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures resulted in lower incidence of CNS toxicity. Neutropenia was the principal toxicity and precluded dose escalation to levels greater than 750 mg/m2 on the single-dosing (3-hour) schedule and 150 mg/m2/d x 5 (total dose, 750 mg/m2) on the multiple-dosing schedule. Thrombocytopenia, anemia, and nonhematologic effects occurred less frequently. Responses were observed in several patients with platinum- and taxane-refractory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and troughs was observed in the pharmacologic studies. The maximal PZA concentrations achieved in both studies exceeded drug concentrations associated with significant cytotoxicity in preclinical studies and correlated with the occurrence of CNS toxicity. Conclusion: Neutropenia is the dose-limiting toxicity on both schedules and 750 mg/m2 and 150 mg/m2/d are the recommended starting doses of PZA on single-and multiple-dosing schedules, respectively, for minimally pretreated patients in phase II studies; slightly lower doses are recommended for more heavily pretreated subjects. The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase II evaluations of this agent.

UR - http://www.scopus.com/inward/record.url?scp=0029045628&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029045628&partnerID=8YFLogxK

M3 - Article

C2 - 7636538

AN - SCOPUS:0029045628

VL - 13

SP - 1975

EP - 1984

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 8

ER -