A Phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients

Jean L. Grem, Nancy Harold, Bruce Keith, Alice P. Chen, Viven Kao, Chris H. Takimoto, J. Michael Hamilton, Janet Pang, Marie Pace, Gada B. Jasser, Mary G. Quinn, Brian P. Monahan

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Purpose: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases I and II through a mechanism distinct from other topoisomerase poisons. PZA shows schedule-independent cytotoxicity against tumor cells, whereas host toxicity is greater with shorter infusions. We assessed the clinical toxicities and pharmacologic effects of PZA given as a 24-h i.v. infusion weekly for 3 of 4 weeks. Experimental Design: Thirty-two adult patients with solid tumors received PZA at five dose levels (100-351 mg/m2). Plasma samples were obtained at the end of the PZA infusion at all of the dose levels, with extended sampling in a cohort treated at the recommended dose. Results: Dose-limiting granulocytopenia and mucositis occurred in 2 of 6 patients at 351 mg/m2, but lower doses were well tolerated. No responses were seen, but 28% had stable disease for ≥3 months. Plasma levels strongly correlated with the degree of granulocytopenia. Extended pharmacokinetics in 7 patients treated with 281 mg/m2 indicated the following averages: maximum plasma level, 1.6 μM; area under the plasma concentration-time curve, 56 μM-h; terminal half-life, 27 h; urinary recovery, 17% over 72 h. DNA fragmentation in post-PZA bone marrow mononuclear cells was seen in 9 of 28 samples (all at ≥281 mg/m2). Conclusions: Unlike other schedules of PZA, neurotoxicity and thrombocytopenia were not problematic with a weekly 24-h infusion of PZA. The recommended Phase II dose is 281 mg/m2, which was well tolerated. Both end of infusion plasma levels and presence of DNA damage correlated with granulocyte toxicity.

Original languageEnglish (US)
Pages (from-to)2149-2156
Number of pages8
JournalClinical Cancer Research
Volume8
Issue number7
StatePublished - Jan 1 2002

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NSC 366140
Intravenous Infusions
Neoplasms
Agranulocytosis
Appointments and Schedules
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Mucositis
Poisons
DNA Fragmentation
Granulocytes
Bone Marrow Cells
Thrombocytopenia
Nucleic Acids
DNA Damage
Half-Life

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A Phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients. / Grem, Jean L.; Harold, Nancy; Keith, Bruce; Chen, Alice P.; Kao, Viven; Takimoto, Chris H.; Hamilton, J. Michael; Pang, Janet; Pace, Marie; Jasser, Gada B.; Quinn, Mary G.; Monahan, Brian P.

In: Clinical Cancer Research, Vol. 8, No. 7, 01.01.2002, p. 2149-2156.

Research output: Contribution to journalArticle

Grem, JL, Harold, N, Keith, B, Chen, AP, Kao, V, Takimoto, CH, Hamilton, JM, Pang, J, Pace, M, Jasser, GB, Quinn, MG & Monahan, BP 2002, 'A Phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients', Clinical Cancer Research, vol. 8, no. 7, pp. 2149-2156.
Grem, Jean L. ; Harold, Nancy ; Keith, Bruce ; Chen, Alice P. ; Kao, Viven ; Takimoto, Chris H. ; Hamilton, J. Michael ; Pang, Janet ; Pace, Marie ; Jasser, Gada B. ; Quinn, Mary G. ; Monahan, Brian P. / A Phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients. In: Clinical Cancer Research. 2002 ; Vol. 8, No. 7. pp. 2149-2156.
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abstract = "Purpose: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases I and II through a mechanism distinct from other topoisomerase poisons. PZA shows schedule-independent cytotoxicity against tumor cells, whereas host toxicity is greater with shorter infusions. We assessed the clinical toxicities and pharmacologic effects of PZA given as a 24-h i.v. infusion weekly for 3 of 4 weeks. Experimental Design: Thirty-two adult patients with solid tumors received PZA at five dose levels (100-351 mg/m2). Plasma samples were obtained at the end of the PZA infusion at all of the dose levels, with extended sampling in a cohort treated at the recommended dose. Results: Dose-limiting granulocytopenia and mucositis occurred in 2 of 6 patients at 351 mg/m2, but lower doses were well tolerated. No responses were seen, but 28{\%} had stable disease for ≥3 months. Plasma levels strongly correlated with the degree of granulocytopenia. Extended pharmacokinetics in 7 patients treated with 281 mg/m2 indicated the following averages: maximum plasma level, 1.6 μM; area under the plasma concentration-time curve, 56 μM-h; terminal half-life, 27 h; urinary recovery, 17{\%} over 72 h. DNA fragmentation in post-PZA bone marrow mononuclear cells was seen in 9 of 28 samples (all at ≥281 mg/m2). Conclusions: Unlike other schedules of PZA, neurotoxicity and thrombocytopenia were not problematic with a weekly 24-h infusion of PZA. The recommended Phase II dose is 281 mg/m2, which was well tolerated. Both end of infusion plasma levels and presence of DNA damage correlated with granulocyte toxicity.",
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T1 - A Phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients

AU - Grem, Jean L.

AU - Harold, Nancy

AU - Keith, Bruce

AU - Chen, Alice P.

AU - Kao, Viven

AU - Takimoto, Chris H.

AU - Hamilton, J. Michael

AU - Pang, Janet

AU - Pace, Marie

AU - Jasser, Gada B.

AU - Quinn, Mary G.

AU - Monahan, Brian P.

PY - 2002/1/1

Y1 - 2002/1/1

N2 - Purpose: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases I and II through a mechanism distinct from other topoisomerase poisons. PZA shows schedule-independent cytotoxicity against tumor cells, whereas host toxicity is greater with shorter infusions. We assessed the clinical toxicities and pharmacologic effects of PZA given as a 24-h i.v. infusion weekly for 3 of 4 weeks. Experimental Design: Thirty-two adult patients with solid tumors received PZA at five dose levels (100-351 mg/m2). Plasma samples were obtained at the end of the PZA infusion at all of the dose levels, with extended sampling in a cohort treated at the recommended dose. Results: Dose-limiting granulocytopenia and mucositis occurred in 2 of 6 patients at 351 mg/m2, but lower doses were well tolerated. No responses were seen, but 28% had stable disease for ≥3 months. Plasma levels strongly correlated with the degree of granulocytopenia. Extended pharmacokinetics in 7 patients treated with 281 mg/m2 indicated the following averages: maximum plasma level, 1.6 μM; area under the plasma concentration-time curve, 56 μM-h; terminal half-life, 27 h; urinary recovery, 17% over 72 h. DNA fragmentation in post-PZA bone marrow mononuclear cells was seen in 9 of 28 samples (all at ≥281 mg/m2). Conclusions: Unlike other schedules of PZA, neurotoxicity and thrombocytopenia were not problematic with a weekly 24-h infusion of PZA. The recommended Phase II dose is 281 mg/m2, which was well tolerated. Both end of infusion plasma levels and presence of DNA damage correlated with granulocyte toxicity.

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