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

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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.

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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