A phase I and pharmacologic study of pyrazoloacridine (NSC 366140) and carboplatin in patients with advanced cancer

Alex Adjei, Joel M Reid, Charles Erlichman, Jeff A Sloan, Henry Clement Pitot, Steven Robert Alberts, Richard M. Goldberg, Lorelei J. Hanson, Stacie Ruben, Scott A. Boerner, Pamela Atherton, Matthew M. Ames, Scott H Kaufmann

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. We previously demonstrated cytotoxic synergy between combinations of PZA and platinum compounds. Subsequent studies revealed that PZA inhibits removal of platinum-DNA adducts in cultured A549 cells. Based on these results, we undertook a phase I study of the combination of PZA and carboplatin (CBDCA). Patients and methods: Twenty-eight patients received 76 28-day courses (median 2.5, range 1-6) of CBDCA (30-minute infusion) followed by PZA (3-hour infusion), through six dose levels [PZA/CBDCA] (200/AUC 3, 400/AUC 3, 400/AUC 4, 400/AUC 5, 500/AUC 5, 600/AUC 5 mg/m2/AUC). Pharmacokinetic analyses were performed to evaluate the disposition of PZA. Retention of platinum-DNA adducts in peripheral blood mononuclear cells of patients was also evaluated. Results: The most common and dose-limiting toxicity was myelosuppression, consisting of neutropenia and leukopenia. Non-hematologic toxicities of anorexia, nausea and stomatitis were mild to moderate. In six patients evaluated at the MTD, CBDCA did not appear to: affect the pharmacokinetics of PZA. One patient with malignant melanoma had a partial response. Disease stabilization for greater than 4 courses of treatment occurred in 4 patients. Conclusion: The combination of PZA and CBDCA was well tolerated and may have utility in some tumor types.

Original languageEnglish (US)
Pages (from-to)297-304
Number of pages8
JournalInvestigational New Drugs
Volume20
Issue number3
DOIs
StatePublished - 2002

Fingerprint

NSC 366140
Carboplatin
Area Under Curve
Neoplasms
DNA Adducts
Platinum
Pharmacokinetics
Platinum Compounds
Acridines
Stomatitis
Leukopenia
Anorexia
Neutropenia

Keywords

  • Phase I
  • Platinum
  • Pyrazoloacridine
  • Topoisomerases

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

A phase I and pharmacologic study of pyrazoloacridine (NSC 366140) and carboplatin in patients with advanced cancer. / Adjei, Alex; Reid, Joel M; Erlichman, Charles; Sloan, Jeff A; Pitot, Henry Clement; Alberts, Steven Robert; Goldberg, Richard M.; Hanson, Lorelei J.; Ruben, Stacie; Boerner, Scott A.; Atherton, Pamela; Ames, Matthew M.; Kaufmann, Scott H.

In: Investigational New Drugs, Vol. 20, No. 3, 2002, p. 297-304.

Research output: Contribution to journalArticle

Adjei, Alex ; Reid, Joel M ; Erlichman, Charles ; Sloan, Jeff A ; Pitot, Henry Clement ; Alberts, Steven Robert ; Goldberg, Richard M. ; Hanson, Lorelei J. ; Ruben, Stacie ; Boerner, Scott A. ; Atherton, Pamela ; Ames, Matthew M. ; Kaufmann, Scott H. / A phase I and pharmacologic study of pyrazoloacridine (NSC 366140) and carboplatin in patients with advanced cancer. In: Investigational New Drugs. 2002 ; Vol. 20, No. 3. pp. 297-304.
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abstract = "Background: Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. We previously demonstrated cytotoxic synergy between combinations of PZA and platinum compounds. Subsequent studies revealed that PZA inhibits removal of platinum-DNA adducts in cultured A549 cells. Based on these results, we undertook a phase I study of the combination of PZA and carboplatin (CBDCA). Patients and methods: Twenty-eight patients received 76 28-day courses (median 2.5, range 1-6) of CBDCA (30-minute infusion) followed by PZA (3-hour infusion), through six dose levels [PZA/CBDCA] (200/AUC 3, 400/AUC 3, 400/AUC 4, 400/AUC 5, 500/AUC 5, 600/AUC 5 mg/m2/AUC). Pharmacokinetic analyses were performed to evaluate the disposition of PZA. Retention of platinum-DNA adducts in peripheral blood mononuclear cells of patients was also evaluated. Results: The most common and dose-limiting toxicity was myelosuppression, consisting of neutropenia and leukopenia. Non-hematologic toxicities of anorexia, nausea and stomatitis were mild to moderate. In six patients evaluated at the MTD, CBDCA did not appear to: affect the pharmacokinetics of PZA. One patient with malignant melanoma had a partial response. Disease stabilization for greater than 4 courses of treatment occurred in 4 patients. Conclusion: The combination of PZA and CBDCA was well tolerated and may have utility in some tumor types.",
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T1 - A phase I and pharmacologic study of pyrazoloacridine (NSC 366140) and carboplatin in patients with advanced cancer

AU - Adjei, Alex

AU - Reid, Joel M

AU - Erlichman, Charles

AU - Sloan, Jeff A

AU - Pitot, Henry Clement

AU - Alberts, Steven Robert

AU - Goldberg, Richard M.

AU - Hanson, Lorelei J.

AU - Ruben, Stacie

AU - Boerner, Scott A.

AU - Atherton, Pamela

AU - Ames, Matthew M.

AU - Kaufmann, Scott H

PY - 2002

Y1 - 2002

N2 - Background: Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. We previously demonstrated cytotoxic synergy between combinations of PZA and platinum compounds. Subsequent studies revealed that PZA inhibits removal of platinum-DNA adducts in cultured A549 cells. Based on these results, we undertook a phase I study of the combination of PZA and carboplatin (CBDCA). Patients and methods: Twenty-eight patients received 76 28-day courses (median 2.5, range 1-6) of CBDCA (30-minute infusion) followed by PZA (3-hour infusion), through six dose levels [PZA/CBDCA] (200/AUC 3, 400/AUC 3, 400/AUC 4, 400/AUC 5, 500/AUC 5, 600/AUC 5 mg/m2/AUC). Pharmacokinetic analyses were performed to evaluate the disposition of PZA. Retention of platinum-DNA adducts in peripheral blood mononuclear cells of patients was also evaluated. Results: The most common and dose-limiting toxicity was myelosuppression, consisting of neutropenia and leukopenia. Non-hematologic toxicities of anorexia, nausea and stomatitis were mild to moderate. In six patients evaluated at the MTD, CBDCA did not appear to: affect the pharmacokinetics of PZA. One patient with malignant melanoma had a partial response. Disease stabilization for greater than 4 courses of treatment occurred in 4 patients. Conclusion: The combination of PZA and CBDCA was well tolerated and may have utility in some tumor types.

AB - Background: Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. We previously demonstrated cytotoxic synergy between combinations of PZA and platinum compounds. Subsequent studies revealed that PZA inhibits removal of platinum-DNA adducts in cultured A549 cells. Based on these results, we undertook a phase I study of the combination of PZA and carboplatin (CBDCA). Patients and methods: Twenty-eight patients received 76 28-day courses (median 2.5, range 1-6) of CBDCA (30-minute infusion) followed by PZA (3-hour infusion), through six dose levels [PZA/CBDCA] (200/AUC 3, 400/AUC 3, 400/AUC 4, 400/AUC 5, 500/AUC 5, 600/AUC 5 mg/m2/AUC). Pharmacokinetic analyses were performed to evaluate the disposition of PZA. Retention of platinum-DNA adducts in peripheral blood mononuclear cells of patients was also evaluated. Results: The most common and dose-limiting toxicity was myelosuppression, consisting of neutropenia and leukopenia. Non-hematologic toxicities of anorexia, nausea and stomatitis were mild to moderate. In six patients evaluated at the MTD, CBDCA did not appear to: affect the pharmacokinetics of PZA. One patient with malignant melanoma had a partial response. Disease stabilization for greater than 4 courses of treatment occurred in 4 patients. Conclusion: The combination of PZA and CBDCA was well tolerated and may have utility in some tumor types.

KW - Phase I

KW - Platinum

KW - Pyrazoloacridine

KW - Topoisomerases

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