A phase I study of 9-aminocamptothecin as a colloidal dispersion formulation given as a fortnightly 72-h infusion

Jorge Leguizamo, Mary Quinn, Chris H. Takimoto, Michael D. Liang, Abdel Salam Attia Ismail, Janet Pang, William Dahut, Jean L. Grem

Research output: Contribution to journalArticle

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Abstract

Purpose: A phase I pharmacologic study was undertaken to determine the maximum tolerated dose (MTD), to characterize the pharmacokinetic profile, and to evaluate all toxicities of the aqueous colloidal dispersion formulation of 9-aminocampothecin (9-AC). Methods: 9-AC was administered as a constant 72-h i.v. infusion every 2 weeks to adult cancer patients at dose rates ranging from 25 to 59 μg/m2 per hour. Results: Twenty patients with refractory solid tumors received a total of 86 courses of 9-AC at four dose levels. Myelosuppression, particularly granulocytopenia, was the most common toxicity. Two of six assessable patients entered at 59 μg/m2 per hour had dose-limiting toxicity (grade 3 diarrhea or need for a 2-week treatment delay to permit granulocyte recovery), whereas lower doses were well tolerated. At the recommended dose, 47 μg/m2 per hour, the average steady-state plasma levels (Cpss) and area under the curve (AUC) of 9-AC lactone and total drug were 15 and 75 nM, and 1034 and 4220 nM·h, respectively. A moderate correlation was seen between 9-AC lactone AUC and the percentage decrease in granulocytes. Conclusions: The recommended phase II dose of 9-AC colloidal dispersion as a 72-h infusion every 14 days is 47 μg/m2 per hour (1.13 mg/m2 per day). The Cpss of 9-AC lactone at this dose exceeded the 10 nM threshold level for preclinical activity.

Original languageEnglish (US)
Pages (from-to)333-338
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume52
Issue number4
DOIs
StatePublished - Oct 1 2003

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9-aminocamptothecin
Lactones
Toxicity
Granulocytes
Area Under Curve
Agranulocytosis
Pharmacokinetics
Maximum Tolerated Dose
Refractory materials
Dosimetry
Tumors
Diarrhea
Neoplasms
Plasmas
Recovery
Pharmaceutical Preparations

Keywords

  • Camptothecin
  • Pharmacodynamics
  • Pharmacokinetics
  • Phase I
  • Topoisomerase I

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A phase I study of 9-aminocamptothecin as a colloidal dispersion formulation given as a fortnightly 72-h infusion. / Leguizamo, Jorge; Quinn, Mary; Takimoto, Chris H.; Liang, Michael D.; Ismail, Abdel Salam Attia; Pang, Janet; Dahut, William; Grem, Jean L.

In: Cancer Chemotherapy and Pharmacology, Vol. 52, No. 4, 01.10.2003, p. 333-338.

Research output: Contribution to journalArticle

Leguizamo, Jorge ; Quinn, Mary ; Takimoto, Chris H. ; Liang, Michael D. ; Ismail, Abdel Salam Attia ; Pang, Janet ; Dahut, William ; Grem, Jean L. / A phase I study of 9-aminocamptothecin as a colloidal dispersion formulation given as a fortnightly 72-h infusion. In: Cancer Chemotherapy and Pharmacology. 2003 ; Vol. 52, No. 4. pp. 333-338.
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AU - Takimoto, Chris H.

AU - Liang, Michael D.

AU - Ismail, Abdel Salam Attia

AU - Pang, Janet

AU - Dahut, William

AU - Grem, Jean L.

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N2 - Purpose: A phase I pharmacologic study was undertaken to determine the maximum tolerated dose (MTD), to characterize the pharmacokinetic profile, and to evaluate all toxicities of the aqueous colloidal dispersion formulation of 9-aminocampothecin (9-AC). Methods: 9-AC was administered as a constant 72-h i.v. infusion every 2 weeks to adult cancer patients at dose rates ranging from 25 to 59 μg/m2 per hour. Results: Twenty patients with refractory solid tumors received a total of 86 courses of 9-AC at four dose levels. Myelosuppression, particularly granulocytopenia, was the most common toxicity. Two of six assessable patients entered at 59 μg/m2 per hour had dose-limiting toxicity (grade 3 diarrhea or need for a 2-week treatment delay to permit granulocyte recovery), whereas lower doses were well tolerated. At the recommended dose, 47 μg/m2 per hour, the average steady-state plasma levels (Cpss) and area under the curve (AUC) of 9-AC lactone and total drug were 15 and 75 nM, and 1034 and 4220 nM·h, respectively. A moderate correlation was seen between 9-AC lactone AUC and the percentage decrease in granulocytes. Conclusions: The recommended phase II dose of 9-AC colloidal dispersion as a 72-h infusion every 14 days is 47 μg/m2 per hour (1.13 mg/m2 per day). The Cpss of 9-AC lactone at this dose exceeded the 10 nM threshold level for preclinical activity.

AB - Purpose: A phase I pharmacologic study was undertaken to determine the maximum tolerated dose (MTD), to characterize the pharmacokinetic profile, and to evaluate all toxicities of the aqueous colloidal dispersion formulation of 9-aminocampothecin (9-AC). Methods: 9-AC was administered as a constant 72-h i.v. infusion every 2 weeks to adult cancer patients at dose rates ranging from 25 to 59 μg/m2 per hour. Results: Twenty patients with refractory solid tumors received a total of 86 courses of 9-AC at four dose levels. Myelosuppression, particularly granulocytopenia, was the most common toxicity. Two of six assessable patients entered at 59 μg/m2 per hour had dose-limiting toxicity (grade 3 diarrhea or need for a 2-week treatment delay to permit granulocyte recovery), whereas lower doses were well tolerated. At the recommended dose, 47 μg/m2 per hour, the average steady-state plasma levels (Cpss) and area under the curve (AUC) of 9-AC lactone and total drug were 15 and 75 nM, and 1034 and 4220 nM·h, respectively. A moderate correlation was seen between 9-AC lactone AUC and the percentage decrease in granulocytes. Conclusions: The recommended phase II dose of 9-AC colloidal dispersion as a 72-h infusion every 14 days is 47 μg/m2 per hour (1.13 mg/m2 per day). The Cpss of 9-AC lactone at this dose exceeded the 10 nM threshold level for preclinical activity.

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