A phase I and pharmacologic study of 9-aminocamptothecin administered as a 120-h infusion weekly to adult cancer patients.

Abstract

PURPOSE:

To define the toxicity profile and the recommended phase II doses of 9-aminocamptothecin (9-AC) administered as a weekly 120-h infusion.

METHODS:

9-AC was administered over 120 h weekly to 55 adult cancer patients with solid tumors over doses ranging from 0.41 to 0.77 mg/m2 per day in a phase I and pharmacologic study. 9-AC formulated in dimethylacetamide/polyethylene glycol (DMA) was administered on a 3 of 4-week schedule, and the newer colloidal dispersion (CD) formulation was given on a 2 of 3-week schedule.

RESULTS:

Overall, 193 courses of therapy were administered over 122 dose levels. On the 3 of 4-week schedule, 9-AC DMA infused at > or = 0.6 mg/m2 per day for 120 h weekly produced dose-limiting neutropenia, thrombocytopenia, and diarrhea, or resulted in 1-2-week treatment delays. Shortening treatments to 2 of 3 weeks resulted in dose-limiting neutropenia and fatigue at infusion rates > 0.72 mg/m2 per day. The ratio of 9-AC lactone to total (carboxylate + lactone) drug plasma concentrations at steady-state was 0.15 +/- 0.07. Clinical toxicities and drug pharmacokinetics were not substantially different between the DMA and CD formulations. One objective response was observed in a patient with bladder cancer and minor responses were observed in patients with lung and colon cancers. Plasma area under the concentration versus time curve for 9-AC lactone modestly correlated with the degree of thrombocytopenia (r=0.51) using a sigmoid Emax pharmacodynamic model.

CONCLUSION:

The recommended phase II dose for the 9-AC DMA formulation is 0.48 mg/m2 per h over 120 h for 3 of 4 weeks and for the 9-AC CD formulation is 0.6 mg/m2 per day over 120 h for 2 of 3 weeks. Both regimens were well tolerated and feasible to administer.

• Authors: R R Thomas, W Dahut, N Harold, J L Grem, B P Monahan, M Liang, R A Band, J Cottrell, V Llorens, J A Smith, W Corse, S G Arbuck, J Wright, A P Chen, J D Shapiro, J M Hamilton, C J Allegra, C H Takimoto
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 48 Issue 3 Pg. 215-22 (Sep 2001) ISSN: 0344-5704 [Print] Germany
• PMID: 11592343 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• 9-aminocamptothecin
• Camptothecin

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Area Under Curve
• Camptothecin (administration & dosage, analogs & derivatives, pharmacokinetics)
• Dose-Response Relationship, Drug
• Female
• Follow-Up Studies
• Hematologic Tests
• Humans
• Infusions, Intravenous
• Male
• Metabolic Clearance Rate
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Platelet Count