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Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors.
- Source :
-
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 1999 Feb; Vol. 17 (2), pp. 685-96. - Publication Year :
- 1999
-
Abstract
- Purpose: We conducted a phase I dose-escalation trial of orally administered irinotecan (CPT-11) to characterize the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic profile, and antitumor effects in patients with refractory malignancies.<br />Patients and Methods: CPT-11 solution for intravenous (IV) use was mixed with CranGrape juice (Ocean Spray, Lakeville-Middleboro, MA) and administered orally once per day for 5 days every 3 weeks to 28 patients. Starting dosages ranged from 20 to 100 mg/m2/d.<br />Results: Grade 4 delayed diarrhea was the DLT at the 80 mg/m2/d dosage in patients younger than 65 years of age and at the 66 mg/m2/d dosage in patients 65 or older. The other most clinically significant toxicity of oral CPT-11 was neutropenia. A linear relationship was found between dose, peak plasma concentration, and area under the concentration-time curve (AUC) for both CPT-11 and SN-38 lactone, implying no saturation in the conversion of irinotecan to SN-38. The mean metabolic ratio ([AUC(SN-38 total) + AUC(SN-38G total)]/AUC(CPT-11 total)) was 0.7 to 0.8, which suggests that oral dosing results in presystemic conversion of CPT-11 to SN-38. An average of 72% of SN-38 was maintained in the lactone form during the first 24 hours after drug administration. One patient with previously treated colorectal cancer and liver metastases who received oral CPT-11 at the 80 mg/m2/d dosage achieved a confirmed partial response.<br />Conclusion: The MTD and recommended phase II dosage for oral CPT-11 is 66 mg/m2/d in patients younger than 65 years of age and 50 mg/m2/d in patients 65 or older, administered daily for 5 days every 3 weeks. The DLT of diarrhea is similar to that observed with IV administration of CPT-11. The biologic activity and favorable pharmacokinetic characteristics make oral administration of CPT-11 an attractive option for further clinical development.
- Subjects :
- Administration, Oral
Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Phytogenic adverse effects
Camptothecin adverse effects
Camptothecin blood
Camptothecin pharmacokinetics
Camptothecin therapeutic use
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Irinotecan
Male
Middle Aged
Antineoplastic Agents, Phytogenic pharmacokinetics
Antineoplastic Agents, Phytogenic therapeutic use
Camptothecin analogs & derivatives
Neoplasms drug therapy
Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0732-183X
- Volume :
- 17
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 10080615
- Full Text :
- https://doi.org/10.1200/JCO.1999.17.2.685