Details

Autor(en) / Beteiligte

• Paul A. Vasey
• Stan B. Kaye
• Rosemary Morrison
• Chris Twelves
• Peter Wilson
• Ruth Duncan
• Alison H. Thomson
• Lilian S. Murray
• Tom E. Hilditch
• Tom Murray
• Sally Burtles
• D. Fraier
• E. Frigerio
• Jim Cassidy

Titel

Phase I Clinical and Pharmacokinetic Study of PK1 [N-(2-Hydroxypropyl)methacrylamide Copolymer Doxorubicin]: First Member of a New Class of Chemotherapeutic Agents—Drug-Polymer Conjugates

Ist Teil von

• Clinical cancer research, 1999-01, Vol.5 (1), p.83

Ort / Verlag

American Association for Cancer Research

Erscheinungsjahr

1999

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• PK1 comprises doxorubicin covalently bound to N -(2-hydroxypropyl)methacrylamide copolymer by a peptidyl linker. Following cellular uptake via pinocytosis, the linker is cleaved by lysosomal enzymes, allowing intratumoral drug release. Radically altered plasma and tumor pharmacokinetics, compared to free doxorubicin, and significant activity in animal tumors have been demonstrated preclinically. We aimed to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of PK1 as an i.v. infusion every 3 weeks to patients with refractory or resistant cancers. Altogether, 100 cycles were administered (range, 20–320 mg/m 2 doxorubicin-equivalent) to 36 patients (20 males and 16 females) with a mean age of 58.3 years (age range, 34–72 years). The maximum tolerated dose was 320 mg/m 2 , and the dose-limiting toxicities were febrile neutropenia and mucositis. No congestive cardiac failure was seen despite individual cumulative doses up to 1680 mg/m 2 . Other anthracycline-like toxicities were attenuated. Pharmacokinetically, PK1 has a distribution t 1/2 of 1.8 h and an elimination t 1/2 averaging 93 h. 131 I-labeled PK1 imaging suggests PK1 is taken up by some tumors. Responses (two partial and two minor responses) were seen in four patients with NSCLC, colorectal cancer, and anthracycline-resistant breast cancer. PK1 demonstrated antitumor activity in refractory cancers, no polymer-related toxicity, and proof of principle that polymer-drug conjugation decreases doxorubicin dose-limiting toxicities. The recommended Phase II dose is 280 mg/m 2 every 3 weeks. Studies are planned in colorectal, NSCLC, and breast cancer patients.