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CRC Department of Medical Oncology, Beatson Oncology Centre, Glasgow, United Kingdom, G11 6NT [P. A. V., S. B. K., R. M., C. T., P. W.]; The School of Pharmacy, University of London, London, United Kingdom, WC1N 1AX [R. D.]; Departments of Medicine and Therapeutics [A. H. T., S. M.] and Clinical Physics and Bio-Engineering [T. E. H.] and Radionuclide Dispensary [T. M.], Western Infirmary, Glasgow, United Kingdom, G116NT; Cancer Research Campaign, London, United Kingdom [S. B.]; Bioanalytical Laboratory, Pharmacokinetics and Metabolism Department, Pharmacia and Upjohn, Nerviano, Italy [D. F., E. F.]; Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom, AB25 2ZD [J. C.]
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/m2 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/m2, and the dose-limiting toxicities were febrile neutropenia and mucositis. No congestive cardiac failure was seen despite individual cumulative doses up to 1680 mg/m2. Other anthracycline-like toxicities were attenuated. Pharmacokinetically, PK1 has a distribution t1/2 of 1.8 h and an elimination t1/2 averaging 93 h. 131I-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/m2 every 3 weeks. Studies are planned in colorectal, NSCLC, and breast cancer patients.
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