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

PK1 comprises doxorubicin covalently bound to N-(2-hydroxypropyl)methacryla mide copolymer by a peptidyl Linker, Following cellular uptake via pinocyto sis, 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 demon strated preclinically, We aimed to determine the maximum tolerated dose, to xicity profile, and pharmacokinetics of PK1 as an i.v. infusion every 3 wee ks 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 dose s 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 eliminat ion t(1/2) averaging 93 h. I-131-labeled PK1 imaging suggests PK1 is taken up by some tumors, Responses (two partial and two minor responses) were see n in four patients with NSCLC, colorectal cancer, and anthracycline-resista nt breast cancer. PK1 demonstrated antitumor activity in refractory cancers, no polymer-relat ed 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 breas t cancer patients.