Phase I Trials Of CRC Technologies' PK-1

Doxorubicin has been a valuable drug for the management of patients with a range of malignancies for many years, but its use has been limited by both its acute toxicity (myelosuppression) and cumulative toxicity (cardiotoxicity). Liposomal products seeking to reduce these toxicities are starting to come into use (Marketletters passim), but another approach was presented at the Eighth European Cancer Conference held in Paris, France, on November 1.

The new approach consists of linking doxorubicin to a polymer (HPMA) via a peptidyl spacer. Once the conjugate is taken up by cells (by endocytosis, a different mechanism than with conventional doxorubicin), this linkage is cleaved by lysosomal proteases, releasing free doxorubicin to exert its cytotoxic effects. This approach, originally developed by Ruth Duncan while working with the UK's Cancer Research Campaign, should mean that free doxorubicin is not available in the circulation (or at least not in such high concentrations) to cause general toxicities.

Chris Twelves of Glasgow's Western Infirmary told the meeting that improved antitumor activity, as well as reductions in myelogenous and cardiac toxicities, have been observed in preclinical models. In a Phase I trial to determine the maximum tolerated dose of PK1, doses of between 20mg/m2 to 320 mg/m2 given as an infusion every three weeks were studied in 19 patients, and there are early indications that toxicities may be ameliorated. For example, cumulative doses of up to 1400mg/m2 have been given to some of these patients without cardiotoxicity; with conventional doxorubicin, this cardiotoxicity can be observed after just 500mg/m2. There were two responses in the study, both partial responses in patients with non-small cell lung cancer.