HPMA copolymer-camptothecin MAG-CPT PNU

Camptothecin (CPT) from an Oriental tree, Camptotheca acuminata, is an inhibitor of topoisomerase I and has exhibited a promising antitumour ac- 

Two dosing schedules were studied dicing Phase I evaluation of MAG-CPT. An i.v. infusion over 30 min every 28 days [114], and as an alternative, daily treatment (x3) repeated every four weeks [115]. hi the first study [114] 62 patients were entered starting at a dose of 30 mg/m (camptothecin-equivalent). Dose escalation progressed to an MTD of 240 mg/m with 200 mg/m the recommended dose for further studies. At 240mg/m the DLTs included grade 4 neutropenia and thrombocytopenia, and grade 3 diarrhoea. Severe and impredictable cystitis was also seen. 

In the recently reported Phase 1 study [114], MAG-CPT was administered as a 30 min infusion on three consecutive days every four weeks. The starting dose was 17 mg/m /day and this was escalated to 130 mg/m /day total dose per cycle = 390 mg/m. Haematological toxicity was rare, but cumulative bladder toxicity was dose-hmiting at doses of 68 mg/m or greater. This could only be resolved by withdrawal of treatment. Of the 16 patients entered in this trial, 11 were evaluable for chnical responses after two courses. These two Phase I studies were the first involving HPMA copolymer conjugates in which no objective clinical responses were seen. However, one patient with renal cell carcinoma had tumour shrinkage and a colon patient had stable disease for 62 days. 

A second lead HPMA copolymer-platinate (AP5346) has been identified with a similar Gly-Phe-Leu-Gly-aminomalonate side chain, but in this case terminating in a 1,2-diaminocyclohexyl (DACH) palatinate (Fig. 8). hi Phase 1 clinical trial, it was administered as intravenous infusion of 80-1280 mg Pt/m once a week in 28-day cycle to patients with a broad cross-section of tumour types. Out of the 12 evaluable patients, one demonstrated a partial response. Dose hmiting toxicity was neutropenia but also nausea, vomiting, asthenia, fatigue and diarrhoea were observed (as presented in October 2004 at the 16th 

EORTC-NCI-AACR Symposium in Geneva). An Investigational New Drug application was filed with the FDA in December 2004. 

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