Purpose NC-6004, a novel cisplatin nanoparticle developed using micellar technology exhibits sustained release of cisplatin and selective distribution to tumors. Preclinical data demonstrated a favorable tolerability profile and preserved or improved anti-tumor activity compared to cisplatin across animal models. We evaluated the safety and tolerability of NC-6004 and gemcitabine using a Bayesian continual reassessment model (N-CRM) to determine the optimal dose. Experimental Design Patients with advanced solid tumors received NC-6004 at 60-180mg/m2 on Day 1 and gemcitabine at 1250 mg/m2 on Days 1 and 8 every three weeks. Dose escalation of NC-6004 began with a single patient run-in until a dose limiting toxicity occurred at 180mg/m2. Cohorts of four patients were enrolled at doses predicted by the N-CRM. The maximum tolerated dose (MTD) was defined as having the greatest probability of target toxicity < 25%. Quality of life was assessed using EORTC-QLQ-C30. Results Among 22 patients, the most common Grade 3/4 hematologic adverse events were leukopenia (68%) and thrombocytopenia (59%). Of 20 pretreated patients evaluable for response, half were previously exposed to a platinum agent. The MTD was 135 mg/m2. Nine patients were treated at the MTD with median treatment duration of 15 weeks (range, 3-50). Tumor shrinkage occurred in 11 (55%), partial responses in 3 (15%) and stable disease in 14 (70%). Most patients reported stable or improved EORTC QLQ-C30 scores. Conclusions Greater cisplatin equivalent doses were achieved with no clinically significant neuro-, oto- or nephrotoxicity. These data demonstrate tolerability and promising activity of NC-6004 in combination with gemcitabine.
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