First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours.

This phase I clinical trial investigated the safety, tolerability, pharmacokinetics (how the body handles the drug), and preliminary anti-tumor activity of PM00104 (Zalypsis), a new synthetic drug, in patients with advanced solid tumors. A total of 47 patients were enrolled across three centers and received PM00104 in a dose-escalation study, administered as either a 1-hour (27 patients) or 3-hour (20 patients) intravenous infusion every three weeks. The study identified dose-limiting toxicities (DLTs), which included reversible nausea, vomiting, fatigue, elevated liver enzymes (transaminases), low platelet count (thrombocytopenia) for the 1-hour schedule, and reversible low blood pressure (hypotension) and low white blood cell count (neutropenia) for the 3-hour schedule. Based on these DLTs, the recommended phase II dose (RP2D) was established at 3.0 mg/m² for the 1-hour schedule and 2.8 mg/m² for the 3-hour schedule. Common drug-related side effects at these recommended doses were mild to moderate nausea, fatigue, and bone marrow suppression (myelosuppression). Pharmacokinetic analysis showed that the drug's exposure in the body increased proportionally with the dose up to the RP2D. Preliminary anti-tumor activity was observed: one patient with advanced urothelial carcinoma experienced a 49% tumor shrinkage, and three other patients achieved stable disease (meaning their cancer did not grow) for six months or longer. The study concluded that PM00104 is generally well-tolerated, causes manageable and reversible side effects, and shows early signs of effectiveness against tumors. The 1-hour, 3-weekly schedule is now being further evaluated in phase II clinical trials.