Phase I, open-label, dose-escalating clinical and pharmacokinetic study of PM00104 administered weekly resting every fourth week, intravenously, over 1 hour to patients with advanced malignant solid tumors or lymphoma

Background: PM00104 (Zalypsis®) is a new synthetic alkaloid related to jorumycin. Preliminary data on mechanism of action suggested DNA‐binding properties acting at minor groove and effects on the cell cycle (phase S). PM00104 shows a broad spectrum of activity against solid tumors both in vitro (bladder, gastric, kidney, melanoma, pancreas, prostate, sarcoma, thyroid, leukemia and lymphoma cell lines) and in vivo (xenografts of breast, gastric, prostate, and renal tumor). Methods: Patients (n=49) with metastatic or advanced solid tumors were enrolled in a phase I, open‐label, dose‐escalating clinical and pharmacokinetic study of PM00104 administered weekly resting every fourth week, intravenously, over 1 hour. The starting dose was 0.75 mg/m2 and the study followed an accelerated escalation design from 0.75 to 3.037 mg/m2 distributed in 9 dose levels Results: Median age of patients (pts) was 58 (range, 22–76 y), 29 pts were males. The median ECOG was 1 (0–2). The most frequent cancer types were colorectal, gastric, esophageal and melanoma tumors (n=15/5/4/4). Most patients were heavily pretreated with a median of 3 (1–9) prior lines. A median of 2 cycles of Zalypsis (1–8) were given to each pt. Common mild (G1–2) toxicities were asthenia, anorexia, nausea/emesis, stomatitis, weight decreased, headache and hypotension. The highest dose achieved was 3.035 mg/m2, where 2 pts had DLTs: one had G4 asthenia and G3 nausea, and the other had G4 neutropenia and thrombopenia. At the next lowest level (2.5 mg/m2) 3 pts had DLTs (G3 asthenia and nausea in one pt; febrile neutropenia, G4 thrombopenia and G3 anemia in one pt, and G1 neutropenia and thrombopenia that resulted in two skipped doses in the third pt). Thus, this dose level was declared the MTD. The RD was 2 mg/m2, at which 24 pts were treated and only one pt had DLT (G4 asymptomatic lipase increase). Preliminary PK data showed a relatively prolonged half‐life (up to 60 h, with a median value at the RD of 21 h), a wide distribution and high inter‐patient variability. Efficacy data showed prolonged stabilization > 3 months in 12 pts, mostly with gastrointestinal tumors (colon, pancreas, esophageal and gastroesophageal junction, n=1 each) Conclusions: PM00104 shows acceptable safety and tolerability profile and prolonged stabilization (SD ≥3 months) in different tumor types. DLTs were manageable hematological and gastrointestinal toxicities. The RD for phase II studies is 2 mg/m2 weekly. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B149.