Novel marine-derived anticancer agents: A phase I clinical, pharmacological, and pharmacodynamic study of dolastatin 10 (NSC 376128) in patients withadvanced solid tumors

Dolastatin (DOLA)-10 is a pentapeptide isolated from the mollusc Dolabella auricularia with clinically promising antitumor activity documented in vari ous in vitro and in vivo tumor models. The objectives of this Phase I study were to determine the maximum tolerated dose, evaluate toxic effects, and document any antitumor activity of this novel agent. Using an electrospray ionization mass spectroscopy system, we also characterized the clinical pha rmacokinetics, pharmacodynamics, and metabolism of DOLA-10, The maximum tol erated dose was reached at 300 mu g/m(2), Granulocytopenia, the dose-limiti ng toxicity, was documented in 33% of the patients treated at that dose lev el. There were no episodes of thrombocytopenia or severe anemia (Hgb < 8), and no major nonhematological toxicity was observed. Stabilization of tumor growth was observed in four patients, but no objective responses were seen . Whereas a two-compartment model described the DOLA-10 plasma concentratio n-time data reasonably well, a three-compartment model consistently perform ed better. After a rapid distribution phase, DOLA-10 plasma levels declined with mean beta and gamma half-lives of 0.99 and 18.9 h, respectively. Sign ificant interpatient and intrapatient variability in DOLA-10 plasma clearan ces was observed. The mean area under the concentration-time curve increase d proportionally as the dose was escalated, but there was significant overl ap between dose levels. The area under the concentration-time curve and the percentage of decline in neutrophils were correlated. A single DOLA-10 met abolite was detected in five patients. Unlike the in vitro studies of DOLA- 10, the principal metabolite detected was an N-demethyl derivative, confirm ed by mass spectroscopy. In all five subjects, the concentration of this me tabolite never exceeded 2% of the simultaneously measured parent drug conce ntration. The available preclinical, pharmacological, and clinical data sug gest that further study of escalated DOLA-10 dosing with cytokine support i s warranted.