A phase I and pharmacodynamic evaluation of polyethylene glycol-conjugatedL-asparaginase in patients with advanced solid tumors

Purpose: To evaluate the in vitro activity of polyethylene glycol-conjugate d L-asparaginase (PEG-L-asparaginase) against fresh human tumor specimens, using the human tumor clonogenic assay (HTCA), and to perform a phase I dos e-escalation clinical trial of PEG-L-asparaginase. The goal of the clinical study was to determine the toxicity and optimum biologic dose of PEG-L-asp araginase based on depletion of serum L-asparagine in patients with advance d solid tumors. Methods: A modified method for determination of serum L-asp aragine is described. PEG-L-asparaginase was administered by intramuscular injection every 2 weeks to 28 patients with various types of advanced solid tumor malignancies. At least 3 patients were evaluated at each dose level: 250 IU/m(2), 500 IU/m(2), 1,000 IU/m(2), 1,500 IU/m(2), 2,000 IU/m(2). Res ults: The in vitro HTCA studies suggested good antitumor activity against m alignant melanoma and multiple myeloma. Serum L-asparagine was most consist ently and profoundly depleted (up to 4 weeks) in patients treated with 2,00 0 IU/m(2) Patients receiving this dose level also showed more frequent grad e 1, grade 2, and occasional grade 3 toxicities of fatigue/weakness, nausea /vomiting, and anorexia/ weight loss. Three patients developed hypersensiti vity reactions, but these were not dose related. Two patients developed dee p vein thromboses. We saw no episodes of clinical pancreatitis, but there w ere minor fluctuations of serum amylase and lipase. We saw no partial or co mplete responses in patients treated in this study, including 11 patients w ith malignant melanoma. Conclusions: We conclude that PEG-L-asparaginase is generally well tolerated in patients with advanced solid tumors, and a dos age of 2,000 IU/m(2) by intramuscular injection every 2 weeks results in si gnificant depletion of serum L-asparagine.