PHASE-I HUMAN CLINICAL-TRIAL OF ONCONASE(R) (P-30 PROTEIN) ADMINISTERED INTRAVENOUSLY ON A WEEKLY SCHEDULE IN CANCER-PATIENTS WITH SOLID TUMORS

ONCONASE(R) (ONC), previously known as P-30 Protein, is a novel amphibian protein isolated from Rana pipiens eggs/early embryos (1) which demonstrates cytostatic and cytotoxic activity against several human tumor cell lines in vitro, as well as anti-tumor activity in vivo. Animal toxicology studies in rats and dogs revealed dose-dependent weight loss, some skeletal muscle and myocardial degenerative changes, a decrease in albumin and bilirubin levels in rats, and a dose-related elevation of serum transaminases and alkaline phosphatase in both species. A human weekly schedule Phase I study of intravenous bolus ONC was initiated, with dose levels ranging from 60 mug/m2 (anticipated human dose) to 960 mug/m2. Five patients were treated per dose level, without dose escalations within the same patients. Dose levels were doubled in new groups of patients with a variety of relapsing and resistant tumors. A correlation was noted between the dose level and the number of doses (cumulative effect), and the toxicities observed. The dose limiting toxicity was renal as manifested by proteinuria with edema, +/- azotemia and fatigue. Other side effects included flushing, myalgias, transient dizziness, and decreased appetite. Two patients, one at 480 mug/m2 and another at 960 mug/m2 levels, developed reversible hypotensive reactions preceded by flushing. The maximum tolerated dose (MTD) appears to be 960 mug/m2. Incidental findings included some objective responses in non-small cell lung, esophageal, and colorectal carcinomas. It has been concluded that ONCONASE was well tolerated by the majority of patients, demonstrated a consistent and reversible clinical toxicity patterns, did not induce most of the toxicities (such as, e.g., myelosuppression and alopecia) associated with most of the chemotherapeutic agents and, in view of its demonstrated objective clinical activity observed in patients harboring resistant solid tumors, the Phase II clinical trials have been initiated and are currently ongoing.