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 amphib ian protein isolated from Rana pipiens eggs/early embryos (1) which de monstrates cytostatic and cytotoxic activity against several human tum or cell lines in vitro, as well as anti-tumor activity in vivo. Animal toxicology studies in rats and dogs revealed dose-dependent weight lo ss, some skeletal muscle and myocardial degenerative changes, a decrea se in albumin and bilirubin levels in rats, and a dose-related elevati on of serum transaminases and alkaline phosphatase in both species. A human weekly schedule Phase I study of intravenous bolus ONC was initi ated, with dose levels ranging from 60 mug/m2 (anticipated human dose) to 960 mug/m2. Five patients were treated per dose level, without dos e escalations within the same patients. Dose levels were doubled in ne w groups of patients with a variety of relapsing and resistant tumors. A correlation was noted between the dose level and the number of dose s (cumulative effect), and the toxicities observed. The dose limiting toxicity was renal as manifested by proteinuria with edema, +/- azotem ia and fatigue. Other side effects included flushing, myalgias, transi ent dizziness, and decreased appetite. Two patients, one at 480 mug/m2 and another at 960 mug/m2 levels, developed reversible hypotensive re actions preceded by flushing. The maximum tolerated dose (MTD) appears to be 960 mug/m2. Incidental findings included some objective respons es in non-small cell lung, esophageal, and colorectal carcinomas. It h as been concluded that ONCONASE was well tolerated by the majority of patients, demonstrated a consistent and reversible clinical toxicity p atterns, did not induce most of the toxicities (such as, e.g., myelosu ppression and alopecia) associated with most of the chemotherapeutic a gents and, in view of its demonstrated objective clinical activity obs erved in patients harboring resistant solid tumors, the Phase II clini cal trials have been initiated and are currently ongoing.