PHASE-II AND PHARMACODYNAMIC STUDIES OF PYRAZINE DIAZOHYDROXIDE (NSC-361456) IN PATIENTS WITH ADVANCED RENAL AND COLORECTAL-CANCER

Pyrazine diazohydroxide (PZDH) is a novel antitumor agent that forms D NA adducts via the reactive pyrazine diazonium ion, In a recent Phase I study of PZDH, we identified a recommended Phase II dose of 100 mg/m (2)/day x 5, given as a 5-min i.v. bolus with the cycles repeated ever y 42 days (N. J. Vogelzang, et at, Cancer Res., 54: 114-119, 1994). Th ere was a moderate negative correlation between serum chloride concent ration and logarithm platelet nadir, suggesting the hypothesis that PZ DH is activated in an acidic environment, leading to more toxicity in acidotic patients, Therefore, the University of Chicago Phase II coope rative network conducted two Phase II studies of PZDH in renal cancer (15 patients, 2 with liver metastases) and in 5-fluorouracil-refractor y colorectal cancer (14 patients, 13 with liver metastases) to determi ne efficacy in each disease and to correlate safety and tolerance of t he drug with PZDH pharmacokinetics/pharmacodynamics and with arterial blood gas measurements, There were no responses seen in either tumor t ype, The primary toxicity of PZDH was myelosuppression with neutropeni a (absolute neutrophil count, < 1000/mu l) and thrombocytopenia (<50,0 00 cells/mu l), seen in 41 and 24% of all cycles, respectively, Other grade 3 and 4 toxicities were rare, Pharmacodynamic analysis revealed no significant correlation between plasma levels at 5, 60, and 120 min ; WBCs; absolute neutrophil and platelet count nadirs; and initial ser um chloride or blood pH levels, The colorectal patients experienced si gnificantly more thrombocytopenia than did the renal cancer patients ( median platelet nadir after cycle 1 was 151 x 10(3)/mu l for renal pat ients versus 76 x 10(3)/mu l for colon patients; P = 0.04), suggesting either that prior 5-fluorouracil and leucovorin reduced bone marrow r eserve or that colorectal patients with liver metastases experienced m ore PZDH toxicity, Regression analyses revealed a possible relationshi p (P = 0.06) between serum pH and thrombocytopenia (i.e., for each inc rease of 0.03 in pH, there was a 34% increase in the platelet nadir), but there was no relationship between serum chloride and thrombocytope nia, Curiously, an increase in alkaline phosphatase was associated wit h an increase in the platelet nadir (P = 0.02), If PZDH continues to b e developed as an antineoplastic agent, further studies of these relat ionships are suggested.