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Phase I and Pharmacokinetic Study of a New Antineoplastic Agent: Pyrazine Diazohydroxide (NSC 361456)¹

Section of Hematology/Oncology [N. J. V., R. M., L. J., F. B., R. L. S., M. J. R.], Committee on Clinical Pharmacology [R. M., R. L. S., M. J. R.], and Cancer Research Center IN. J. V., R. M., R. L. S., M. J. R.], University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637-1470

² To whom reprint requests should be addressed, at the Section of Hematology/ Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637.

Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent that appears to form DNA adducts via the reactive pyrazine diazonium ion and produces substantial antitumor activity in preclinical models. We conducted a phase I trial to determine the maximally tolerated dose of PZDH that could be administered as a 5-min i.v. bolus for 5 consecutive days repeated every 28 days. Thirty-one patients with advanced cancer refractory to standard therapy received a total of 65 cycles of therapy at 7 sequential PZDH dose levels: 18, 36, 45, 56, 75, 100, and 133 mg/m²/day. At the maximally tolerated dose (133 mg/m²/day x 5), all 4 patients experienced grade 3–4 thrombocytopenia, and 3 of 4 had grade 3–4 neutropenia. At the recommended phase II dose (100 mg/m²/day x 5), the median WBC nadir following the first cycle was 2.5 x 10³/µl (range, 0.6–7.6) occurring on day 36, and the median platelet nadir was 87 x 10³/µl (range, 9–155) occurring on day 26. Nausea and vomiting occurred at all dose levels, but were well controlled with ondansetron. No evidence of hepatic, renal, pulmonary, cardiac, venous, dermatological, or neurological toxicity was observed. Pharmacokinetic evaluations were performed on 28 of the 31 patients using an analytical method including derivatization of the parent drug to 2-chloropyrazine. We report the total 2-chloropyrazine, which represents PZDH converted per method plus PZDH converted in vivo. Although the assay quantitation limit is 10 ng/ml, PZDH could only be detected at the first dose level for 30–90 min after the i.v. bolus. Compartmental modeling of the first 4 dose levels was most consistent with a 2-compartment model. Subsequent dose levels revealed a third phase to the plasma decay curve. The area under the plasma drug concentration-time curve increased proportionally with dose; there was no evidence for dose-dependent pharmacokinetics. Pharmacokinetic parameters for 12 patients analyzed by the 3-compartment model revealed an -half-life (t) of 2.83 ± 1.57 (mean ± SD), a t of 11.9 ± 4.42, and a t of 161 ± 47.1 min, with a mean clearance of 1.86 ± 0.91 liters/min. At the 100- and 133-mg/m² dose levels, the mean areas under the plasma drug concentration-time curve were 105 and 169 µg min/ml, respectively. There was a moderate correlation between body surface area and clearance (r = 0.45, P = 0.015) but a better correlation between weight and clearance (r = 0.53, P = 0.004). At the recommended phase II dose, there are insufficient data available to assess whether variability in bone marrow toxicity is due to pharmacokinetic variability or to other factors. We identified a correlation (r = –0.68, P = 0.004) between serum chloride concentration and platelet nadir in patients treated at the 100- and 133-mg/m² dose levels. Phase II studies at a PZDH dose of 100 mg/m²/day x 5 every 42 days should be considered, although dose based upon body weight may be more appropriate. Additional phase I studies to explore and possibly modulate the relationship between PZDH toxicity and serum chloride are also warranted.

¹ Supported in part by National Cancer Institute Contract NO1-CM-07301 and USPHS Grant CA 14599. Presented in part at the 28th Annual Meeting of the American Association for Cancer Research, May 23–26, 1992, San Diego, CA.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/25/93. Accepted 10/25/93.