PHASE-I TRIAL OF CONTINUOUS-INFUSION FLAVOPIRIDOL, A NOVEL CYCLIN-DEPENDENT KINASE INHIBITOR, IN PATIENTS WITH REFRACTORY NEOPLASMS

Purpose: We conducted a phase I trial of the cyclin-dependent kinase i nhibitor, flavopiridol (National Service Center [NSC] 649890), to dete rmine the maximum-tolerated dose (MTD), toxicity profile, and pharmaco logy of flavopiridol given as a 72-hour infusion every 2 weeks. Patien ts and Methods: Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first- cycle pharmacokinetic sampling. Results: Forty-nine patients defined o ur first MTD, 50 mg/m(2)/d x 3 with dose-limiting toxicity (DLT) of se cretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received ant idiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m(2)/d x 3 with DLT of hypotension at 98 mg/m(2)/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/m(2)/d x 3, which in some patients preve nted chronic therapy every 2 weeks. In some patients, ADP wets not suc cessful, requiring dose-deescalation. Although approximately 70% of pa tients displayed predictable flavopiridol pharmacology, we observed un expected interpatient variability and postinfusion peaks in approximat ely 30% of Eases. At the two MTDs, we achieved a mean plasma flavopiri dol concentration of 271 nM(50 mg/m(2)/d x 3) and 344 nM (78 mg/m(2)/d x 3), respectively. One partial response in a patient with renal canc er and minor responses (n = 3) in patients with non Hodgkin's lymphoma , colon, and renal cancer occurred. Conclusion: The MTD of infusional flavopiridol is 50 mg/m(2)/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m(2)/d x 3. With ADP, 78 mg/m(2)/d x 3 was the MTD, with d ose-limiting hypotension at 98 mg/m(2)/d x 3. Based on chronic tolerab ility, 50 mg/m(2)/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate , and colon cancer, and non-Hodgkin's lymphoma. Concentrations of flav opiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.