Phase I trial of continuous infusion flavopiridol, a novel cyclin- dependent kinase inhibitor, in patients with refractory neoplasms

Adrian M. Senderowicz*, Donna Headlee, Sherman F. Stinson, Richard M. Lush, Nelson Kalil, Lourdes Villalba, Kimberly Hill, Seth M. Steinberg, William D. Figg, Anne Tompkins, Susan G. Arbuck, Edward A. Sausville

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

390 Scopus citations

Abstract

Purpose: We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks. Patients 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 our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute- phase reactants, particularly at doses >50 mg/m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer 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/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/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 flavopiridol (200 to 400 nM) needed far cyclin- dependent kinase inhibition in preclinical models were achieved safely.

Original languageEnglish
Pages (from-to)2986-2999
Number of pages14
JournalJournal of Clinical Oncology
Volume16
Issue number9
DOIs
StatePublished - Sep 1998

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