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A Phase I Study of Flavopiridol in Combination With Gemcitabine and Irinotecan in Patients With Metastatic Cancer

Fekrazad, Houman M., MD*; Verschraegen, Claire F., MD*; Royce, Melanie, MD*; Smith, Harriet O., MD; Chyi Lee, Fa, MD*; Rabinowitz, Ian, MD*

American Journal of Clinical Oncology: August 2010 - Volume 33 - Issue 4 - p 393-397
doi: 10.1097/COC.0b013e3181b2043f
Original Articles: Clinical Trials

Background: Flavopiridol (HMR 1275) is a synthetic flavone with antineoplastic properties through inhibition of cyclin-dependent kinase inhibitor. Flavopiridol synergizes in a sequence-dependent fashion with chemotherapy. Major adverse events of flavopiridol in single agent phase I studies are secretory diarrhea, neutropenia, thrombosis, and fatigue.

Patients and Methods: Patients with advanced solid tumors were treated with gemcitabine 800 mg/m2 and irinotecan 80 mg/m2 on day 1, followed by flavopiridol, starting dose of 30 mg/m2 on day 2 with increment of 15 mg/m2 per dose level, repeated on days 8 and 9 for the first 6 patients (3-week cycle), and then repeated on days 15 and 16 for the remainder patients (4-week cycle). The protocol had to be amended for inability to redose after 1 week.

Results: Fourteen women and 7 men with advanced solid tumors were enrolled. The median age was 51 years and the median number of prior chemotherapies was 3 (0–9). Neutropenic sepsis (1 patient), grade 3 diarrhea (1 patient), and neutropenia (2 patients) preventing retreatment on day 8 were observed among the 6 subjects treated on the first schedule. The recommended phase II dose of flavopiridol was 45 mg/m2 in combination with irinotecan and gemcitabine every 2 weeks. Dose-limiting toxicities were electrolyte imbalance with fatigue (1 patient), and renal failure and dyspnea with hypoxia (1 patient each), seen at 45 and 60 mg/m2 doses, respectively. The most common side effects were fatigue (81%), nausea (71%), diarrhea (67%), transient myelosuppression (43%), and vomiting (24%).

Conclusions: The every 2 week dosing is well tolerated with a phase II recommended dose of 45 mg/m2 of flavopiridol in combination with irinotecan (80 mg/m2) and gemcitabine (800 mg/m2).

From the *University of New Mexico Cancer Center, Albuquerque, NM; and †Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY.

Reprints: Claire F. Verschraegen, MD, 900 Camino de Salud, NE, Albuquerque, New Mexico 87131. E-mail:

© 2010 Lippincott Williams & Wilkins, Inc.