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/m and irinotecan 80 mg/m on day 1, followed by flavopiridol, starting dose of 30 mg/m on day 2 with increment of 15 mg/m 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/m 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/m 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/m of flavopiridol in combination with irinotecan (80 mg/m) and gemcitabine (800 mg/m).
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/m and irinotecan 80 mg/m on day 1, followed by flavopiridol, starting dose of 30 mg/m on day 2 with increment of 15 mg/m 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/m 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/m 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/m of flavopiridol in combination with irinotecan (80 mg/m) and gemcitabine (800 mg/m).
Authors: Richard Gorlick; E Anders Kolb; Peter J Houghton; Christopher L Morton; Geoffrey Neale; Stephen T Keir; Hernan Carol; Richard Lock; Doris Phelps; Min H Kang; C Patrick Reynolds; John M Maris; Catherine Billups; Malcolm A Smith Journal: Pediatr Blood Cancer Date: 2012-02-07 Impact factor: 3.167