A phase I study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer.
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.


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).
Fekrazad
Houman M
HM
University of New Mexico Cancer Center, Albuquerque, USA.
Verschraegen
Claire F
CF
Royce
Melanie
M
Smith
Harriet O
HO
Chyi Lee
Fa
F
Rabinowitz
Ian
I
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005419:Flavonoids / Q000627:therapeutic use / Q000633:toxicity*; D006801:Humans; D000077146:Irinotecan; D008017:Life Expectancy; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D018579:Patient Selection; D010880:Piperidines / Q000627:therapeutic use / Q000633:toxicity*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; D003841:Deoxycytidine; C077990:alvocidib; D000077146:Irinotecan; D002166:Camptothecin; D000093542:Gemcitabine