A phase I clinical trial of FOLFIRI in combination with the pan-cyclin-dependent kinase (CDK) inhibitor flavopiridol Journal Article
| Authors: | Dickson, M. A.; Shah, M. A.; Rathkopf, D.; Tse, A.; Carvajal, R. D.; Wu, N.; Lefkowitz, R. A.; Gonen, M.; Cane, L. M.; Dials, H. J.; Schwartz, G. K. |
| Article Title: | A phase I clinical trial of FOLFIRI in combination with the pan-cyclin-dependent kinase (CDK) inhibitor flavopiridol |
| Abstract: | Background: The cyclin-dependent kinase inhibitor flavopiridol increases irinotecan- and fluorouracil-induced apoptosis. We conducted a phase I trial of FOLFIRI + flavopiridol in patients with advanced solid tumors. Design: FOLFIRI + flavopiridol were administered every 2 weeks. Based on sequence-dependent inhibition, flavopiridol was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses were determined, one with flavopiridol administered over 1 h, and one with flavopiridol split as a 30-min bolus followed by a 4-h infusion. Results: A total of 74 patients were enrolled and 63 were evaluable. The MTD with FOLFIRI was flavopiridol 80 mg/m2 over 1 h or 35 mg/m2 bolus + 35 mg/m2 over 4 h. Dose-limiting toxicities were diarrhea, fatigue, neutropenia, and neuropathy. Clinical activity included 2 partial responses in small bowel cancer and bladder cancer and 1 complete response in mucosal melanoma. Stable disease was seen in 22 patients. Pharmacokinetic studies showed increasing Cmax with increasing flavopiridol dose. Clinical benefit was correlated with the presence of wild-type p53. Of 25 patients with colorectal cancer, 11 had as best response SD for >3 m (median 6 m, range 4.2-15.4 m), despite failing ≥1 irinotecan-containing regimen. Conclusions: Treatment with flavopiridol and FOLFIRI is a safe and effective regimen. Concentrations of flavopiridol that enhance the effects of FOLFIRI can be achieved. Clinical activity is encouraging and includes prolonged stable disease in patients with irinotecan-refractory colorectal cancer. © 2010 Springer-Verlag. |
| Keywords: | adult; controlled study; human tissue; aged; major clinical study; clinical trial; fatigue; neutropenia; fluorouracil; advanced cancer; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; liver cell carcinoma; side effect; pancreas cancer; colorectal cancer; melanoma; progression free survival; multiple cycle treatment; neutrophil count; ovary cancer; breast cancer; anemia; bone marrow suppression; basal cell carcinoma; leukopenia; nausea; neuropathy; carcinoembryonic antigen; lung cancer; combination chemotherapy; continuous infusion; bladder cancer; protein p53; urogenital tract cancer; irinotecan; drug dose escalation; febrile neutropenia; lymphocytopenia; prostate cancer; chemotherapy induced emesis; head and neck cancer; dosage schedule comparison; folinic acid; thrombosis; drug response; stomach cancer; bile duct carcinoma; flavopiridol; maximum plasma concentration; leukocyte count; maximum tolerated dose; phase 1 clinical trial; embolism; drug dose increase; anus cancer; esophagus cancer; thymus cancer; liposarcoma; motor neuropathy; small intestine cancer; cdks and cdk inhibitors; gastrointestinal cancers: colorectal; novel antitumor agents; pharmacokinetics and pharmacodynamics; phase i trials |
| Journal Title: | Cancer Chemotherapy and Pharmacology |
| Volume: | 66 |
| Issue: | 6 |
| ISSN: | 0344-5704 |
| Publisher: | Springer |
| Date Published: | 2010-11-01 |
| Start Page: | 1113 |
| End Page: | 1121 |
| Language: | English |
| DOI: | 10.1007/s00280-010-1269-1 |
| PROVIDER: | scopus |
| PMCID: | PMC2957673 |
| PUBMED: | 20953860 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: CCPHD" - "Source: Scopus" |
