A phase I clinical trial of FOLFIRI in combination with the pan-cyclin-dependent kinase (CDK) inhibitor flavopiridol View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-02-21

AUTHORS

Mark A. Dickson, Manish A. Shah, Dana Rathkopf, Archie Tse, Richard D. Carvajal, Nian Wu, Robert A. Lefkowitz, Mithat Gonen, Lauren M. Cane, Heather J. Dials, Gary K. Schwartz

ABSTRACT

BackgroundThe 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.DesignFOLFIRI + 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.ResultsA 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.ConclusionsTreatment 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. More... »

PAGES

1113-1121

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Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00280-010-1269-1

DOI

http://dx.doi.org/10.1007/s00280-010-1269-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1012653343

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20953860


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29 schema:description BackgroundThe 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.DesignFOLFIRI + 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.ResultsA 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.ConclusionsTreatment 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.
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35 schema:keywords Cmax
36 ConclusionsTreatment
37 FOLFIRI
38 I trial
39 MTD
40 ResultsA total
41 SD
42 activity
43 advanced solid tumors
44 apoptosis
45 benefits
46 bladder cancer
47 bolus
48 bowel cancer
49 cancer
50 clinical activity
51 clinical benefit
52 clinical trials
53 colorectal cancer
54 combination
55 complete response
56 concentration
57 concentrations of flavopiridol
58 cyclin-dependent kinase inhibitor flavopiridol
59 diarrhea
60 disease
61 dose
62 doses
63 effect
64 effective regimen
65 fatigue
66 flavopiridol
67 infusion
68 inhibition
69 irinotecan
70 irinotecan-refractory colorectal cancer
71 kinase inhibitor flavopiridol
72 m2
73 melanoma
74 mucosal melanoma
75 neuropathy
76 neutropenia
77 p53
78 pan-cyclin
79 partial response
80 patients
81 pharmacokinetic study
82 phase I clinical trial
83 phase I trial
84 presence
85 regimen
86 response
87 sequence-dependent inhibition
88 small bowel cancer
89 solid tumors
90 stable disease
91 study
92 total
93 toxicity
94 trials
95 tumors
96 weeks
97 wild-type p53
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