The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: Preclinical investigations and results of a phase I dose-escalation clinical trial Journal Article
| Authors: | Luke, J. J.; D'adamo, D. R.; Dickson, M. A.; Keohan, M. L.; Carvajal, R. D.; Maki, R. G.; de Stanchina, E.; Musi, E.; Singer, S.; Schwartz, G. K. |
| Article Title: | The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: Preclinical investigations and results of a phase I dose-escalation clinical trial |
| Abstract: | Purpose: Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas. Experimental Design: Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion. Results: Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m 2 bolus; 50 mg/m 2 bolus+40 mg/m 2 infusion) both in combination with doxorubicin (60 mg/m 2). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing C max with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks. Conclusions: The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified. ©2012 AACR. |
| Keywords: | adult; clinical article; controlled study; aged; middle aged; human cell; drug tolerability; neutropenia; doxorubicin; advanced cancer; cancer combination chemotherapy; diarrhea; dose response; drug dose comparison; drug efficacy; drug potentiation; drug safety; heart left ventricle failure; monotherapy; nonhuman; mouse; animals; mice; animal tissue; multiple cycle treatment; leukopenia; nausea; antineoplastic combined chemotherapy protocols; animal experiment; animal model; in vivo study; in vitro study; tumor xenograft; dose-response relationship, drug; mice, scid; drug evaluation, preclinical; drug dose escalation; febrile neutropenia; lymphocytopenia; sarcoma; lung embolism; confusion; tissue distribution; blood sampling; immunoblotting; flavonoids; flavopiridol; piperidines; maximum plasma concentration; intestine perforation; maximum tolerated dose; cancer control; drug dose increase; psychosis; ic 50; cyclin-dependent kinases; chronic lymphatic leukemia; brain ischemia; nerve sheath neoplasms; hematologic disease; neoplasm grading |
| Journal Title: | Clinical Cancer Research |
| Volume: | 18 |
| Issue: | 9 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2012-05-01 |
| Start Page: | 2638 |
| End Page: | 2647 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-11-3203 |
| PROVIDER: | scopus |
| PMCID: | PMC3343204 |
| PUBMED: | 22374332 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 June 2012" - "CODEN: CCREF" - "Source: Scopus" |
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