The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial.

[dedifferentiated liposarcoma]

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 .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 .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 .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 CDK 4 is known to be amplified .

Diseases
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Diseases presenting "progressive well" symptom

dedifferentiated liposarcoma

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