The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and phase I clinical trial
Mené sur 31 patients atteints d'un sarcome de stade avancé, cet essai de phase I évalue l'ajout de flavopiridol, un inhibiteur de kinases dépendantes des cyclines, à la doxorubicine
Purpose: Dysregulated cyclin-dependent kinases (CDKs) 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 performed 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 2 flavopiridol schedules; a 1 hour bolus and split dosing as a 30 minute bolus followed by a 4 hour infusion. Results: Pre-clinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour prior to flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in 2 schedules (90 mg/m2 bolus; 50 mg/m2 bolus + 40 mg/m2 infusion) both in combination with doxorubicin (60 mg/m2). Dose-limiting toxicities were neutropenia, leukopenia and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing Cmax with increasing dose. RECIST responses included 2 partial responses however stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and de-differentiated liposarcoma, 8 had stable disease greater than 12 weeks. Conclusions: The sequential combination of doxorubicin followed flavopiridol is well tolerated on both schedules. Disease control was observed in well- and de-differentiated liposarcoma specifically, a disease where CDK4 is known to be amplified.