Phase I Clinical and Pharmacokinetic Study of Flavopiridol Administered as a Daily 1-Hour Infusion in Patients With Advanced Neoplasms

Abstract

The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m(2)/d for 5 days, 50 mg/m(2)/d for 3 days, and 62.5 mg/m(2)/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.

Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki‐67 labeling index

“…44 Interestingly, both compounds already demonstrated antitumor activity in some patients with refractory NHLs. 45,46 …”

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

“…48 Cdk5 is highly expressed in a variety of tumors 47,[50][51][52] and several clinical trials studying the use of roscovitine and other nonselective Cdk5 inhibitors in patients with cancer have either been completed or are ongoing. [60][61][62][63][64][65][66] Our studies demonstrated that the Cdk5-specific inhibitor CIP resulted in a dosedependent reduction in tumor cell proliferation and an increase in the percentage of early apoptotic cells in culture ( Figure 6). The optimal formulation of CIP for in vivo administration has yet to be determined.…”

The CDK inhibitors in cancer research and therapy

“…It is also the Wrst CDK inhibitor used in human clinical trials. Several phase I clinical trials showed that Xavopiridol as single agent has an antitumor eVect in patients with renal, prostate and colon cancer, metastatic gastric cancer and non-Hodgkin's lymphoma Tan et al 2002;Thomas et al 2002;Whitlock et al 2005). Secretory diarrhea, neutropenia, nausea, vomiting and proinXammatory syndrome were reported as main drug adverse eVects (DAE).…”