Purpose: Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells--G1, S, and G2/M.
Methods: Temsirolimus (G1 inhibitor), topotecan (S inhibitor), and bortezomib (G2/M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen.
Results: Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m(2) IV D1, 8; and bortezomib 0.6 mg/m2 IV D1, 4, 8, 11 [DOSAGE ERROR CORRECTED] of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G2/M and S phases to G1 phase and the quiescent G0 phase. Eighteen percent of subjects (11/62) achieved partial response (n = 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n = 9).
Conclusion: Combining drugs with inhibitory activity of G1 phase, S phase, and G2/M phase is safe and warrants further evaluation.
Keywords: bortezomib; cell cycle; oncology; pharmacodynamics; phase I; temsirolimus; topotecan.