TY - JOUR
T1 - Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non-small cell lung cancer
AU - Eberhardt, Wilfried E E
AU - Mitchell, Paul
AU - Schiller, Joan H.
AU - Brown, Michael P.
AU - Thomas, Michael
AU - Mills, Glenn
AU - Jehl, Valentine
AU - Urva, Shweta R.
AU - De Leo, Jeffrey J.
AU - Gogov, Sven
AU - Papadimitrakopoulou, Vassiliki
N1 - Funding Information:
Michael P. Brown has received grant funding from Novartis and served as an advisory board member for Novartis.
Funding Information:
Acknowledgments This study was supported by Novartis Pharmaceuticals Corporation. Editorial assistance in the preparation of this manuscript was provided by Melanie Leiby, PhD, of ApotheCom (Yardley, PA, USA) and was funded by Novartis Pharmaceuticals Corporation.
Funding Information:
Glenn Mills and Vassiliki Papadimitrakopoulou have grant funding from Novartis Pharmaceuticals. Paul Mitchell declares no conflict of interest.
PY - 2014/2
Y1 - 2014/2
N2 - Introduction: One standard of care for advanced non-small cell lung cancer (NSCLC) is paclitaxel plus carboplatin±bevacizumab. This two-step phase I study evaluated the feasibility of adding everolimus to paclitaxel plus carboplatin±bevacizumab for advanced NSCLC. Methods: Adults with advanced NSCLC naive to systemic therapy were enrolled. A Bayesian dose-escalation model was used to identify feasible daily or weekly everolimus doses given with paclitaxel (200 mg/m2 q21 days) and carboplatin (AUC 6 mg/mL/min q21 days) (step 1) and paclitaxel (200 mg/m2 q21 days), carboplatin (AUC 6 mg/mL/min q21 days), and bevacizumab (15 mg/kg q21 days) (step 2). Primary endpoint was end-of-cycle 1 dose-limiting toxicity (DLT) rate. Secondary endpoints included safety; relative dose intensities of paclitaxel, carboplatin, and bevacizumab; pharmacokinetics; and tumor response. Results Fifty-two patients were enrolled and received everolimus 5 mg/day plus carboplatin and paclitaxel (step 1 daily; n=13); everolimus 30 mg/week plus carboplatin and paclitaxel (step 1 weekly; n=13); everolimus 5 mg/day plus carboplatin, paclitaxel, and bevacizumab (step 2 daily; n=13); or everolimus 30 mg/week plus carboplatin, paclitaxel, and bevacizumab (step 2 weekly; n=13). End-of-cycle1 DLT rate was 16.7% (step 1 daily), 30.8% (step 1 weekly), 30.0% (step 2 daily), and 16.7% (step 2 weekly). Cycle 1 DLTs were grade 3 neutropenia, anal abscess, diarrhea, and thrombocytopenia and grade 4 myalgia, cellulitis, neutropenia, febrile neutropenia, pulmonary embolism, and thrombocytopenia. The most common adverse events were neutropenia, fatigue, anemia, and thrombocytopenia. One patient (step 2 daily) experienced complete response, 10 patients partial response. Conclusions: The feasible everolimus doses given with carboplatin and paclitaxel±bevacizumab were 5 mg/day and 30 mg/week. Neither schedule was very well tolerated in this unselected NSCLC population.
AB - Introduction: One standard of care for advanced non-small cell lung cancer (NSCLC) is paclitaxel plus carboplatin±bevacizumab. This two-step phase I study evaluated the feasibility of adding everolimus to paclitaxel plus carboplatin±bevacizumab for advanced NSCLC. Methods: Adults with advanced NSCLC naive to systemic therapy were enrolled. A Bayesian dose-escalation model was used to identify feasible daily or weekly everolimus doses given with paclitaxel (200 mg/m2 q21 days) and carboplatin (AUC 6 mg/mL/min q21 days) (step 1) and paclitaxel (200 mg/m2 q21 days), carboplatin (AUC 6 mg/mL/min q21 days), and bevacizumab (15 mg/kg q21 days) (step 2). Primary endpoint was end-of-cycle 1 dose-limiting toxicity (DLT) rate. Secondary endpoints included safety; relative dose intensities of paclitaxel, carboplatin, and bevacizumab; pharmacokinetics; and tumor response. Results Fifty-two patients were enrolled and received everolimus 5 mg/day plus carboplatin and paclitaxel (step 1 daily; n=13); everolimus 30 mg/week plus carboplatin and paclitaxel (step 1 weekly; n=13); everolimus 5 mg/day plus carboplatin, paclitaxel, and bevacizumab (step 2 daily; n=13); or everolimus 30 mg/week plus carboplatin, paclitaxel, and bevacizumab (step 2 weekly; n=13). End-of-cycle1 DLT rate was 16.7% (step 1 daily), 30.8% (step 1 weekly), 30.0% (step 2 daily), and 16.7% (step 2 weekly). Cycle 1 DLTs were grade 3 neutropenia, anal abscess, diarrhea, and thrombocytopenia and grade 4 myalgia, cellulitis, neutropenia, febrile neutropenia, pulmonary embolism, and thrombocytopenia. The most common adverse events were neutropenia, fatigue, anemia, and thrombocytopenia. One patient (step 2 daily) experienced complete response, 10 patients partial response. Conclusions: The feasible everolimus doses given with carboplatin and paclitaxel±bevacizumab were 5 mg/day and 30 mg/week. Neither schedule was very well tolerated in this unselected NSCLC population.
KW - Dose-limiting toxicity
KW - Everolimus
KW - Non-small cell lung cancer
UR - http://www.scopus.com/inward/record.url?scp=84899126795&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899126795&partnerID=8YFLogxK
U2 - 10.1007/s10637-013-9958-3
DO - 10.1007/s10637-013-9958-3
M3 - Article
C2 - 23579358
AN - SCOPUS:84899126795
SN - 0167-6997
VL - 32
SP - 123
EP - 134
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 1
ER -