Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non-small cell lung cancer

Wilfried E E Eberhardt, Paul Mitchell, Joan H. Schiller, Michael P. Brown, Michael Thomas, Glenn Mills, Valentine Jehl, Shweta R. Urva, Jeffrey J. De Leo, Sven Gogov, Vassiliki Papadimitrakopoulou

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)123-134
Number of pages12
JournalInvestigational New Drugs
Volume32
Issue number1
DOIs
StatePublished - 2014

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Carboplatin
Paclitaxel
Non-Small Cell Lung Carcinoma
Neutropenia
Therapeutics
Thrombocytopenia
Area Under Curve
Everolimus
Bevacizumab
Febrile Neutropenia
Cellulitis
Myalgia
Feasibility Studies
Standard of Care
Pulmonary Embolism
Abscess
Fatigue
Anemia
Diarrhea
Appointments and Schedules

Keywords

  • Dose-limiting toxicity
  • Everolimus
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Eberhardt, W. E. E., Mitchell, P., Schiller, J. H., Brown, M. P., Thomas, M., Mills, G., ... Papadimitrakopoulou, V. (2014). Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non-small cell lung cancer. Investigational New Drugs, 32(1), 123-134. https://doi.org/10.1007/s10637-013-9958-3

Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non-small cell lung cancer. / Eberhardt, Wilfried E E; Mitchell, Paul; Schiller, Joan H.; Brown, Michael P.; Thomas, Michael; Mills, Glenn; Jehl, Valentine; Urva, Shweta R.; De Leo, Jeffrey J.; Gogov, Sven; Papadimitrakopoulou, Vassiliki.

In: Investigational New Drugs, Vol. 32, No. 1, 2014, p. 123-134.

Research output: Contribution to journalArticle

Eberhardt, WEE, Mitchell, P, Schiller, JH, Brown, MP, Thomas, M, Mills, G, Jehl, V, Urva, SR, De Leo, JJ, Gogov, S & Papadimitrakopoulou, V 2014, 'Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non-small cell lung cancer', Investigational New Drugs, vol. 32, no. 1, pp. 123-134. https://doi.org/10.1007/s10637-013-9958-3
Eberhardt, Wilfried E E ; Mitchell, Paul ; Schiller, Joan H. ; Brown, Michael P. ; Thomas, Michael ; Mills, Glenn ; Jehl, Valentine ; Urva, Shweta R. ; De Leo, Jeffrey J. ; Gogov, Sven ; Papadimitrakopoulou, Vassiliki. / Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non-small cell lung cancer. In: Investigational New Drugs. 2014 ; Vol. 32, No. 1. pp. 123-134.
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abstract = "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.",
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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

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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.

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