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

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/m(2) q21 days) and carboplatin (AUC 6 mg/mL/min q21 days) (step 1) and paclitaxel (200 mg/m(2) 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-cycle 1 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.

• Authors: 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 1 Pg. 123-34 (Feb 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 23579358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Bevacizumab
• Everolimus
• Carboplatin
• Paclitaxel
• Sirolimus

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Bevacizumab
• Carboplatin (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Demography
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Everolimus
• Feasibility Studies
• Female
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Male
• Middle Aged
• Neoplasm Staging
• Paclitaxel (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Treatment Outcome