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

• Published in: Investigational new drugs Vol. 32; no. 1; pp. 123 - 134
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2014; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Biological and medical sciences; Bone marrow; Cancer therapies; Carboplatin - administration & dosage; Carboplatin - adverse effects; Carboplatin - pharmacokinetics; Carboplatin - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Chemotherapy; Clinical trials; Cytotoxicity; Demography; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Everolimus; Feasibility Studies; Female; Hospitals; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Medical prognosis; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Neutropenia; Oncology; Paclitaxel - administration & dosage; Paclitaxel - adverse effects; Paclitaxel - pharmacokinetics; Paclitaxel - therapeutic use; Patients; Pharmaceutical sciences; Pharmaceuticals; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase I Studies; Pneumology; Radiation therapy; Signal transduction; Sirolimus - administration & dosage; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; Sirolimus - pharmacokinetics; Sirolimus - therapeutic use; Studies; Thrombocytopenia; Toxicity; Treatment Outcome; Tuberous sclerosis; Tumors; Tumors of the respiratory system and mediastinum; United States > US; Europe; Everolimus; Dose-limiting toxicity; Non-small cell lung cancer; Antineoplastic agent; Lung cancer; Monoclonal antibody; non-small cell lung carcinoma; Bevacizumab; Taxane derivatives; Paclitaxel; Bronchus disease; Advanced stage; Protein synthesis inhibitor; Antiangiogenic agent; Antimitotic; Platinum II Complexes; Lung disease; Respiratory disease; Lactone; Malignant tumor; Macrolide; Vascular endothelium growth factor; Treatment; Carboplatin; Dose limiting toxicity; Feasibility; Cancer
• ISSN: 0167-6997; 1573-0646; 1573-0646
• DOI: 10.1007/s10637-013-9958-3

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.