| General information |
| Database: | DB00969 |
| Objective: | Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed. |
| Authors: | Ciunci CA, et al |
| Title: | Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer. |
| Journal: | Cancer. |
| Year: | 2014 |
| PMID: | 24108668 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | everolimus, cetuximab
|
| Target: | NA
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | everolimus+cetuximab |
| Study Type: | Phase I and pharmacodynamic trial |
| Key Patients Feature: | patients with advanced cancer |
| Biomarker: | [(18)F]Fluorodeoxyglucose positron emission tomography (FDGPET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrastenhanced magnetic resonance imaging (DCEMRI) was performed as an indicator of tumor perfusion changes, at 3 time points. |
| Biomark Analysis: | Mean change in maximum standardized uptake value (SUV(max)) for those treated initially with everolimus was 24% (2% to 54%), and with cetuximab was 5% (23 to 36%). The K(trans) measured by DCEMRI did not decrease, regardless of runin drug. |
| Control Group Info: | single arm |
| Treatment Info: | patients were randomized to a runin of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m(2) loading, 250 mg/m(2) maintenance) weekly, followed by the combination in this doseescalation study. |
| Primary End Point: | phase 2 dose and toxicity characterization. |
| Secondary End Point: | NA |
| Patients Number: | 29 |
| Trial Results |
| DLT_MTD: | Doselimiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patientThe recommendedphase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. |
| Objective Response Rate: | NA |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most common grade 2 and worse toxicities experienced were rash (10 patients, 34% of total patients, 31% of the 70 mg group), fatigue (7 patients, 24% of total patients, 6% of the 70 mg group), elevated alkaline phosphatase (6 patients, 21% of total patients, 31% of the 70 mg group), and hypoalbuminemia (6 patients, 21% of total patients, 25% of the 70 mg group). |
| Conclusions: | Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommendedphase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population |