Entry Detail
| General information | |
| Database: | DB00566 |
| Objective: | Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. |
| Authors: | Wagle N, et al |
| Title: | Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. |
| Journal: | Cancer Discov. |
| Year: | 2104 |
| PMID: | 24625776 |
| Trial Design | |
| Clinical Trial Id: | NCT01184326 |
| Agent: | pazopanib |
| Target: | Plateletderived growth factor receptor Mast/stem cell growth factor receptor Vascular endothelial growth factor receptor 2 |
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | everolimus and pazopanib |
| Study Type: | Phase I Trial |
| Key Patients Feature: | NA |
| Biomarker: | alterations in the mTOR pathway |
| Biomark Analysis: | Here, they identify two activating mTOR mutations in a patient with exquisite sensitivity to everolimus and pazopanib, suggesting an approach to identifying patients who might benefi t most from mTOR inhibitors. |
| Control Group Info: | single arm |
| Treatment Info: | A standard 3 + 3 design was used starting with pazopanib 600 mg and everolimus 5 mg given orally once daily on a continuous basis during a 28day cycle. The dose escalation was planned to alternate sequential escalations up to pazopanib 800 mg daily and everolimus 10 mg daily, or deescalation to pazopanib 400 mg daily and everolimus 5 mg daily. |
| Primary End Point: | MTD and DLT |
| Secondary End Point: | NA |
| Patients Number: | 9 |
| Trial Results | |
| DLT_MTD: | NA |
| 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): | Throughout the study, 5 of 9 treated patients experienced grade 3 or higher treatmentrelated toxicity (56%; 95% CI: 21.2%-86.3%). Hematologic toxicities during this trial included grade 3 febrile neutropenia and thrombocytopenia, each in 1 patient. One patient experienced a grade 3 pneumothorax, considered possibly related to study therapy. Other nonhematologic toxicities included anorexia (1 patient), bone pain (1 patient), diarrhea (2 patients; 1 patient with grade 3), fatigue (5 patients), dysgeusia (1 patient), headache (1 patient), hypertension (2 patients), mucositis (3 patients), musculoskeletal (muscle stiffness after prolonged periods of sitting, 1 patient), nausea (4 patients), palmoplantar erythrodysesthesia syndrome (2 patients), pneumonia (1 patient, grade 3), pruritus (1 patient, grade 3), rash (3 patients, 1 patients with grade 3), vomiting (3 patients), and weight loss (1 patient). Grade 3 and 4 laboratory toxicities included increased ALT, hypophosphatemia, and hypouricemia each in 1 patient, and increased lipase in 2 patients. |
| Conclusions: | The use of precision (or ¡°personalized¡±) medicine approaches to screen cancer patients for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR. |