Entry Detail
| General information | |
| Database: | DB00810 |
| Objective: | The primary objectives of thisphase I study were to evaluate the safety and maximum tolerated dose (MTD) of SAR245409, a panclass I phosphatidylinositol 3kinase (PI3K)/mammalian target of rapamycin inhibitor, combined with erlotinib in patients with advanced solid tumors. |
| Authors: | J nne PA, et al |
| Title: | Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors. |
| Journal: | J Thorac Oncol. |
| Year: | 2014 |
| PMID: | 24496004 |
| Trial Design | |
| Clinical Trial Id: | NA |
| Agent: | erlotinib, SAR245409 |
| Target: | SAR245409: Phosphoinositide 3 kinase Serine/threonineprotein kinase mTOR |
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | SAR245409 (XL765) + erlotinib |
| Study Type: | Phase I safety and pharmacokinetic study |
| Key Patients Feature: | patients with advanced solid tumors were enrolled. Patients with lung cancer (n = 37) had received an epidermal growth factor receptor (EGFR) inhibitor before study entry. |
| Biomarker: | PI3K and EGFR/mitogenactivated protein kinase signaling pathways in tumor and skin samples |
| Biomark Analysis: | Suppression of PI3K and EGFR/mitogenactivated protein kinase signaling pathway biomarkers was observed in skin and tumor samples. |
| Control Group Info: | single arm |
| Treatment Info: | SAR245409 30, 50, 70, or 90 mg once daily (QD) or 20 or 30 mg twice daily (BID) was administered, in combination with erlotinib 100 mg QD, in 28day cycles. Dose escalation of SAR245409 followed a standard 3 + 3 design. |
| Primary End Point: | patients were evaluated for adverse events (AEs). |
| Secondary End Point: | Additional evaluations included pharmacokinetics, pharmacodynamic effects on PI3K and EGFR/mitogenactivated protein kinase signaling pathways in tumor and skin samples, and tumor response. |
| Patients Number: | 46 |
| Trial Results | |
| DLT_MTD: | Doselimiting toxicity (DLT) was defined as the occurrence of a specified event during cycle 1 that warranted a dose reduction or, that in the opinion of the Cohort Review Committee, was of potential clinical significance such that further dose escalation would expose patients to unacceptable risk (including gastrointestinal AEs, hyperglycemia, hematologic AEs, and liver enzyme elevations; a full definition is provided in Supplemental Digital Content 1, Doselimiting toxicity (DLT) was defined as the occurrence of a specified event during cycle 1 that warranted a dose reduction or, that in the opinion of the Cohort Review Committee, was of potential clinical significance such that further dose escalation would expose patients to unacceptable risk (including gastrointestinal AEs, hyperglycemia, hematologic AEs, and liver enzyme elevations; a full definition is provided in Supplemental Digital Content 1, Doselimiting toxicity (DLT) was defined as the occurrence of a specified event during cycle 1 that warranted a dose reduction or, that in the opinion of the Cohort Review Committee, was of potential clinical significance such that further dose escalation would expose patients to unacceptable risk (including gastrointestinal AEs, hyperglycemia, hematologic AEs, and liver enzyme elevations; a full definition is provided in Supplemental Digital Content 1, MTDs were determined to be SAR245409 70 mg QD plus erlotinib 100 mg QD and SAR245409 20 mg BID plus erlotinib 100 mg QD. |
| 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 frequently reported AEs (any grade), regardless of causality, were diarrhea (28 patients; 60.9%), rash (21 patients; 45.7%), nausea (20 patients; 43.5%), and vomiting (15 patients; 32.6%) |
| Conclusions: | MTDs of SAR245409 and erlotinib they were below the singleagent doses of either agent, despite the lack of major pharmacokinetic interaction. |