| General information |
| Database: | DB00958 |
| Objective: | The optimal weekly oral dose of sirolimus and intravenous nanoparticle albuminbound paclitaxel (nabpaclitaxel) were evaluated |
| Authors: | AbuKhalaf MM, et al |
| Title: | Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albuminbound paclitaxel in patients with advanced solid tumors. |
| Journal: | Cancer. |
| Year: | 2015 |
| PMID: | 25649370 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | sirolimus/rapamycin
|
| Target: | Serine/threonineprotein kinase mTOR
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | sirolimus + nanoparticle albuminbound paclitaxel |
| Study Type: | Phase Ib study |
| Key Patients Feature: | patients with advanced solid tumors |
| Biomarker: | phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography |
| Biomark Analysis: | Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease. |
| Control Group Info: | single arm |
| Treatment Info: | this study was performed to evaluate escalating doses of oral sirolimus (560 mg) on days 2, 9, and 16 with intravenous nabpaclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28day cycle. A runin treatment of nabpaclitaxel (day 14) and sirolimus (day 7) was administered for pharmacokinetic and pharmacodynamic assessments |
| Primary End Point: | Clinical trial endpoints included doselimiting toxicities (DLTs), maximum tolerated doses, and response rates. |
| Secondary End Point: | NA |
| Patients Number: | 23 |
| Trial Results |
| DLT_MTD: | DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nabpaclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. |
| Objective Response Rate: | 27% |
| Disease Control Rate: | 68.20% |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Allgrade adverse events that occurred in more than 10% of patients are reported in Table 2. The most common allgrade hematologic events were neutropenia (14 patients or 61%) and anemia (13 patients or 57%). Fatigue (10 patients or 43%), anorexia (14 patients or 61%), alopecia (10 patients or 43%), and nausea/vomiting (10 patients or 43%) were also frequently reported. Metabolic abnormalities occurred in 21 of 23 patients, with hyperglycemia being the most common. Most events were grade 1 or 2. |
| Conclusions: | Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nabpaclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors |