Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel in patients with advanced solid tumors.

Abstract

BACKGROUND:

The optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated.

METHODS:

A phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for 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.

RESULTS:

Twenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). 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). 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.

CONCLUSIONS:

Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel 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.

• Authors: Maysa M Abu-Khalaf, Megan A Baumgart, Scott N Gettinger, Indukala Doddamane, David P Tuck, Shihe Hou, Nianhang Chen, Catherine Sullivan, Kimberly Lezon-Geyda, Daniel Zelterman, Christos Hatzis, Hari Deshpande, Michael P Digiovanna, Masoud Azodi, Peter E Schwartz, Lyndsay N Harris
• Journal: Cancer (Cancer) Vol. 121 Issue 11 Pg. 1817-26 (Jun 01 2015) ISSN: 1097-0142 [Electronic] United States
• PMID: 25649370 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Cancer Society.

Chemical References

• Albumin-Bound Paclitaxel
• Albumins
• Fluorodeoxyglucose F18
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Paclitaxel
• Sirolimus

Topics

• Adult
• Aged
• Albumin-Bound Paclitaxel
• Albumins (administration & dosage, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacokinetics)
• Cohort Studies
• Female
• Fluorodeoxyglucose F18
• Humans
• Male
• Middle Aged
• Nanoparticles (administration & dosage)
• Neoplasms (diagnostic imaging, drug therapy, metabolism)
• Paclitaxel (administration & dosage, pharmacokinetics)
• Positron-Emission Tomography (methods)
• Sirolimus (administration & dosage, pharmacokinetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Treatment Outcome