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Cancer. 2015 Jun 1;121(11):1817-26. doi: 10.1002/cncr.29254. Epub 2015 Feb 3.

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

Author information

1
Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
2
Department of Medical Oncology, University of Rochester, Rochester, New York.
3
Department of Diagnostic Imaging, Yale University School of Medicine, New Haven, Connecticut.
4
EMD Serono, Billerica, Massachusetts.
5
Celgene Corporation, Berkeley Heights, New Jersey.
6
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut.
7
Department of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut.
8
Department of Medical Oncology, Case Western University, Cleveland, Ohio.

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.

KEYWORDS:

[18F]fludeoxyglucose positron emission tomography (FDG-PET); mammalian target of rapamycin (mTOR); nanoparticle albumin-bound paclitaxel (nab-paclitaxel); sirolimus; solid tumors

PMID:
25649370
DOI:
10.1002/cncr.29254
[Indexed for MEDLINE]
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