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

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

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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