title: 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: Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
authors: Maysa M
authors: MM
authors: Abu-Khalaf
authors: Department of Medical Oncology, University of Rochester, Rochester, New York.
authors: Megan A
authors: MA
authors: Baumgart
authors: Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
authors: Scott N
authors: SN
authors: Gettinger
authors: Department of Diagnostic Imaging, Yale University School of Medicine, New Haven, Connecticut.
authors: Indukala
authors: I
authors: Doddamane
authors: EMD Serono, Billerica, Massachusetts.
authors: David P
authors: DP
authors: Tuck
authors: Celgene Corporation, Berkeley Heights, New Jersey.
authors: Shihe
authors: S
authors: Hou
authors: Celgene Corporation, Berkeley Heights, New Jersey.
authors: Nianhang
authors: N
authors: Chen
authors: Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
authors: Catherine
authors: C
authors: Sullivan
authors: Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
authors: Kimberly
authors: K
authors: Lezon-Geyda
authors: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut.
authors: Daniel
authors: D
authors: Zelterman
authors: Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
authors: Christos
authors: C
authors: Hatzis
authors: Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
authors: Hari
authors: H
authors: Deshpande
authors: Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
authors: Michael P
authors: MP
authors: Digiovanna
authors: Department of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut.
authors: Masoud
authors: M
authors: Azodi
authors: Department of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut.
authors: Peter E
authors: PE
authors: Schwartz
authors: Department of Medical Oncology, Case Western University, Cleveland, Ohio.
authors: Lyndsay N
authors: LN
authors: Harris
mesh_terms: D000328:Adult; D000368:Aged; D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015331:Cohort Studies; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D019788:Fluorodeoxyglucose F18; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D020123:Sirolimus
keywords: [18F]fludeoxyglucose positron emission tomography (FDG-PET); mammalian target of rapamycin (mTOR); nanoparticle albumin-bound paclitaxel (nab-paclitaxel); sirolimus; solid tumors