title: Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors.
abstract: OBJECTIVE
  There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs.
  
  
  METHODS
  We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS.
  
  
  RESULTS
  A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%).
  
  
  CONCLUSIONS
  The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD. hobday.timothy@mayo.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hobday
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Diane
authors.initials: D
authors.lastname: Reidy-Lagunes
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Strosberg
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kaubisch
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Manisha
authors.initials: M
authors.lastname: Shah
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Hedy Lee
authors.initials: HL
authors.lastname: Kindler
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Timothy J. Hobday, Rui Qin, and Charles Erlichman, Mayo Clinic, Rochester, MN; Diane Reidy-Lagunes, Memorial Sloan Kettering Cancer Center, New York; Andreas Kaubisch, Montefiore Medical Center, Bronx, NY; Malcolm J. Moore, Princess Margaret Hospital, Toronto, Ontario, Canada; Jonathan Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Manisha Shah, Ohio State University, Columbus, OH; Hedy Lee Kindler, University of Chicago, Chicago, IL; Heinz-Josef Lenz, University of Southern California, Los Angeles, CA; and Helen Chen, National Cancer Institute, Rockville, MD.
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus