PMID- 26686201
OWN - NLM
STAT- MEDLINE
DCOM- 20161107
LR  - 20220316
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 34
IP  - 1
DP  - 2016 Feb
TI  - A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in 
      advanced solid tumors (PJC008/NCImusical sharp9041).
PG  - 104-11
LID - 10.1007/s10637-015-0313-8 [doi]
AB  - BACKGROUND: There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR 
      pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer 
      activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, 
      with temsirolimus was evaluated in patients with advanced solid tumors to 
      determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor 
      activity. METHODS: Patients were enrolled using 3 + 3 design, and were given 
      intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. 
      Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood 
      was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine 
      phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug 
      levels was performed on Day 1 and 8 of cycle 2. RESULTS: Twenty-one patients were 
      enrolled, 6 at dose level (DL) 1, 7 at DL -1, and 8 at DL -2. No effect of 
      temsirolimus on trebananib PK was observed. The most common treatment-related 
      adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea 
      (52 %), rash (43 %) and mucositis (43 %). The most common grade >/= 3 AEs included 
      lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 
      response evaluable patients, 1 partial response was observed (ER+/HER2-/PIK3CA 
      mutant breast cancer) and 4 patients had prolonged SD >/= 24 weeks. No correlation 
      with clinical benefit was observed with change in number TEMs or TP expression in 
      TEMs with treatment. CONCLUSIONS: The MTD was exceeded at trebananib 10 mg/kg 
      weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities 
      including fatigue, edema, and anorexia.
FAU - Chiu, Joanne W
AU  - Chiu JW
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada.
FAU - Hotte, Sebastien J
AU  - Hotte SJ
AD  - Juravinski Cancer Centre and Escarpment Cancer Research Institute, Hamilton, ON, 
      Canada.
FAU - Kollmannsberger, Christian K
AU  - Kollmannsberger CK
AD  - British Columbia Cancer Agency, Vancouver, BC, Canada.
FAU - Renouf, Daniel J
AU  - Renouf DJ
AD  - British Columbia Cancer Agency, Vancouver, BC, Canada.
FAU - Cescon, David W
AU  - Cescon DW
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada.
FAU - Hedley, David
AU  - Hedley D
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada.
FAU - Chow, Sue
AU  - Chow S
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada.
FAU - Moscow, Jeffrey
AU  - Moscow J
AD  - National Cancer Institute, Cancer Therapy Evaluation Program, Rockville, MD, USA.
FAU - Chen, Zhuo
AU  - Chen Z
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada.
FAU - Perry, Meghan
AU  - Perry M
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada.
FAU - Diaz-Padilla, Ivan
AU  - Diaz-Padilla I
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada.
FAU - Tan, David
AU  - Tan D
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada.
FAU - Hirte, Hal
AU  - Hirte H
AD  - Juravinski Cancer Centre and Escarpment Cancer Research Institute, Hamilton, ON, 
      Canada.
FAU - McWhirter, Elaine
AU  - McWhirter E
AD  - Juravinski Cancer Centre and Escarpment Cancer Research Institute, Hamilton, ON, 
      Canada.
FAU - Chen, Helen
AU  - Chen H
AD  - National Cancer Institute, Cancer Therapy Evaluation Program, Rockville, MD, USA.
FAU - Siu, Lillian L
AU  - Siu LL
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada.
FAU - Bedard, Philippe L
AU  - Bedard PL
AD  - Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, 
      University Health Network, Suite 5-125, 610 University Avenue, Toronto, ON, M5G 
      2M9, Canada. philippe.bedard@uhn.ca.
AD  - Department of Medicine, University of Toronto, Toronto, ON, Canada. 
      philippe.bedard@uhn.ca.
LA  - eng
GR  - U01 CA132123/CA/NCI NIH HHS/United States
GR  - UM1 CA186644/CA/NCI NIH HHS/United States
GR  - U01-CA-132123/CA/NCI NIH HHS/United States
GR  - UM1CA186644/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20151219
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Recombinant Fusion Proteins)
RN  - 624KN6GM2T (temsirolimus)
RN  - W36ZG6FT64 (Sirolimus)
RN  - X8Y5U6NC7E (trebananib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Anorexia/chemically induced/epidemiology
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse 
      effects/therapeutic use
MH  - Edema/chemically induced/epidemiology
MH  - Fatigue/chemically induced/epidemiology
MH  - Female
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/pathology
MH  - Recombinant Fusion Proteins/administration & dosage
MH  - Sirolimus/administration & dosage/analogs & derivatives
MH  - Treatment Outcome
PMC - PMC4718956
OTO - NOTNLM
OT  - AMG386
OT  - Combination therapy
OT  - Phase 1
OT  - Temsirolimus
OT  - Trebananib
EDAT- 2015/12/22 06:00
MHDA- 2016/11/08 06:00
PMCR- 2015/12/19
CRDT- 2015/12/22 06:00
PHST- 2015/10/14 00:00 [received]
PHST- 2015/12/03 00:00 [accepted]
PHST- 2015/12/22 06:00 [entrez]
PHST- 2015/12/22 06:00 [pubmed]
PHST- 2016/11/08 06:00 [medline]
PHST- 2015/12/19 00:00 [pmc-release]
AID - 10.1007/s10637-015-0313-8 [pii]
AID - 313 [pii]
AID - 10.1007/s10637-015-0313-8 [doi]
PST - ppublish
SO  - Invest New Drugs. 2016 Feb;34(1):104-11. doi: 10.1007/s10637-015-0313-8. Epub 
      2015 Dec 19.