title: Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor, onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour.
abstract: Gastrointestinal stromal tumours (GIST) treated with the tyrosine kinase inhibitor (TKI) imatinib can become resistant when additional mutations in the receptor tyrosine kinases KIT or PDGFRA block imatinib activity. Mutated KIT requires the molecular chaperone heat-shock protein 90 (HSP90) to maintain stability and activity. Onalespib (AT13387) is a potent non-ansamycin HSP90 inhibitor. We hypothesised that the combination of onalespib and imatinib may be safe and effective in managing TKI-resistant GIST.
  
  
  
  In this dose-escalation study, we evaluated the safety and efficacy of combination once-weekly intravenous onalespib for 3 weeks and daily oral imatinib in 28-d cycles. Twenty-six patients with TKI-resistant GIST were enrolled into four sequential dose cohorts of onalespib (dose range, 150-220 mg/m(2)) and imatinib 400 mg. The relationship between tumour mutational status (KIT/PDGFRA) and efficacy of treatment was explored.
  
  
  
  Common onalespib-related adverse events were diarrhoea (58%), nausea (50%), injection site events (46%), vomiting (39%), fatigue (27%), and muscle spasms (23%). Overall, 81% of patients reported more than one onalespib-related gastrointestinal disorder. Nine patients (35%) had a best response of stable disease, including two patients who had KIT mutations known to be associated with resistance to imatinib and sunitinib. Disease control at 4 months was achieved in five patients (19%), and median progression-free survival was 112 d (95% confidence interval 43-165). One patient with PDGFRA-mutant GIST had a partial response for more than 376 d.
  
  
  
  The combination of onalespib plus imatinib was well tolerated but exhibited limited antitumour activity as dosed in this TKI-resistant GIST patient population. Trial registration ID: clinicaltrials.gov: NCT01294202.
authors.affiliation: Dana-Farber Cancer Institute and Ludwig Center at Harvard Medical School, Boston, MA, USA; Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: Andrew_Wagner@dfci.harvard.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.affiliation: Northwestern University Medical School, Division of Hematology/Oncology, 676 N. St. Claire Street, Suite 850, Chicago, IL 60611, USA. Electronic address: m-agulnik@northwestern.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Agulnik
authors.affiliation: VA Portland Health Care System and Oregon Health and Science University Knight Cancer Institute, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA. Electronic address: Heinrich@ohsu.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.affiliation: West Cancer Center/UTHSC, Memphis, TN, USA; West Clinic, 7495 Wolf River Blvd, Germantown, TN 38138, USA. Electronic address: dmahadevan@westclinic.com.
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
authors.affiliation: Duke Cancer Institute, Box 3198, Durham, NC 27710, USA. Electronic address: Richard.riedel@duke.edu.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Riedel
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA. Electronic address: Margaret.vonmehren@fccc.edu.
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.affiliation: University of Texas-MD Anderson Cancer Center, Houston, TX, USA; University of Miami Miller School of Medicine, 1120 NW 14th Street, CRB 610.06, Miami, FL 33136, USA. Electronic address: jtrent@med.miami.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Trent
authors.affiliation: Dana-Farber Cancer Institute and Ludwig Center at Harvard Medical School, Boston, MA, USA; Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: george_demetri@dfci.harvard.edu.
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.affiliation: VA Portland Health Care System and Oregon Health and Science University Knight Cancer Institute, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA. Electronic address: corlessc@ohsu.edu.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, UK. Electronic address: Murray.Yule@astx.com.
authors.forename: Murray
authors.initials: M
authors.lastname: Yule
authors.affiliation: Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, UK. Electronic address: John.lyons@astx.com.
authors.forename: John F
authors.initials: JF
authors.lastname: Lyons
authors.affiliation: Astex Pharmaceuticals, Inc., 4420 Rosewood Drive, Suite 200, Pleasanton, CA 94588, USA. Electronic address: Aram.oganesian@astx.com.
authors.forename: Aram
authors.initials: A
authors.lastname: Oganesian
authors.affiliation: Astex Pharmaceuticals, Inc., 4420 Rosewood Drive, Suite 200, Pleasanton, CA 94588, USA. Electronic address: Harold.keer@astx.com.
authors.forename: Harold
authors.initials: H
authors.lastname: Keer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000556:secondary; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate / Q000009:adverse effects / Q000627:therapeutic use*; D007275:Injections, Intravenous; D054833:Isoindoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone
keywords: Non-ansamycin HSP90 inhibitor; Onalespib (AT13387); TKI-resistant GIST