title: A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.
abstract: BACKGROUND
  Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation.
  
  
  METHODS
  A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752.
  
  
  RESULTS
  A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles.
  
  
  CONCLUSIONS
  Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Brana
authors.affiliation: Sheba Medical Center, Ramat Gan, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Berger
authors.affiliation: Sheba Medical Center, Ramat Gan, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Golan
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Haluska
authors.affiliation: Greenville Health System - Cancer Institute, Greenville, SC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Edenfield
authors.affiliation: Sarasota Memorial Hospital, Sarasota, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fiorica
authors.affiliation: Greenville Health System - Cancer Institute, Greenville, SC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Stephenson
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: L P
authors.initials: LP
authors.lastname: Martin
authors.affiliation: University of Texas - MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Westin
authors.affiliation: Abington Memorial Hospital, Abington, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hanjani
authors.affiliation: Merck & Co., Inc., North Wales, PA, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Jones
authors.affiliation: H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Almhanna
authors.affiliation: H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Wenham
authors.affiliation: 1] H Lee Moffitt Cancer Center, Tampa, FL, USA [2] M2Gen Tampa, Tampa, FL, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Sullivan
authors.affiliation: M2Gen Tampa, Tampa, FL, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Dalton
authors.affiliation: Merck & Co., Inc., North Wales, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gunchenko
authors.affiliation: Merck & Co., Inc., North Wales, PA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Cheng
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: L L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Gray
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001555:Benzene Derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011422:Propionates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D016032:Randomized Controlled Trials as Topic; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D051880:Receptors, Notch / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013450:Sulfones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014018:Tissue Distribution
chemical_list: C554093:3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001555:Benzene Derivatives; D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D011422:Propionates; D051880:Receptors, Notch; D013450:Sulfones; C515074:ridaforolimus; C569480:dalotuzumab; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus