title: A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors.
abstract: BACKGROUND
  To determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus.
  
  
  METHODS
  Escalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus. Blood samples were collected for PK analysis. Archival tissue specimens were collected for Notch pathway biomarker analysis and genotyping of frequent oncogenic mutations.
  
  
  RESULTS
  Seventeen patients with refractory advanced solid tumors were enrolled in three dose levels (DLs): DL1 (RO4929097 10 mg; Temsirolimus 25 mg), DL2 (RO4929097 20 mg; Temsirolimus 25 mg), and DL3 (RO4929097 20 mg; Temsirolimus 37.5 mg). The most common toxicities related to the study drug combination included: fatigue (82 %; grade 3 6 %), mucositis, (71 %; grade 3 6 %), neutropenia (59 %; grade 3 12 %), anemia (59 %; grade 3 0 %), and hypertriglyceridemia (59 %; grade 3 0 %). Two dose-limiting toxicities, grade 3 rash and grade 3 mucositis, were observed in the same patient in the first dose level prompting dose expansion. Eleven patients (73 %) had stable disease as their best response. Co-administration of RO4929097 was associated with increased clearance and reduced exposure to temsirolimus, suggestive of drug-drug interaction via CYP3A4 induction. No correlation between the expression of Notch pathway biomarkers or genotype and time to progression was noted.
  
  
  CONCLUSIONS
  RO4929097 can be safely combined with temsirolimus in patients with advanced solid tumors. The RP2D was established at 20 mg of RO4929097 combined with 37.5 mg of temsirolimus.
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, 610 University Avenue, 5-125, M5G 2M9, Toronto, ON, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Diaz-Padilla
authors.forename: Hal
authors.initials: H
authors.lastname: Hirte
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
authors.forename: Brenda
authors.initials: B
authors.lastname: Cohen
authors.forename: Michael
authors.initials: M
authors.lastname: Reedjik
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.forename: Sebastien J
authors.initials: SJ
authors.lastname: Hotte
authors.forename: Albiruni A R
authors.initials: AA
authors.lastname: Razak
authors.forename: Eric X
authors.initials: EX
authors.lastname: Chen
authors.forename: Irene
authors.initials: I
authors.lastname: Brana
authors.forename: Monika
authors.initials: M
authors.lastname: Wizemann
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Philippe L
authors.initials: PL
authors.lastname: Bedard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D000970:Antineoplastic Agents; D001552:Benzazepines; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D020123:Sirolimus; C499374:NOTCH3 protein, human; C401859:temsirolimus; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons