title: Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer.
abstract: BACKGROUND
  The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective gamma-secretase inhibitor in patients with advanced triple-negative breast cancer.
  
  
  METHODS
  The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination.
  
  
  CONCLUSIONS
  The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m2. At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients (N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%]).
authors.affiliation: Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy.
authors.forename: Marzia A
authors.initials: MA
authors.lastname: Locatelli
authors.affiliation: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Aftimos
authors.affiliation: Department of Hematology and Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.affiliation: Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA.|Yale Cancer Center, New Haven, CT, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: Breast Cancer Research Program, Stanford Cancer Institute, Stanford, CA, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pegram
authors.affiliation: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.affiliation: Pfizer Oncology, Groton, CT, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: Rossano
authors.initials: R
authors.lastname: Cesari
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: Yuqiu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: M Naveed
authors.initials: MN
authors.lastname: Shaik
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Kern
authors.affiliation: Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Curigliano
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018450:Disease Progression; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000453:epidemiology; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000009:adverse effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D014633:Valine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D014839:Vomiting / Q000139:chemically induced / Q000453:epidemiology
chemical_list: D043823:Taxoids; D013764:Tetrahydronaphthalenes; D000077143:Docetaxel; D014633:Valine; C550722:nirogacestat
keywords: NOTCH signaling; PF-03084014; breast cancer; gamma secretase; triple-negative