Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer

Oncotarget. 2017 Jan 10;8(2):2320-2328. doi: 10.18632/oncotarget.13727.


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.

Results and 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%]).

Keywords: NOTCH signaling; PF-03084014; breast cancer; gamma secretase; triple-negative.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Disease Progression
  • Docetaxel
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neutropenia / chemically induced
  • Neutropenia / epidemiology
  • Taxoids / administration & dosage*
  • Taxoids / adverse effects
  • Tetrahydronaphthalenes / administration & dosage*
  • Tetrahydronaphthalenes / adverse effects
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / epidemiology
  • Triple Negative Breast Neoplasms / pathology
  • Valine / administration & dosage
  • Valine / adverse effects
  • Valine / analogs & derivatives*
  • Vomiting / chemically induced
  • Vomiting / epidemiology


  • Taxoids
  • Tetrahydronaphthalenes
  • Docetaxel
  • Valine
  • nirogacestat