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

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

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Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy.
Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Department of Hematology and Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA.
Yale Cancer Center, New Haven, CT, USA.
Breast Cancer Research Program, Stanford Cancer Institute, Stanford, CA, USA.
Pfizer Oncology, Groton, CT, USA.
Pfizer Oncology, Milan, Italy.
Pfizer Oncology, San Diego, CA, USA.



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.


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.


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%]).


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

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