Research Papers:

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

Marzia A. Locatelli, Philippe Aftimos, E. Claire Dees, Patricia M. LoRusso, Mark D. Pegram, Ahmad Awada, Bo Huang, Rossano Cesari, Yuqiu Jiang, M. Naveed Shaik, Kenneth A. Kern and Giuseppe Curigliano _

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Oncotarget. 2017; 8:2320-2328. https://doi.org/10.18632/oncotarget.13727

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Marzia A. Locatelli1, Philippe Aftimos2, E. Claire Dees3, Patricia M. LoRusso4,9, Mark D. Pegram5, Ahmad Awada2, Bo Huang6, Rossano Cesari7, Yuqiu Jiang8, M. Naveed Shaik8, Kenneth A. Kern8 and Giuseppe Curigliano1

1 Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy

2 Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

3 Department of Hematology and Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

4 Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA

5 Breast Cancer Research Program, Stanford Cancer Institute, Stanford, CA, USA

6 Pfizer Oncology, Groton, CT, USA

7 Pfizer Oncology, Milan, Italy

8 Pfizer Oncology, San Diego, CA, USA

9 Yale Cancer Center, New Haven, CT, USA

Correspondence to:

Giuseppe Curigliano, email:

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

Received: July 25, 2016 Accepted: November 22, 2016 Published: November 30, 2016


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%]).

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