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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.

Author information

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
Yale Cancer Center, New Haven, CT, USA.
6
Breast Cancer Research Program, Stanford Cancer Institute, Stanford, CA, USA.
7
Pfizer Oncology, Groton, CT, USA.
8
Pfizer Oncology, Milan, Italy.
9
Pfizer Oncology, San Diego, CA, USA.

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.

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

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