Abstract
BackgroundThe 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.MethodsThe 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 ConclusionsThe 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%]).
Highlights
Triple-negative breast cancer (TNBC) is defined by the lack of estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors, and it accounts for approximately 15% of all breast cancer cases
A‘Treatment-related’ indicates that the adverse event has been related to PF-03084014 and/or docetaxel. bThree patients developed grade 3 pneumonia, and one patient each experienced aspartate aminotransferase elevation, dehydration, hyponatremia, colitis, hypokalemia, prolonged prothrombin time, and decreased performance status
Seven additional patients with Metastatic TNBC (mTNBC) were treated in first-line at dose 2b in the expansion phase
Summary
Triple-negative breast cancer (TNBC) is defined by the lack of estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors, and it accounts for approximately 15% of all breast cancer cases. Metastatic TNBC (mTNBC) is associated with a poor prognosis [1,2,3]. N (%) Metastatic Locally recurrent mg PF-03084014 100 mg BID/ docetaxel 100 mg/m2 (n = 3) 43 (32-64). PF-03084014 150 mg BID/ docetaxel 75 mg/m2 (n = 11). 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
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