P3-14-29: Neoadjuvant Sunitinib Administered with Weekly Paclitaxel/Carboplatin in Patients with Locally Advanced Triple-Negative Breast Cancer: A Sarah Cannon Research Institute Phase I/II Trial.
Authors: Yardley DA , Peacock NW , Peyton J , Shipley DL , Spigel S , Barton J , Shih KC , Raefsky E , Liggett W , Burris HA , Hainsworth JD 
Published: June 2012

Abstract
Background: Angiogenesis plays a substantial role in breast cancer development as well as in triple negative breast cancer (TNBC). Sunitinib is an inhibitor of the tyrosine kinase receptors for VEGF, platelet-derived growth factor (PDGF), KIT, RET, and fms-like tyrosine kinase receptor-3 (FLT3). As monotherapy in heavily pretreated breast cancer patients (pts), sunitinib demonstrated a response rate of 15% in TNBC (11% of all pts) with stable disease or better in 16% of all pts. The combination of paclitaxel and carboplatin is ideally suited for further exploration as neoadjuvant chemotherapy for TNBC, based on the established preclinical and clinical sensitivity of TNBC to these cytotoxic agents. This open label, phase I/II trial was designed to evaluate the combination of sunitinib plus paclitaxel and carboplatin as neoadjuvant treatment for locally advanced breast cancer. The primary objective for the phase I portion was to determine the maximum tolerated dose (MTD); these results are presented. Methods: Women with histologically confirmed invasive triple-negative adenocarcinoma of the breast, (defined as &lt;10% staining by IHC for ER/PR; IHC 0–1+ or FISH negative for HER2), with no evidence of metastatic disease and normal LVEF were eligible. All pts received sunitinib (days 1–28), paclitaxel (days 1, 8, 15), and carboplatin (day 1) in 28-day treatment cycles x6. Following 6 cycles, pts had definitive surgery. After ≥2 weeks and evidence of adequate wound healing, maintenance sunitinib 25mg PO daily was initiated to complete a total of 52 weeks. Three dose levels were evaluated as shown in the table below:

Doses were escalated in sequential cohorts of pts using standard phase I methodology. MTD was defined as the highest dose level (DL) producing ≤1 dose limiting toxicities (DLTs) in a pt cohort. The MTD identified in the phase I portion of the study will be used in the phase II portion, which will evaluate the efficacy, safety, and tolerability of this combination in pts with locally advanced TNBC.
Results: 15 women with TNBC were enrolled between 10/2009 and 2/2011 [median age 53 years (range: 40–78)]. Due to grade 3 neutropenia resulting in the inability to deliver cycle 1 day 15 paclitaxel in the first pt treated at both DLs 1 and 2, these DLs were expanded to 6 pts each. No additional cycle 1 DLTs were noted in the 5 additional pts at either DL. Three pts were accrued to DL 3; there were 2 DLTs noted among these pts (grade 3 febrile neutropenia; grade 3 neutropenia with cycle 2 day 1 treatment delay). However, due to the development of grade 3/4 neutropenia in subsequent cycles in 5 of 6 DL 2 pts, resulting in dose delays and requiring dose reductions, the MTD of this combination was defined as DL 1 (paclitaxel 70mg/m2 (Days 1, 8, 15); carboplatin AUC=5 (Day 1); sunitinib 25mg PO daily).
Conclusions: The administration of sunitinib with paclitaxel plus carboplatin as neoadjuvant therapy is feasible with neutropenia defining the MTD of this combination. The phase II portion of this study is ongoing.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-29.