OT3-01-01: Randomized Phase II Study of Fulvestrant Versus Fulvestrant Plus Bortezomib in Postmenopausal Women with Estrogen Receptor (ER) Positive, Aromatase-Inhibitor (AI) Resistant Metastatic Breast Cancer (MBC): New York Cancer Consortium Trial P8457.

Abstract

Abstract Background: Bortezomib ia proteasome inhibitor that enhances fulvestrant-mediated aggregation of the ER in the cytoplasm without blocking ER degradation in the nucleus in ER+ human breast cancer cell lines, thereby promoting cytoplasmic ER aggresomes which activate a sustained unfolded protein response leading to apoptotic cell death; the combination also induces tumor regression in a tamoxifen resistant T47D-cyclin D1 xenograft model more effectively than either agent alone (Clin Cancer Res 2011; 17: 2292–2300). Hypothesis: We hpothesize that the combination of fulvestrant and bortezomib will be more effective than fulvestrant alone in ER+, AI-resistant MBC. Trial design: This is an open-label randomized phase II design in which patients with MBC are randomized to receive fulvestrant alone (500 mg IM day −14, day +1, and day +14 during cycle 1, then 500 mg every 4 weeks on day +1 during cycle 2 and thereafter) or in combination with bortezomib (1.6 mg/m2 IV days +1, +8, +15 every cycle). Stratification factors for randomization include performance status (ECOG 0 vs. 1–2), measurable disease (yes vs. no), and prior chemotherapy for MBC (yes vs. no). Patients who progress on fulvestrant alone may cross over to the combination. Eligibility criteria: Postmenopausal women with ER+, Her2-negative, MBC who have progressive disease during AI therapy for metastatic disease, or relapse while receiving adjuvant AI therapy. Up to one prior chemotherapy regimen for metastatic disease is permitted. Specific aims: Primary Objective: To determine if the addition of bortezomib to fulvestrant significantly improves median progression-free survival (PFS), defined as the time from cycle 1, day 1 of therapy until disease progression or death from any cause. Secondary Objectives: To determine: (1) adverse event rates in both arms, (2) the clinical benefit rate (CBR — objective response [by RECIST 1.1] and/or progression free at 24 weeks), (3) the objective response and CBR after crossover from fulvestrant to fulvestrant plus bortezomib. Translational Objectives: To perform an exploratory analysis of the effects of the combination on intratumoral nuclear/cytoplasmic ER ratio, unfolded protein response (BiP), apoptotis (cleaved caspase 3, Bc1-2 phospho JNK.) Statistical methods: he median PFS for patients receiving fulvestrant alone is expected to be approximately 5.4 months based upon patients with AI-resistant disease enrolled on the CONFIRM trial ( J Clin Oncol 2010; 28: 4594–4600). The trial is designed to detect a 70% improved in median PFS to 9.0 months (alpha=0.10, beta =0.10), which will require 59 eligible patients in each arm. Present accrual and target accrual: 24/118 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-01.