PYTHIA: A phase II study of palbociclib plus fulvestrant for pretreated patients with ER+/HER2- metastatic breast cancer

Abstract

Background: Palbociclib is an oral, potent, selective inhibitor of CDK4/6, blocking cell cycle progression from G1 into S phase. Preclinical data indicate that palbociclib has enhanced activity against luminal ER+ human breast cancer (BC) cell lines in vitro, combined with endocrine treatment. Randomized clinical trials showed significant PFS prolongation in patients with newly diagnosed and pretreated metastatic luminal BC, when palbociclib was combined with letrozole and fulvestrant respectively (PALOMA-1/2 and -3 trials). Predictive biomarkers for patient selection to receive palbociclib plus endocrine treatment are still missing. Trial design: PYTHIA (IBCSG 53-14/BIG 14-04) is a phase II, single-arm, multicenter, study of fulvestrant and palbociclib in postmenopausal women with ER+/HER2-, advanced BC, who progressed after prior endocrine treatment (1st or 2nd line; up to 1 line of prior chemotherapy is allowed). Patients are enrolled concurrently in the AURORA program (NCT02102165), a longitudinal cohort study with extensive molecular characterization of matched primary-metastatic BC, and plasma samples. The primary endpoint is PFS, based on local assessment as per RECIST 1.1. Secondary endpoints are safety and tolerability, as well as disease control rate. Correlative objectives will assess the potential predictive value of: i) mutations and copy number aberrations in a panel of cancer-related genes, ii) gene signatures inferred by RNA sequencing, iii) early FDG-PET/CT assessment performed for a subset of 30 patients, at baseline and Day 28, and iv) a serum thymidine kinase-1 (TK1) assay, performed at baseline, Day 14 and after Cycle 1. The sample size of 120 patients was selected to have 80% power to detect a HR of 2.0 for biomarker-positive patients, with 30-50% prevalence (two-sided α = 0.05). Enrollment opened in May 2016, with the target-recruitment being 120 patients at 21 sites in Belgium, Italy and the UK. Clinical trial identification: NCT02536742 Legal entity responsible for the study: International Breast Cancer Study Group (IBCSG) Funding: Pfizer Disclosure: All authors have declared no conflicts of interest.