Abstract OT1-01-04: VENTANA (SOLTI-1501): Oral metronomic vinorelbine combined with endocrine therapy in luminal/HER2-negative early breast cancer: A window of opportunity trial
Authors: Adamo B , Vidal M , Gomez Pardo P , Zaragoza K , Ciruelos E , Virizuela JA , Blanch Tormo S , Pérez-Fidalgo JA , Murillo L , Lopez-Gonzalez A , Amillano Parraga K , Martinez Jañez N , Gonzàlez Farré X , Prat A 
Published: March 2017

Abstract
BACKGROUND
The CDK4/6 inhibitor palbociclib, in combination with endocrine therapy (ET), has been approved for patients (pts) with HR+/HER2- metastatic breast cancer (BC), suggesting that inhibition of the cell cycle in combination with ET is a strategy to keep exploring. In this context, vinorelbine (VNB) inhibits chromosome segregation during mitosis and blocks cells at G2/M. Interestingly, several metronomic schedules of VNB are being used in the clinical setting, a strategy that might not only affect cell-cycle but also aims to target tumor angiogenesis.
VENTANA is a “window-of-opportunity” trial designed to explore whether, similarly to CDK4/6 and mTOR inhibitors, oral metronomic VNB in combination with endocrine therapy induces a superior anti-proliferative effect than ET alone, as suggested by preclinical and clinical studies. We believe that a biological synergy of the combined treatment could open the door to include this treatment strategy in pts with BC as an alternative to CDK4/6 inhibitors.
METHODS
VENTANA is a phase 0 multicenter, three-arm, randomized clinical trial of oral metronomic VNB and letrozole (LET) versus either treatment alone in postmenopausal women with newly diagnosed, untreated HR+ and HER2-, stage I-III operable BC. Other eligibility criteria include primary tumor size ≥1 cm (cT1-3) and N0-1, ECOG PS 0-1 and evaluable diagnostic tumor sample. Pts are randomized (1:1:1) to receive LET 2.5mg daily, oral VNB 50mg 3 days a week, or LET 2.5mg daily and oral VNB 50mg 3 times a week. After 3 weeks of treatment, pts will undergo surgery, and both pre-treatment and post-treatment surgical samples will be analyzed for gene expression. Primary objective is to test if oral metronomic VNB and LET induce a superior anti-proliferative effect than either drug alone in pts with early BC defined as Luminal by PAM50. This will be evaluated by the expression of 11 proliferative genes contained in the PAM50 subtype predictor (BIRC5, CCNB1, CDC20, CDCA1, CEP55, KNTC2, MKI67, PTTG1, RRM2, TYMS and UBE2C) as surrogate signature biomarker of its anticancer activity.
VENTANA is a proof-of-concept study to describe the change in the expression of a proliferation-related gene signature in all 3 treatment arms. Changes in the proliferation signature will be determined by following formula: Mean suppression of proliferation signature score = 100 − [geometric mean (post treatment proliferation score / pre-treatment proliferation score · 100)]. By evaluating other BC-related gene signatures (560 genes), the antiangiogenic and immunogenic potential of the treatment arms will also be compared and genes regulated in a treatment-specific manner identified. All analyses will be performed within the different PAM50-defined subtypes (Luminal, Luminal A or Luminal B).
As the primary endpoint is continuous and there are no previous data to make assumptions about the degree of suppression of these genes, the sample size has not been determined by statistical calculations. A sample size of 20 pts per arm is considered appropriate to support our hypothesis. The targeted accrual of 60 pts will be enrolled in 10 sites across Spain (EudraCT Number 2015-004714-24).
Citation Format: Adamo B, Vidal M, Gomez Pardo P, Zaragoza K, Ciruelos E, Virizuela JA, Blanch Tormo S, Pérez-Fidalgo JA, Murillo L, Lopez-Gonzalez A, Amillano Parraga K, Martinez Jañez N, Gonzàlez Farré X, Prat A. VENTANA (SOLTI-1501): Oral metronomic vinorelbine combined with endocrine therapy in luminal/HER2-negative early breast cancer: A window of opportunity trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-04.