Abstract OT2-16-01: ONCX-NAV-G201: A phase 2, basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors: Triple-negative breast cancer cohort (trial in progress)
Authors: Zelnak Amelia B. , Lenz Heinz-Josef , Culm Kerry , Makris Lukas , Santos Valerie Chamberlain , Youssoufian Hagop , Mockbee Colleen , Miller Kathy D. 
Published: March 2023

Abstract
Objective: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors. Cohort C will enroll triple-negative breast cancer (TNBC) patients. Background: Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aberrant NOTCH signaling is associated with chemotherapy resistance, tumor plasticity, enhanced metastatic potential, promotion of a cancer stem cell phenotype, and immune evasion. In TNBC, aberrant NOTCH expression is associated with poor prognosis, making targeting of this pathway an attractive therapeutic strategy. Additionally, NOTCH may mediate resistance to angiogenesis inhibition. While VEGF inhibitors are approved for the treatment of multiple solid tumors, observed anti-tumor activity is limited in breast cancer. Pre-clinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway targeting. We postulate that navicixizumab will demonstrate anticancer efficacy against TNBC. Methods: Eligible TNBC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 4 prior lines of standard therapy for metastatic disease, including immunotherapy (for PD-L1 positive TNBC patients), and sacituzumab govitecan. TNBC is defined as ER and PR &lt; 1%, and HER2-negative (IHC 0, 1+, or 2+ and negative fluorescence in situ hybridization [FISH]). Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap™ ExTra with the Xerna TME Panel™ to classify patient samples into one of four tumor microenvironment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each TNBC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort C1) or in combination with paclitaxel (80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle) (Cohort C2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of &lt; 5% and a 20% PFS rate at 4 months, with targets of 15% and 40% respectively considered promising for this study. Interim efficacy assessments will be at 10-patient increments following the time patients have had at least 1 post-baseline scan. Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel™ biomarker subtypes.
Citation Format: Amelia B. Zelnak, Heinz-Josef Lenz, Kerry Culm, Lukas Makris, Valerie Chamberlain Santos, Hagop Youssoufian, Colleen Mockbee, Kathy D. Miller. ONCX-NAV-G201: A phase 2, basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors: Triple-negative breast cancer cohort (trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-01.