TNBC is an aggressive subtype of metastatic breast cancer. Eribulin has been shown to have activity in metastatic TNBC and has enhanced efficacy if TGF-β is downregulated. Additionally, down-regulating TGF-β in the tumor microenvironment may decrease tumor growth and increase responsiveness to checkpoint blockade. Bintrafusp alfa* (M7824) is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. Therefore the combination of eribulin with bintrafusp alfa is being tested in this phase I trial to evaluate safety and efficacy for patients with metastatic TNBC.
This is an open-label, single arm phase Ib study in patients with metastatic TNBC. The primary objective is to evaluate the recommended phase-2 dosing of eribulin and bintrafusp. Patients undergo core tissue biopsy and blood work at enrollment. Patients will then receive study drug (bintrafusp alfa) and eribulin with tumor assessments at 6 and 12 weeks. Patients will be treated in a cohort size of 4 with an expansion of up to 20 patients. Bayesian optimal interval (BOIN) design will be employed to identify the RP2D of eribulin by conducting dose de-escalations based on dose-limiting toxicity. Patients undergo repeat core tissue biopsy after 12 weeks of therapy and will continue on study drug until progression of disease or a sustained CR for one year. Eligibility: Inclusion: metastatic TNBC, adequate organ, bone marrow and cardiac parameters. Exclusion: prior immunotherapy, IBC, history of autoimmune disease, HIV, Hep-B, Hep-C, active tuberculosis, pregnant. PD-L1 positivity is not an eligibility requirement. CORRELATIVE SCIENCE: Biopsies and blood are being obtained at baseline and after 2 months of therapy as well as requested at the time of progression of disease. Peripheral blood mononuclear cells (PBMCs will be evaluated for immunophenotyping, T cell activation and function as well as T cell repertoire analysis. PD-L1 staining will be done on tumor and infiltrating immune cells. From the tumor samples, TIL will be measured and characterized as well as tumor-tissue gene expression.
NCT03579472.
The University of Texas MD Anderson Cancer Center.
Merck/EMD-Serono.
J.K. Litton: Research grant / Funding (institution): astra zeneca; Advisory / Consultancy, uncompensated: astra zeneca; Advisory / Consultancy, uncompensated: Pfizer; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Novartis; Advisory / Consultancy, uncompensated: Genentech; Research grant / Funding (institution): Genentech. S. Damodaran: Research grant / Funding (institution): emd serono. I.I. Wistuba: Research grant / Funding (institution): emd serono. L. Ojalvo: Full / Part-time employment: emd serono. I. Dussault: Full / Part-time employment: emd serono. C. Helwig: Full / Part-time employment: Merck. All other authors have declared no conflicts of interest.