November 14, 2019
Translational Research in Oncology (TRIO), a global academic clinical research organization, today announced enrollment of the first patient in a Phase I study with its partner Molecular Templates (Nasdaq: MTEM).
This Phase I first-in-human study is an open-label, dose escalation and expansion study of MT-5111 given as monotherapy in subjects with HER2-positive solid tumors. The primary objective of the trial is to evaluate the safety and tolerability and determine the recommended Phase II dose of MT-5111 in subjects with advanced HER2-positive solid tumors.
“We are excited to be working with Molecular Templates and their novel therapeutic for patients with previously treated advanced HER2-positive solid tumors,” says Launa Aspeslet, PhD, CEO of TRIO. “Given TRIO’s extensive experience in the HER2 space, as a direct result of the work by our Executive Director, Dr. Dennis Slamon, this study is the perfect fit for TRIO. Our team is focused on supporting several aspects of this trial, including clinical study de-sign, site recruitment and operational execution.”
“We are excited to have enrolled the first patient in this important first-in-human trial,” stated Dr. Brian Van Tine, Sarcoma Program Director and Associate Professor in the Division of Medical Oncology at Washington University in St. Louis. “Although patients with advanced HER2-positive breast or gastric cancer currently have a number of anti-HER2 therapies available, it is key to continue looking for novel options since patients will ultimately become re-sistant to standard therapies. MTEM is exploring an innovative anti-HER2 agent and we are excited to be part of this trial and to have enrolled its first patient.”
MT-5111 is an engineered toxin body (ETB) consisting of a single chain varia-ble fragment (scFv) antibody with affinity for HER2, fused to the enzymatically active de-immunized Shiga-like toxin-A subunit (SLTA). MT-5111 specifically binds and kills HER2-expressing cells in a manner consistent with SLTA-mediated cellular cytotoxicity. MT-5111 has been specifically designed to avoid competition with and to overcome the primary mechanisms of tumor re-sistance to current HER2 targeted therapies. To accomplish this, first, MT-5111 binds a HER2 domain that is distinct from the trastuzumab and pertuzumab binding sites, which results in MT-5111 HER2-mediated binding and cell kill-ing even in the presence of these monoclonal antibodies. As such, MT-5111 may have the potential to be combined with other HER2-targeted therapies. Second, SLTA is a large molecule protein and is not a substrate of drug efflux transporters such as MDR1 which has been demonstrated to be one of the pri-mary mechanisms of resistance to the antibody drug conjugate, T-DM1. Third, MT-5111-mediated ribosomal inhibition and cell death take place intracellular-ly so changes in the tumor microenvironment which inhibit immune-mediated mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC) are not expected to inhibit MT-5111 activity. Finally, mutations to the HER2 kinase domain that can induce constitutive downstream signaling to drive tu-mor proliferation are not expected to interfere with MT-5111 activity given that its mechanism of action is not dependent upon kinase domain binding and MT-5111 works directly on ribosomes to mediate ribosomal inhibition and cell death. Together, MT-5111 represents a novel HER2-targeted therapy which could provide benefit in subjects with HER2-positive cancers and potentially overcome mechanisms of tumor resistance to existing HER2 targeted therapies.