*2.2.1.4 Conclusions/future directions*

*Advances in Precision Medicine Oncology*

TRAEs included hypophosphatemia (n = 1).

**2.2 Company sponsored clinical research**

*Chawla, Principal Investigator*

efficacy of chemotherapy and radiotherapy [34].

lower the risk of hepatotoxicity.

*2.2.1.2 Methods*

*2.2.1.1 Background & rationale*

*2.1.3.4 Conclusions/future directions*

reached, and 100 mg/m<sup>2</sup>

is on-going.

*2.1.3.3 Preliminary results presented at the ASCO annual meeting in June, 2019*

The Phase I part of study included 9 patients who were treated successfully at 3 dose levels. No dose-limiting toxicities (DLTs) were observed, the MTD was not

dose. Safety analysis: At Dose 1 (n = 3): Grade 3 treatment-related adverse events (TRAEs) included dyslipidemia (n = 1) and hyperglycemia (n = 1). At Dose 2 (n = 3): Grade 3 TRAEs included increased ALT (n = 1). At Dose 3 (n = 3): Grade 3

The primary endpoint has been met with no DLTs, the MTD was not reached and Dose 3 (100 mg/m2) of ABI-009 has been designated as the phase 2 dose which

*2.2.1 Phase I Study of INBRX-109 in Subjects With Locally Advanced or* 

*Metastatic Solid Tumors Including Sarcomas (NCT03715933) Sant P.* 

The initiation of the extrinsic apoptosis pathway is mediated by several death domain receptors including death receptor 5 (DR5), a transmembrane protein receptor activated by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [31]. The DR5 apoptosis pathway naturally occurs to rid the body of neoplastic cells and is known to be crucial in immune system surveillance against cancer growth and metastasis. Normally, when an anchorage-dependent cell becomes detached, the cell will undergo a process of detachment-induced apoptosis called anoikis, initiated by a death receptor-mediated apoptotic pathway. A reduction in DR5 expression was found in melanoma tumor samples, strongly implying the TRAIL/DR5 pathway is associated with the prevention of tumor metastasis [32]. In 1999, Walczak et al. observed tumor cells to have a significantly higher sensitivity to TRAIL than normal cells, emphasizing its potential as a therapeutic cancer agent [33]. The subsequent development of agonistic antibodies against DR5 (i.e. recombinant human TRAIL proteins) was shown to be successful in stimulating apoptosis when tested in various tumor cell lines, and was later also shown to enhance the

INBRX-109 is a tetravalent DR5 agonist antibody designed to initiate the DR5 apoptosis pathway and precisely engineered to avoid unnecessary crosslinking to

This is the first in-human, open-label, non-randomized Phase I clinical trial for INBRX-109. Eligible patients had metastatic or unresectable solid tumors refractory to standard treatment or for which there is no FDA approved standard treatment. Phase I consists of two parts, part 1 being a 3 + 3 dose escalation cohort and part 2 being a dose expansion cohort. Safety, tolerability and dose-limiting toxicity were measured and analyzed using the National Cancer Institute's Common Terminology

ABI-009 was designated as the recommended Phase II

**10**

NBRX-109, a precisely engineered tetravalent DR5 agonist antibody, showed promising results that warrant further exploration. The pharmacokinetics of INBRX-109 were essentially dose-proportional across all three dose levels, supporting dosing every three weeks with no premedications necessary. Specifically, the chondrosarcoma cohort of this Phase I study has been expanded to include twenty patients and is currently ongoing.
