A Phase 1, Open Label, Dose Escalation Study Of Mgd009, A Humanized B7-H3 X Cd3 Dart Protein, In Combination With Mga012, An Anti-Pd-1 Antibody, In Patients With Relapsed Or Refractory B7-H3-Expressing Tumors.

TPS2601 Background: T cells naturally undergo activation-induced upregulation of co-inhibitory pathways, which may limit the antitumor immune response. Blocking these inhibitory pathways may enhance the antitumor activity of CD3 bispecifics. MGD009 is a clinical stage B7-H3 x CD3 DART protein designed to redirect T cells to kill B7-H3 expressing tumor cells. B7-H3, a member of B7 family of immune regulators, is overexpressed in a variety of solid tumors and has limited expression in normal tissues. In preclinical studies, MGD009 causes T-cell infiltration, activation and expansion in the tumors. It upregulates PD-1 on T cells and PD-L1 on tumor cells and immune cells in vitro. Preliminary observations in patients enrolled in the ongoing phase 1 dose escalation trial with MGD009 alone indicate evidence of PD-1 up-regulation on both peripheral CD4 and CD8 T-cells. MGA012 is an anti-PD-1 antibody under investigation in an ongoing Phase 1 clinical trial and has shown clinical responses. In vitro and in vivo studies have shown enhanced antitumor activity with the combination of MGD009 and MGA012 beyond that achieved with MGD009 alone. A combination approach that blocks checkpoint inhibition of T cells with MGA012, while recruiting cytotoxic and helper T cells to B7-H3-expressing tumors with MGD009, may show anti-tumor activity in a variety of tumors. Methods: This is a Phase 1, open-label, dose escalation, and cohort expansion study designed to characterize the safety, tolerability, PK, pharmacodynamics, immunogenicity, and preliminary antitumor activity of MGD009 in combination with MGA012, both administered by IV infusion. Patients with B7-H3-expressing unresectable, locally advanced or metastatic solid tumors of any histology will be enrolled in the Dose Escalation Phase. Prior checkpoint inhibitor therapy is allowed. Dose escalation uses a 3+3+3 design, with patients treated every 2 weeks with escalating doses of IV MGD009 (starting dose 3µg/kg) and MGA012 at a dose of 3mg/kg in all cohorts. Cohort expansions will be limited to 6 tumor types (N = 20/cohort) treated at the maximum tolerated dose of the combination. Clinical trial information: NCT03406949.