A First in-Human Phase 1a/1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of IMGS-001 in Patients with Relapsed or Refractory Advanced Solid Tumors
Introduction
As a significant portion of cancer patients present with “cold” tumors lacking pre-existing immune infiltration and/or higher numbers of mutational neoantigens, these tumors are almost completely resistant to checkpoint blockade and therefore represent a significant unmet medical need. IMGS-001 is a fully human, dual specific immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds both PD-L1 and PD-L2, silencing the entire PD-1 inhibitory circuit, with an engineered fragment crystallizable (Fc) region designed to induce robust antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP). IMGS-001 is engineered through point mutations to induce ADCC and ADCP with >100 fold the efficiency of unmodified human IgG1. IMGS-001 mediated killing of PD-L1+ and PD-L2+ tumor and stromal cells can reduce the level of multi-modal immune suppression throughout the tumor microenvironment while catalyzing cross presentation of tumor antigens to the adaptive immune system. IMGS-001 also blocks binding of the T cell co-inhibitory receptor PD 1 with its ligands, restoring activation and function to tumor-specific T cells. In addition, IMGS-001 blocks binding of PD-L1 to B7-1, increasing costimulation of tumor-specific T cells. A first-in-human phase 1a/1b study is being initiated to investigate IMGS-001 safety and efficacy in solid tumor patients.
Methods
Phase 1a is enrolling patients with advanced solid tumors refractory to standard of care therapy. Using a Bayesian Optimal Interval (BOIN) dose-escalation design, a starting dose of 0.3 mg/kg (Q2W) will escalate up to 15 mg/kg based on DLT assessments. Additional patients will be dosed at the highest two doses for dose optimization up to approximately 25 patients. Phase 1b is a two-stage design enrolling patients across the following five tumor types with PD-L1 expression >5%: triple negative breast, bladder, gastric/esophageal, colorectal, and ovarian. The two-part design will initially enroll up to 10 subjects at the highest Phase 1a dose. Cohorts that meet prespecified efficacy criteria will proceed to a dose optimization study randomly assigning (1:1) 40 subjects between two doses studied in Phase 1a. The primary Phase 1a objective is to assess IMGS-001 safety, as well as pharmacokinetics and preliminary anti-tumor activity. Phase 1b will define the pharmacologically optimal dose (POD) after pooling and evaluating all available PK, PD, target engagement, efficacy, safety, and tolerability data from both study phases. The study efficacy analysis will include ORR and PFS, as well as exploratory tissue and serum biomarker analyses.
Results
This Phase 1a/1b study has been cleared to proceed under FDA IND with multiple U.S. sites now open to enrollment in 3Q 2023. Preliminary Phase 1a results to be reported in 2024.
Conclusion
IMGS-001 is a fully human, dual specific monoclonal antibody that binds both PD-L1 and PD-L2 therefore addressing the PD-1 inhibitory circuit fully, and is engineered with mutations to elicit effector cell killing via ADCC/ADCP. A first in human Ph 1a/1b clinical trial has started 3Q2023 to investigate IMGS-001 safety and efficacy across a variety of solid tumor types. The study will enroll approximately 25 patients in Phase 1a and up to 250 in Phase 1b, with initial results of the dose escalation portion expected to be available in 2024.