Vaccinex, Inc. announced the initiation of a single-arm open label, Phase Ib/2 study to evaluate pepinemab in combination with avelumab as second line combination immunotherapy for patients with metastatic pancreatic adenocarcinoma (PDAC), NCT05102721. The principal goal of this proof-of-concept study is to investigate the safety and efficacy of the combination of pepinemab and the PD-L1 immune checkpoint inhibitor (ICI), avelumab, in patients with PDAC, with particular attention to changes in the tumor microenvironment. Potential Mechanism of Action for pepinemab in combination with ICIs in PDAC Tumors that are characterized by a high level of immunosuppressive myeloid cells may be potential candidates for treatment with pepinemab.

The tumor microenvironment (TME) of PDAC is characterized by dense fibrotic tissue and abundance of highly suppressive myeloid cells that creates an immunologically “cold” setting with a minimal adaptive T-cell response that limit the efficacy of immune therapies. In PDAC, both SEMA4D and PD-1 are expressed on CD8+T cells in the TME. Myeloid cells within the TME express a high level of SEMA4D receptors and signaling through this pathway induces their suppressive activity.

This suggests that blocking SEMA4D may represent a novel immunotherapeutic strategy for PDAC. In preclinical oncogene driven PDAC tumor models, treatment with Sema4D blocking antibody in combination with immune checkpoint blockade and standard of care chemotherapy increased penetration of effector T cells and improved response to treatment. These observations in PDAC are consistent with a large body of preclinical and clinical data showing that pepinemab promotes infiltration and activation of dendritic cells and CD8+ T-cells and reverses immunosuppression within the tumor microenvironment.

The single-arm, open label Phase 1b/2 study was designed to evaluate the use of pepinemab, a humanized IgG4 monoclonal antibody that inhibits SEMA4D, in combination with the anti-PD-L1 immune checkpoint inhibitor (ICI), avelumab, as second line treatment for patients with metastatic pancreatic adenocarcinoma who have received first line treatment with either 5-floururacil (5-FU) or gemcitabine. The trial was designed at the ASCO-AACR Clinical Trial workshop to integrate evaluation of safety and efficacy. The study will be conducted in two segments utilizing a Simon two-stage design.

The Phase 1b stage is intended to establish the tolerability (defined as the maximally tolerated dose) of the combination. Phase 2 begins after 16 subjects are enrolled at the recommended Phase2 dose and successful completion of futility evaluation in Phase 1b. The Phase 2 expansion stage is intended to assess the efficacy of the combination therapy.

Efficacy, defined as objective response rate, will be assessed by RECIST1.1 criteria and iRECIST. When combined with the 16 patients from the Phase 1b segment, the overall study cohort will have an evaluable sample of 40 patients. Robust correlative analysis of TME and genomic profiling of tumor biopsies will be conducted to ascertain mechanisms of treatment response and failure.