On March 21, 2023 Vaccinex, Inc. (Nasdaq: VCNX), a clinical-stage biotechnology company pioneering a differentiated approach to treating cancer and neurodegenerative disease through the inhibition of SEMA4D, reported 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 (Press release, Vaccinex, MAR 21, 2023, View Source [SID1234629112]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

"We are very pleased to be working with Dr. David Linehan and his team at the University of Rochester Cancer Center and Wilmot Cancer Institute to conduct this important proof-of-concept study evaluating pepinemab and avelumab in PDAC. The team received a grant from the Gateway Discovery Award to support the trial concept," said Maurice Zauderer, CEO of Vaccinex. "Metastatic pancreatic adenocarcinoma is the third leading cause of cancer-related deaths. The profoundly immunosuppressive tumor microenvironment (TME) in PDAC remains a significant barrier to effective cytotoxic and immune based therapies. Low response rates to current chemotherapy regimens are evidenced by a 5-year survival rate of only 5-10%, underscoring the significant need for new treatment options. We believe that pepinemab has demonstrated a favorable safety profile when used in combination with the immune checkpoint inhibitor (ICI) avelumab1, and the combination may represent a novel treatment option for patients with this devastating disease."

Dr. Zauderer continued, "The hypothesis for evaluating pepinemab in combination with ICIs in PDAC is supported by a robust body of preclinical studies and human clinical data. These data suggest that treatment with the semaphorin 4D (SEMA4D) blocking antibody, pepinemab, may reverse immunosuppression to promote the infiltration and activation of dendritic cells and CD8+ cells into the TME, rendering "cold" tumors "hot" and leading to enhanced efficacy of ICIs such as avelumab."

Dr. Luis Ruffolo, MD, University of Rochester Medical Center, will be presenting details of these PDAC studies at SSO 2023, International Conference on Surgical Cancer Care in Boston, MA on March 23.

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.

About the Phase 1b/2 Study in Patients with PDAC

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 (Free ASCO Whitepaper)-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.

Vaccinex has global commercial and development rights to pepinemab. The Company is the sponsor of the study which is being primarily funded by a grant from the Gateway Discovery Award (administered by the Conquer Cancer Foundation/ASCO). Pepinemab is being provided by Vaccinex and avelumabis being provided by Merck KGaA, Darmstadt, Germany and Pfizer, Inc. Additional information about the study is available at: clinicaltrials.gov.

Avelumab is co-developed and co-commercialized by Merck KGaA, Darmstadt, Germany and Pfizer Inc

1. Shafique MR, Fisher TL, Evans EE, Leonard JE, et al. Clin Cancer Res. 2021 Jul 1;27(13):3630-3640. doi: 10.1158/1078-0432.CCR-20-4792.