43: An Update On The Phase I Study to Evaluate the Safety and Tolerability of SX-682 in Combination with Anti-PD1 as Maintenance Therapy for Unresectable Pancreatic Adenocarcinoma

Thursday, March 21, 2024

2:12pm – 2:22pm ET

Location: C101

Abstract Presenter(s)

Nicholas A. Ullman, MD

Surgery Resident
University of Rochester Medical Center
Rochester, New York, United States

Submitter(s)

Nicholas A. Ullman, MD

Surgery Resident
University of Rochester Medical Center
Rochester, New York, United States

Author(s)

Nicholas A. Ullman, MD

Surgery Resident
University of Rochester Medical Center
Rochester, New York, United States
RD

Richard Dunne, MD

Medical Oncoligst
University of Rochester, United States
DM

Daniel Mulkerin, MD

Medical Oncologist
University of Rochester, United States
BB

Brian Belt, JD

Linehan Lab Manager
University of Rochester, United States
Luis I. Ruffolo, MD

Surgery Resident
University of Rochester
Rochester, New York, United States
Paul R. Burchard, MD

Surgery Resident
University of Rochester
Rochester, New York, United States
MB

Matthew Byrne, MD

Resident
University of Rochester Medical Center, United States
MG

Mary Georger, MS

Histopathologist
University of Rochester, United States
AH

Aram Hezel, MD

Medical Oncologist
University of Rochester, United States
JZ

Jason Zittel, MD

Medical Oncologist
University of Rochester, United States
WW

Wenjia Wang, MD

Medical Oncologist
University of Rochester, United States
ER

Erika Ramsdale, MD

Medical Oncologist
University of Rochester, United States
VK

Vivek Kaul, MD

Gastroenterologist
University of Rochester, United States
JZ

John Zebala, MD

Syntrix CEO
Syntrix Pharmaceuticals, United States
David Linehan, MD

Surgical Oncologist
University of Rochester Medical Center
Rochester, NY, United States

Disclosure(s):

Nicholas A. Ullman, MD: No financial relationships to disclose

Introduction: Outcomes for unresectable pancreatic ductal adenocarcinoma (PDAC) remain poor; with first-line therapies resulting in significant cytopenias and neuropathy, highlighting the need for effective, less toxic maintenance therapies. There are currently no approved maintenance treatments for PDAC not associated with BRCA or DNA-repair mutations. Here we present pre-clinical data demonstrating synergistic effect of CXC chemokine receptor-2 (CXCR2) inhibition and anti-PD1 as well as an update on the Phase-1 study (NCT04477343) evaluating SX-682, an oral CXCR1/2 inhibitor, and nivolumab as maintenance treatment for advanced PDAC.

Methods: Preclinical studies utilized the KP2 PDAC cell line. Following orthotopic injection, treatment with FOLFIRINOX was followed by maintenance SX-682 and anti-PD1 or 5-FU. The trial is an open-label, dose escalation Phase I trial evaluating the combination of SX-682 and nivolumab. Patients must complete at least 16 weeks of first line therapy without disease progression per iRECSIT. Baseline and on treatment biopsies are required. The primary objective is determining maximum tolerated dose using Bayesian optimal interval design. Secondary and exploratory objectives include progression free survival (PFS), overall survival (OS) and alterations in the tumor microenvironment through polychromatic flow cytometry and bulk RNA sequencing.

Results: In preclinical models of maintenance therapy, SX-682 and anti-PD1 therapy increased overall survival vs 5-FU (p< 0.05). At the time of submission, 11 of the 20 planned evaluable patients have been identified. Dose-levels 1 and 2 completed enrollment without dose-limiting toxicity (DLT). There have been two DLTs in Dose-level 3, resulting in a de-escalation to Dose-level 2. PFS and OS for the 11 evaluable subjects are 167 and 537 days, respectively. Flow cytometry analysis of nine paired biopsies suggest a decrease in CXCR2+ Gr-MDSCs, a decrease in regulatory T cells, and an increased CD8 to regulatory T cell ratio within the TME with no alteration in peripheral leukocyte components.

Conclusions: Preclinical PDAC maintenance immunotherapy demonstrates increased survival. Clinical translation of this immunotherapy strategy is underway. At the time of submission there have been two DLTs. P</span>aired tumor biopsies have shown decreased immunosuppressive cell populations within the TME.  

Learning Objectives:

Upon completion, participants will be able to describe the phase I trial schema.
Upon completion, participants will be able to describe the changes demonstrated in the tumor microenvironment.
Upon completion, the participant will be able to define the mechanism of action of the combination immunotherapy regimen.