Abstract PR05: CheMo4METPANC: Combination Chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) Motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in METastatic treatment-naïve PANCreatic adenocarcinoma
Authors: Manji Gulam A. , May Michael , Chalabi Morteza Hajkarim , Pellicciotta Ilenia , Sta Ana Sarah I. , Sender Naomi , Pan Samuel S. , Ross Isabelle V. , Olive Kenneth P. , Wang Shikun , Izar Benjamin , White Ruth A. , Bates Susan E. , Raufi Alexander G. 
Published: January 2024

Abstract
Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a uniformly fatal disease. Immune checkpoint inhibitors have thus far failed to improve outcomes due to an immunosuppressive tumor microenvironment (TME). In preclinical mouse models, signaling through the C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis results in exclusion of anti-tumor immune cells. Using the KPC mouse PDAC model, we have demonstrated that treatment with the combination of a CXCR4 inhibitor (CXCR4i), αPD-1, and gemcitabine improves survival when compared to mice treated with either gemcitabine alone or the combination of CXCR4i and αPD-1 therapy. The goal of this first-in-human study was to test preliminary safety and radiologic response rate of motixafortide (CXCR4i), cemiplimab (αPD1), gemcitabine, and nab-paclitaxel (MCGN) in treatment-naïve mPDAC. Methods: This was an open label, multicenter, investigator-initiated, single arm pilot study evaluating MCGN in mPDAC. This signal seeking study incorporated a six-patient safety run-in cohort with enrollment of four additional patients (N=10). The primary aim of this trial was to study the safety of MCGN. If ≥3 of the initial 10 patients within the pilot stage experienced a partial response (PR) by RECIST criteria within 16 weeks, the combination would be considered promising and an expansion cohort of an additional 30 patients would be enrolled. Clinical trial information: NCT04543071. Results: A total of 11 patients (1 over-enrolled) with mPDAC participated in the study at Columbia University and Brown University (11/9/2020-3/3/2023). The median age was 58y. Two (18%) patients were female and 3 (27%) were black. As of 05/05/23, 6 (55%) patients experienced a partial response (PR) of which 4 (36%) were confirmed PRs with 1 patient experiencing resolution of the hepatic metastatic lesion. Three (27%) patients experienced stable disease. At a median follow-up of 9.5m, 5 remain on study (duration on treatment [DOT]: 11.6, 6.7, 3.7, 2.7, and 2 months), 4 are off treatment due to disease progression (DOT: 13.4, 9.7, 3.7, and 1.5 months), 1 withdrew consent, and 1 was removed per physician discretion. Five patients have died. As of 03/31/23, 9 patients experienced grade 3-4 treatment-related adverse events, including urticaria (18%), and allergic reaction, bone pain, hypertension, hypotension, pain, rash (each 9%). Analyses interrogating the TME, including single-cell profiling, will be presented on paired tumor biopsies obtained on all patients. Conclusions: Preliminary results from this pilot study of MCGN in mPDAC were promising, with a durable PR rate of 55% and disease control rate (DCR) of 82%, compared to historic PRs and DCRs of 23% and 48% reported with gemcitabine and nab-paclitaxel (GN), respectively. Based on these results, the study was amended to transition to a randomized phase 2 trial testing MCGN compared to GN (N=112). The primary endpoint is progression free survival (PFS).
Citation Format: Gulam A. Manji, Michael May, Morteza Hajkarim Chalabi, Ilenia Pellicciotta, Sarah I. Sta Ana, Naomi Sender, Samuel S. Pan, Isabelle V. Ross, Kenneth P. Olive, Shikun Wang, Benjamin Izar, Ruth A. White, Susan E. Bates, Alexander G. Raufi. CheMo4METPANC: Combination Chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) Motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in METastatic treatment-naïve PANCreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR05.