CheMo4METPANC: A randomized phase 2 study with combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) compared to chemotherapy alone in metastatic treatment-naïve pancreatic adenocarcinoma.

TPS4208 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) carries a 5-year relative survival of 3%. Immune checkpoint inhibitors have thus far failed to improve outcomes due to an immunosuppressive tumor microenvironment (TME). 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 in mouse PDAC models. Longitudinal survival studies testing combinations of CXCR4i, aPD-1, and gemcitabine in the KPC mouse model of PDAC demonstrated a survival benefit with the combination of all three agents. Results from a multicenter, investigator-initiated, single arm pilot study evaluating the preliminary safety and efficacy ofMotixafortide (CXCR4i), Cemiplimab (aPD1), Gemcitabine, and Nab-paclitaxel (MCGN) in 11 patients with treatment-naïve mPDAC were recently presented. Seven patients (64%) achieved a partial response, including 6 confirmed partial responses, and 10 patients (91%) had disease control, compared to historic partial response and disease control rates of 23% and 48%, respectively, with gemcitabine and nab-paclitaxel (GN). Preliminary median progression-free survival (PFS) was 9.6 months compared to historic median PFS of 5.5 months with GN. Analysis of paired pre- and on-treatment biopsy samples from demonstrated an increase in CD8+ T-cell density in tumors from all 11 patients treated with MCGN (p=0.007). Based on these promising results, the protocol was amended from a single arm expansion totaling 40 patients to a randomized phase 2 study. Methods: This is an open-label, multicenter, investigator-initiated phase 2 clinical trial. Patients are randomized 2:1 to receive MCGN or GNalone (N=108). The primary endpoint is progression free survival. The study has 80% power to detect an improvement in PFS from 6 to 9.2 months (HR 0.65) with a one-sided alpha of 0.20. One interim analysis for futility is planned when 50% of the PFS events are observed. Secondary objectives include response rate, disease control rate, duration of clinical benefit and overall survival. Patients will undergo optional paired biopsies which will be analyzed in conjunction with samples collected from the phase I pilot study. Exploratory studies include interrogation of the TME using quantitative multiplex immunofluorescence and single-cell RNA sequencing. The randomized phase 2 trial is open to enrollment and one patient has been randomized as of 1/29/2024. Clinical trial information: NCT04543071 .