Abstract B014: CRISTAL-APC - A multi-center, open label Phase I/ II study of VP-002, a C-C motif chemokine receptor 1 (CCR1) inhibitor, in combination with nab-paclitaxel and gemcitabine (nPG) in patients with pancreatic ductal adenocarcinoma (PDAC)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by its complex tumor microenvironment (TME) containing tumor-associated macrophages (TAMs) which are recruited and polarised by C-C motif chemokine receptor 1 (CCR1). CCR1 promotes tumor invasion, is overexpressed compared to normal tissue, and is associated with reduced progression-free survival (PFS) in PDAC patients. VP-002 (BX471, Cycle Pharma) a clinically-tested CCR1 antagonist, resulted in a significant reduction in macrophage populations and has shown antitumor efficacy in subcutaneous xenograft and genetically engineered murine PDAC models, with evidence of synergy and increased survival when combined with gemcitabine-based treatment. Methods: This multi-center, open-label Phase I/II trial evaluates oral VP-002 in combination with nPG in patients with metastatic PDAC (mPDAC). The Phase I part identifies a recommended phase 2 dose (RP2D) assessing treatment-related adverse events and dose limiting toxicities and utilising Bayesian logistic regression model (BLRM)-based dose-finding design. For the Phase I part, eligible mPDAC patients aged ≥18 years in any line of treatment require: ECOG performance status 0/1; adequate renal, hepatic and bone marrow function; and biopsy-amenable tumor. Exclusions include ongoing Grade ≥2 toxicities. Oral VP-002 is dosed between 600–1800 mg/day in divided doses, starting with a 14-day monotherapy run-in followed by on-trial tumor biopsy, then 28-day cycles of continuously dosed oral VP-002 with nPG scheduled on days 1, 8 and 15. Two dosing cohorts will enrol in parallel (increasing chemotherapy dose; increasing VP-002). Phase II will compare overall survival (OS) and other measures of anti-cancer efficacy, including PFS, radiological response, changes in tumor markers and quality of life scores, in untreated mPDAC patients treated at the RP2D of VP-002 and nPG versus standard-of-care nPG alone, randomised in a 2: 1 ratio of experimental to control arm. This will be the first United Kingdom multi-center academic study in mPDAC patients utilising a trial design where information from synthetic control data from trials with highly similar enrolment criteria will be borrowed for power-prior based methods to increase the efficiency of the study. An interim futility analysis is included. Exploratory endpoints to evaluate pharmacodynamic effects or biomarkers predictive of radiological or pathological response from CCR1 inhibition as monotherapy or in combination with chemotherapy include biomarker analysis of infiltrating immune cells using CODEX, genomic sequencing, circulating chemokine profiles, spatial transcriptomic profile and dietary impacts on pharmacokinetics. CRISTAL-APC (Clinical Trial Registry Number: ISRCTN16463547) opened in April 2025 with two patients enrolled into the Phase I escalation as of June 2025. Citation Format: Alexander A. Azizi, Giovanni Codacci Pisanelli, Michael Gill, Helena Rayment, Ruth Okhuarobo, Agata Rohnke, Neel Sharma, Philippa Corrie, Katherine Dempsey, Alimu Dayimu, Nikolaos Demiris, Sabita Islam, Anita Chhabra, Leah Officer-Jones, John Le Quesne, David Chang, Duncan Jodrell, Fieke Froeling, Bristi Basu. CRISTAL-APC - A multi-center, open label Phase I/ II study of VP-002, a C-C motif chemokine receptor 1 (CCR1) inhibitor, in combination with nab-paclitaxel and gemcitabine (nPG) in patients with pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B014.