Multicenter phase 2 study of hydroxychloroquine (HCQ) and chlorphenesin carbamate (CPC) in combination with mFOLFIRINOX in patients with advanced pancreatic adenocarcinoma (PDAC).

4189 Background: PDAC is one of the most lethal malignancies, with most patients (pts) presenting with advanced disease. Although combination chemotherapy, including modified FOLFIRINOX (mFOLFIRINOX) has improved survival, overall prognosis remains poor. Our preclinical studies suggest that HCQ and CPC synergistically enhance the antitumor activity of mFOLFIRINOX by inhibiting autophagy-dependent and AKT-mediated epithelial-mesenchymal transition pathways. Methods: This multicenter, single-arm phase 2 study included pts with locally advanced unresectable or metastatic PDAC in the first-line setting from three academic institutions in Korea. HCQ (200 mg) and CPC (250 mg) were administered orally twice daily in combination with mFOLFIRINOX for up to 24 cycles or until disease progression or unacceptable toxicity occurred. The primary endpoint was safety profile. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), cumulative incidence of new distant metastases, and health-related quality of life (HRQOL). Results: Between December 2021 and February 2023, 45 pts were screened and a total of 40 patients received study treatment. The median age was 61 years, and 23 (57.5%) were male; 73% (n = 29) and 27% (n = 11) had metastatic and locally advanced disease, respectively. The median number of cycles patients received was 13 (range, 1-24). Dose reductions for HCQ and CPC occurred in four (10%) pts each, with median > 90% of treatment compliance for both agents. Safety profiles are mostly consistent with known adverse events (AEs) with mFOLFIRINOX; grade 3-4 neutropenia (40%), nausea (13%), anemia (10%) were most common severe AEs. In the efficacy analysis set (n = 39), the ORR was 39% (CR or PR; n = 15), and the disease control rate was 92.3% (CR, PR or SD; n = 36). Curative-intent conversion surgery was performed in five pts (13%). With a median follow-up of 33.3 months, the median PFS was 7.4 months (95% CI, 6.2–13.3); in pts with objective response, median PFS was 13.6 months (95% CI, 7.4–33.8). The median OS was 14.8 months (95% CI, 9.6–27.9); median 20.5 months (95% CI, 14.8–NE) for locally advanced disease and median 13.9 months (95% CI, 9.2-NE) for metastatic disease. The cumulative incidence of new distant metastases was 38.8% at 12 months. HRQOL indicators did not deteriorate during the first 6 months of study treatment. Conclusions: HCQ and CPC in combination of mFOLFIRINOX were well tolerated and showed clinically promising efficacy outcomes in pts with advanced PDAC. Biomarker analysis using proteomics is ongoing. Clinical trial information: NCT05083780 .