Abstract A115: Clinical advancement of DUO-207: An ultrasmall nanomedicine delivering a gemcitabine prodrug encapsulating paclitaxel for the treatment of metastatic pancreatic cancer

Long-term survival rates for metastatic pancreatic cancer have remained low for decades. Current standard-of-care (SoC) chemotherapy regimens such as gemcitabine-nano albumin-paclitaxel (nab-PTX) and folinic acid-fluorouricil-irinotecan-oxaliplatin (FOLFIRINOX) extend life with median survival times of 8 to 12 months but are associated with significant, often debilitating side effects. Most novel treatments for metastatic pancreatic cancer aim to augment existing SoC chemotherapy rather than improving or replacing the backbone therapies. DUO-207, a novel ultrasmall nanomedicine (∼20 nm), takes a different approach. Its copolymer conjugate carries both gemcitabine and paclitaxel, replacing an entire SoC therapeutic regimen. Here, we describe results from preclinical efficacy, drug-tumor residence time, and toxicology studies. Results from canine toxicology studies supported the design of a Phase 1b clinical trial using the continual reassessment method (CRM), which is also described. A single, biweekly cycle-comparative efficacy and drug-tumor residence time study of DUO-207 was performed in rats bearing MIA-PaCa2 pancreatic tumors. DUO-207 was compared to SoC animal-equivalent doses of nab-PTX and gemcitabine. Tumor volume and weight were monitored. Tumors were collected after the final dose and analyzed for drug concentrations. Additionally, a bridging toxicology study with a recovery period was conducted in canines. Three escalating doses of DUO-207 were compared to SoC. Blood was analyzed for hematological toxicity, organ toxicity biomarkers, and drug toxicokinetics. Toxicology results were then used in a statistical model to explore plausible clinical dose escalation scenarios. In the comparative efficacy study, DUO-207 and SoC arrested tumor growth with similar efficacy. However, the SoC group suffered from severe toxicity that may have compromised tumor growth. Tumor drug concentrations of gemcitabine and paclitaxel were significantly higher in DUO-207–treated rats than SoC. DUO-207–treated canines showed improved clinical observations compared to SoC. As expected, hematologic toxicities occurred in a dose-dependent fashion in the DUO-207 group, but no hepato- or nephrotoxicity was noted. Based on these data, a Phase 1b CRM design has been developed with 90% power to detect the maximum tolerated dose in key scenarios with an average sample size of 11 patients per group. In summary, DUO-207 is a novel, ultrasmall nanomedicine that co-delivers paclitaxel and gemcitabine in a single intravenous infusion to treat inoperable pancreatic cancer and other malignancies. Higher concentrations of both drugs were found in the tumors of rats treated with DUO-207 compared to SoC suggesting, better penetration and retention. DUO-207 demonstrated dose-dependent hematological toxicities, improved clinical observations vs. SoC, and lacked signs of renal or liver toxicity. Toxicokinetic data from canines was used in a statistical model to determine patient numbers for Phase 1b dosing using CRM. Duo Oncology will initiate its clinical trial in Q4 2025. Citation Format: Katherine M. Eichinger, Sam N. Rothstein, Victoria Manax, Lindsay Berry. Clinical advancement of DUO-207: An ultrasmall nanomedicine delivering a gemcitabine prodrug encapsulating paclitaxel for the treatment of metastatic pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A115.