Toxicology and clinical protocol development of DUO-207: An ultrasmall nanomedicine co-delivering gemcitabine and paclitaxel for the treatment of metastatic pancreatic cancer.

749 Background: The long-term survival rates for metastatic pancreatic cancer have remained stubbornly low for decades. Most pancreatic cancers have dense, fibrous stroma tissue surrounding their tumors, which contributes to tumor growth and acts as a barrier to many therapies. Nanomedicines have been developed for use in oncology to reduce toxicity and improve efficacy, but a majority are too large (> 100nm) to effectively penetrate dense stroma. DUO-207 is a novel ultrasmall nanomedicine (~ 20nm) composed of copolymer-conjugated gemcitabine that encapsulates paclitaxel. Numerous preclinical efficacy models have demonstrated DUO-207’s ability to penetrate and accumulate in tumor tissue. Here we describe results from toxicology studies performed in canines that assisted in the design of a phase 1b clinical trial using the continual reassessment method (CRM). Methods: A single cycle, bridging toxicology study of DUO-207 with a recovery period was performed in canines. Animal equivalent doses of nano-albumin-bound paclitaxel (nAb-PTX) and gemcitabine were administered as the standard of care (SoC) comparator. Blood was analyzed for hematological toxicity, biomarkers of major organ toxicity, and drug toxicokinetics. Toxicology results from DUO-207 were then used in a statistical model to explore plausible scenarios for clinical dose escalation. Results: DUO-207 treated canines demonstrated 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. Conclusions: In summary, DUO-207 is a novel, ultrasmall nanomedicine that can co-deliver paclitaxel and gemcitabine in a single intravenous infusion to treat stroma-rich cancers. DUO-207 demonstrated dose dependent hematological toxicities but improved clinical observations compared to SoC and lacked signals of renal and hepatoxicity. Toxicokinetic data from canines was used in a statistical model to determine patient numbers for phase 1b dosing using the CRM. Duo Oncology will conduct its clinical trial in 2025.