Design of a phase 1 trial of <i>Listeria</i> <i>monocytogenes</i> 11-T856-1313 tetanus toxoid (Lm-LLO-TT) for pancreatic ductal adenocarcinoma (PDAC).

e15115 Background: Pancreatic cancer is the third leading cause of cancer mortality in the USA. Despite advances in therapy, the prognosis remains poor. Pancreatic ductal adenocarcinoma (PDAC) is poorly immunogenic, and novel therapies to enhance anticancer immune activity is urgently needed. In preclinical experiments, T856-1313 tetanus toxoid (TT) protein was cloned in bacterium Listeria monocytogenes11 (Listeria) as a fusion protein, designated Lm-LLO-TT. KPC transgenic mice with PDAC were given two TT vaccinations, followed by intraperitoneal (ip) Lm-LLO-TT alternately with low doses of gemcitabine (GEM) (60mg/kg ip) every third day for 6 doses total for two weeks. Listeria-TT accumulated in tumors and metastases with the highest number of bacteria on days 1 and 3. Few normal tissues harbored Listeria strongly suggesting selective accumulation of Listeria to the tumor. Treatment with Lm-LLO-TT resulted in significant improvement in the survival rate of transgenic KPC mice with advanced pancreatic cancer (p &lt; 0.0001). Listeria-TT+GEM led to decreased tumor size (80%) and number of metastases (87%) (p &lt; 0.01). There were increased CD4 T cells attracted to the tumor microenvironment of KPC transgenic mice, producing high levels of perforin and granzyme B. Based on promising preclinical data, a first in human clinical trial is planned with Lm-LLO-TT to selectively deliver highly immunogenic TT into PDAC tumors. Methods: For the phase I trial, key inclusion criteria are patients age &gt; 18, histology proven PDAC with measurable disease on imaging, and at least one prior line of chemotherapy. Primary objective is to assess safety, maximum tolerated dose, and recommended phase 2 dose of ip Lm-LLO-TT and GEM. Secondary endpoints include determination of objective response rate, disease control rate, and 6-month progression free survival. The study is planned to enroll 18 patients. A peritoneal port will be placed allowing for ip injections of Lm-LLO-TT and GEM. Dose escalation will follow a Bayesian Optimal Interval (BOIN) design performed with dose levels 1 to 3 (Table 1). Full treatment cycle will include the first high dose of Lm-LLO-TT on day 1, high dose of Lm-LLO-TT of dose on day 15, followed by multiple low doses of GEM (180 mg/m2) on days 18, 22, 25, 29, and 32, concomitantly with low doses of Lm-LLO-TT (1x10 6 CFU/kg ip) on days 19, 23, 26, 30, and 33. Results: GMP manufacturing of Lm-LLO-TT for use in Phase 1 clinical trial is underway. An Investigational New Drug (IND) application will be filed with the U.S. Food &amp; Drug Administration after completion of GMP. Patient enrollment is pending study activation. Conclusions: Lm-LLO-TT has demonstrated significantly antitumor activity in mice with pancreatic tumors. The planned Phase I first in human study in subjects with PDAC is designed to examine the preliminary clinical safety and benefit of Lm-LLO-TT. Dose Level Lm-LLO-TT (CFU/kg) 1 2x10 7 2 1x10 8 3 5x10 8