Efficacy and Safety of BC-819 and Gemcitabine in Patients With Locally Advanced Pancreatic Adenocarcinoma

This is a multicenter, open label, randomized, phase 2b study, designed to evaluate the safety and efficacy of patients with locally advanced pancreatic adenocarcinoma following intratumoral administration of BC-819 and intravenously administered gemcitabine. Intratumoral injections of BC-819 will be performed using endoscopic ultrasound (EUS).

Primary Objective: To assess the effect of intratumoral endoscopic ultrasound injection of BC-819 administered with intravenous gemcitabine on progression-free survival.

Secondary Objectives: To compare the effects of intratumoral injection of BC-819 administered in combination with intravenous gemcitabine vs. intravenous gemcitabine alone on:

Overall survival, Response rate, Resectability of the target tumor lesion, Quality of life, Safety, Serological Tumor Marker: CA 19-9, Duration of response, Failure-free survival

BC-819 (also known as DTA-H19) is a double-stranded DNA plasmid, 4,560 base pairs (bp) in length, carrying the gene for the Diphtheria toxin A (DT-A) chain under the regulation of the H19 promoter. This is a Targeted Cancer Therapy; DT-A chain expression is triggered by the presence of H19 transcription factors that are only up-regulated in tumor cells. The selective initiation of toxin expression results in selective tumor cell destruction via inhibition of protein synthesis selectively in the tumor cell, enabling highly targeted cancer treatment.

Eligibility Criteria:
Inclusion Criteria:

1. Males or females \> 18 years of age
2. If female, must not be pregnant or nursing; women of child-bearing potential must practice a medically approved method of contraception
3. If male, must practice a medically approved method of contraception if have a partner of childbearing potential
4. Histologically or cytologically confirmed adenocarcinoma of the exocrine pancreas
5. Locally advanced pancreatic cancer (LAPC) that is clinically unresectable as defined in the NCCN Guidelines
6. Karnofsky performance status (KPS) ≥ 70% at baseline
7. Adequate hematological, renal, and hepatic function

   * Platelet count ≥ 100,000/mm3
   * Absolute neutrophil count (ANC) ≥ 1500/mm3
   * Hemoglobin ≥ 10.0 g/dL (may be achieved by transfusion)
   * Creatinine (≤ 1.5 x ULN)
   * ALT, AST (≤ 1.5 x ULN)
   * Total Bilirubin (≤ 1.5 x ULN)
8. Have a target tumor lesion in the pancreas ≤ 6 cm in diameter that is accessible for intratumoral administration by EUS guidance as determined by the physician performing the EUS injection
9. Have a biopsy specimen that is positive for H19 expression (grade 2 or greater staining determined by a pathologist). H19 expression can be determined based on a biopsy specimen collected before study participation, if available.
10. No prior diagnosis of malignancy within 3 years except for curatively treated non-melanoma skin or in situ malignancies
11. Able to comply with the protocol procedures
12. Able and willing to provide written (signed) Informed Consent to participate in the study

Exclusion Criteria:

1. Have distant metastatic spread (such as liver or lung metastases), peritoneal spread or malignant ascites. Regional lymph node involvement may be considered in accordance with the PI's judgment
2. Received any prior therapy for the treatment of pancreatic malignancy (including chemotherapy, immunotherapy, vaccines, monoclonal antibodies, major surgery, or irradiation, whether conventional or investigational, other than up to4 single doses of gemcitabine chemotherapy.Patients who received prior gemcitabine will only be eligible, if they enter the study without evidence of disease progression.
3. Known human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or hepatitis B virus (HBV) infection
4. Have clinically significant pancreatitis within 12 weeks of treatment
5. Have a clinical history of significant coagulopathy
6. Have a medical condition contraindicated for endoscopic-guided delivery and/or for IV administration of Gemcitabine or any intercurrent medical illness or other medical condition that would in the judgment of the investigator compromise patient safety or the objectives of the study
7. Have participated in any experimental therapeutic research study with an unapproved drug within 4 weeks of the screening visit
8. Patients who require ongoing anticoagulation for pre-existing conditions, e.g., thrombophlebitis, pulmonary embolus or atrial fibrillation