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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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A Multi-Center, Open-Label, Randomized, Phase 2b Study to Evaluate the Efficacy and Safety of BC-819 and Gemcitabine in Patients With Locally Advanced Pancreatic Adenocarcinoma

Conditions
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Pancreas, Adenocarcinoma

Intervention / Treatment
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* Biological: Biological/Vaccine: BC-819


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females > 18 years of age If female, must not be pregnant or nursing; women of child-bearing potential must practice a medically approved method of contraception If male, must practice a medically approved method of contraception if have a partner of childbearing potential Histologically or cytologically confirmed adenocarcinoma of the exocrine pancreas Locally advanced pancreatic cancer (LAPC) that is clinically unresectable as defined in the NCCN Guidelines Karnofsky performance status (KPS) ≥ 70% at baseline 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) 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 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. No prior diagnosis of malignancy within 3 years except for curatively treated non-melanoma skin or in situ malignancies Able to comply with the protocol procedures Able and willing to provide written (signed) Informed Consent to participate in the study Exclusion Criteria: 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 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. Known human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or hepatitis B virus (HBV) infection Have clinically significant pancreatitis within 12 weeks of treatment Have a clinical history of significant coagulopathy 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 Have participated in any experimental therapeutic research study with an unapproved drug within 4 weeks of the screening visit Patients who require ongoing anticoagulation for pre-existing conditions, e.g., thrombophlebitis, pulmonary embolus or atrial fibrillation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 8 mg BC-819 and Gemcitabine<br>gemcitabine dose of 1000mg/m2 + 8 mg of BC-819 | Biological: Biological/Vaccine: BC-819<br>* Post screening and prior to randomization, all patients will receive gemcitabine by IV infusion at a dose of 1000mg/m2 once weekly for four weeks. They may also enter the study if they received up to 4 doses of gemcitabine before entering the study. In this case, they will be randomized immediately provided there is no evidence of disease progression. After randomization patients will receive 6 weekly IV infusions of gemcitabine at a dose of 1000mg/m2 + 7 intratumoral injections of BC-819 (8 mg or 12 mg according to allocations by randomization)<br>* Other names: inodiftagene vixteplasmid;|
| Experimental: 12 mg BC-819 and Gemcitabine<br>gemcitabine dose of 1000mg/m2 + 12 mg of BC-819 | Biological: Biological/Vaccine: BC-819<br>* Post screening and prior to randomization, all patients will receive gemcitabine by IV infusion at a dose of 1000mg/m2 once weekly for four weeks. They may also enter the study if they received up to 4 doses of gemcitabine before entering the study. In this case, they will be randomized immediately provided there is no evidence of disease progression. After randomization patients will receive 6 weekly IV infusions of gemcitabine at a dose of 1000mg/m2 + 7 intratumoral injections of BC-819 (8 mg or 12 mg according to allocations by randomization)<br>* Other names: inodiftagene vixteplasmid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | To compare the effect of intratumoral endoscopic ultrasound injection of BC-819 administered with intravenous gemcitabine on progression-free survival. PFS was defined as the time from the date of consent until objective tumor progression or death. Median PFS by Kaplan-Meier analysis was used for evaluation. The target tumor lesion was identified and the longest diameter of the target lesion was measured according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. For disease evaluations after treatment, scans conducted at baseline that were used for tumor measurements were repeated. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was calculated from the date of consent until death due to any cause. | 24 months | 
| Response Rate of Target Lesion | Response rate will be assessed both for the primary target tumor lesion alone and overall, including development of metastases. Target tumor lesions are identified and the longest diameter of the target lesion is measured by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Complete response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also show an increase of at least 5 mm. Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | 8 weeks | 
| Resectability of the Target Tumor Lesion | Resectability of the target tumor lesion was determined by CT/MRI as defined in the National Comprehensive Cancer network (NCCN) guidelines. Resectable tumors have no arterial tumor contact (celiac axis [CA], superior mesenteric artery [SMA], or common hepatic artery [CHA]) and no tumor contact with the superior mesenteric vein (SMV) or portal vein (PV) or ≤180° contact without vein contour irregularity. *Not Applicable refers to another clinically significant abnormality that interfered with resectability determination of the target tumor lesion. | an average of 16 weeks | 
| Quality of Life (QoL) Assessed by Karnofsky Performance Status (KPS) | Quality of life will be assessed by the The Karnofsky Performance Status (KPS) Index. KPS scores over time will be compared to those at baseline and changes from baseline will be presented. KPS scores are on a scale (0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100) of 0 (dead) to 100 (Normal no complaints; no evidence of disease). | Screening, Visit 4 (post gemcitabine induction), Visit 9 (5 weeks), Visit 13 (9 weeks) | 
| Quality of Life Using the Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire | The FACT-G is a 27-item compilation of general questions divided into 4 primary QoL domains: physical well-being, social/family well-being, emotional well-being and functional well-being. The total FACT-G scores will be summarized by descriptive statistics (e.g., n, mean, median, standard deviation and range). The individual FACT-G score will be presented by frequency and percentage. Scores range from 0-108. High total scores represent better general QoL. | Screening, Visit 4 (post gemcitabine induction), Visit 9 (5 weeks), Visit 13 (9 weeks), every 6 months after Visit 13 | 
| Serological Tumor Marker: CA 19-9 | Serum was collected for quantitative measurement of CA 19-9. | 24 months | 
| Extent of Exposure - Gemcitabine Total Exposure (g) | Measured by the average and median number of exposure of the patients to BC-819 and gemcitabine. | 24 months | 
| Extent of Exposure - Gemcitabine Total Number of Treatments | Measured by the average and median number of treatments of the patients to BC-819 and gemcitabine. | 24 months | 
| Extent of Exposure - BC-819 Total Exposure (mg) | Measured by the average and median exposure of the patients to BC-819 and gemcitabine. | 24 months | 
| Extent of Exposure - BC-819 Total Number of Treatments | Measured by the average and median number of treatments of the patients to BC-819 and gemcitabine. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic cancer, Gemcitabine, BC-819, Adenocarcinoma, Resectable, H19 gene, DTA-H19, BioCancell, inodiftagene vixteplasmid