Phase 1/2a DTA-H19 in Patients With Unresectable Pancreatic Cancer

Study Overview
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Brief Summary
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This study is designed to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of DTA-H19 administered intratumorally in patients with unresectable, locally advanced pancreatic cancer. Primary Objective: The primary objective is to determine the maximum tolerated dose (MTD) of intratumoral DTA-H19 and identify any dose limiting toxicities (DLTs). Secondary objectives include determining the adverse events (AEs) profile, effects on clinical laboratory analytes, vital signs, PK, tumor response, and possible tumor resectability after 4 intratumoral administrations of DTA-H19.

Detailed Description
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DTA-H19, is a doubled stranded DNA plasmid that carries the gene for the diphtheria toxn A (DT-A) chain under the regulation of the H19 promoter sequence. This is a Patient-Oriented, Targeted Therapy as DT-A chain expression is triggered by the presence of H19 transcription factors that are upregulated in tumor cells. The selective initiation of toxin expression results in selective tumor cell destruction via inhibition of protein synthesis in the tumor cell, enabling highly targeted cancer treatment.

Official Title
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Phase 1/2a, Dose-Escalation, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Intratumoral Administration of DTA-H19 in Patients With Unresectable Pancreatic Cancer

Conditions
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Pancreatic Neoplasms

Intervention / Treatment
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* Biological: DTA-H19


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent and be between the ages of 18 and 79, inclusive. Have unresectable, locally advanced adenocarcinoma of the pancreas proven by biopsy or cytology (defined as direct extension to the superior mesenteric artery and/or celiac axis with loss of a clear plane between tumor and these arterial structures, or loss of patent superior mesenteric-portal vein confluence). Patients who have been surgically explored and deemed unresectable on that basis are eligible, provided other entry criteria are met. Patients having potentially resectable regional lymph node involvement may be included. Have a target tumor ≤ 6 cm in diameter that is accessible for intratumoral administration by PTA or EUS guidance as determined by the radiologist/gastroenterologist performing the PTA/EUS injection. Have a Karnofsky performance status of ≥ 70%. Have a life expectancy of >= 3 months. If female and of child-bearing potential, have a negative serum pregnancy test during screening. Agree to use of a barrier method of contraception if sexually active (both men and women) from the time of administration of the first treatment and for at least 8 weeks after treatment. Have serum creatinine < 2.0 mg/dL, AST and ALT >= 2.5 x ULN, PT, PPT, and PT/INR within normal limits, absolute neutrophil count (ANC) > 1,500 x 103 cells/mL, platelets ≥ 100,000/mL, and hemoglobin >= 10 mg/dL. Have a biopsy specimen that is positive for H19 expression (grade 2 or greater staining determined by a pathologist). Have screening procedures completed within 4 weeks of starting treatment. No other malignancy present that would interfere with the current intervention. Commit to refrain from any concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy or any other type of therapy for treatment of cancer while on this protocol, therefore any standard treatment should be postponed while on study. Have measurable disease. Exclusion Criteria: Have distant metastatic spread (such as liver or lung metastases), peritoneal spread or malignant ascites. Have prior radiation therapy for pancreatic cancer or radiation to the area of the target tumor field. Endocrine tumors or lymphoma of the pancreas. Have clinically significant pancreatitis within 12 weeks of treatment. If female, be breast feeding. Have a medical condition contraindicated for both percutaneous- and endoscopic- guided delivery 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 a history of coagulopathy. Have participated in any therapeutic research study within the last 4 weeks.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BC-819<br>Intratumoral administration of BC-819 | Biological: DTA-H19<br>* Cohort #1: 4 mg DTA-H19 intratumorally 2 times per week for 2 weeks Cohort #2: 8 mg DTA-H19 intratumorally 2 times per week for 2 weeks<br>* Other names: BC-819;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Tolerated Dose (MTD) & Dose Limiting Toxicity (DLT) of Intratumoral Injections of BC-819 | If 2 patients in any cohort experience DLTs, then the next lower dose will be considered the MTD if there is a lower dose cohort. A DLT is defined as grade 3 or greater toxicity judged to be at least possibly related to the investigational products. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response | Tumor response and progression were defined in accordance with RECIST v. 1.0 and assessed by radiological examination 2 weeks after the end of treatment | 4 weeks | 
| Tumor Resectability | The number of subjects in each cohort whose tumor was resectable at the end of the study was to be presented for the ITT and the per-protocol population. | 5 to 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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H19 gene, plasmid, diphtheria toxin, pancreatic cancer, inodiftagene vixteplasmid, BC-819