Gene Therapy of Pancreatic Ductal Adenocarcinoma

Study Overview
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Brief Summary
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Near 85% of patients with pancreatic adenocarcinoma are diagnosed with a locally advanced and/or metastatic unresectable tumor. In these patients chemotherapy (such as gemcitabine) is given as a palliative therapy. Aim of the present study is to evaluate the feasibility, tolerance and antitumor effect of repeated intratumoral injection of a gene therapy product (with antitumor and chemo sensitizing effects) combined with gemcitabine in patients with unresectable pancreatic carcinoma.

Detailed Description
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This is a gene therapy open non randomized phase I trial for advanced and/or metastatic pancreatic cancer patients. The protocol is based on the administration of increasing doses of a plasmid DNA pre-complexed to PEI (polyethylenimine - non-viral vector) that encodes two genes (somatostatin receptor subtype 2 named sst2 and deoxycitidine kinase :: uridylmonophosphate kinase named dck::umk) which exhibit complementary therapeutic effects. Both transgenes induce an antitumor bystander effect and render gemcitabine treatment more efficient. Intratumor injections of the gene therapy product (CYL-02) will be performed by transgastric or transduodenal route under endoscopic ultrasound guidance. Each injection will be followed standard gemcitabine IV administration every week (1000 mg/m2). Two intratumor injections of a same dose of CYL-02 will be administered at one month interval. Four increasing doses (125 µg, 250 µg, 500 µg and 1 mg) will be tested by group of 6 patients. The primary objectives are: evaluation of local pancreatic and general tolerance; the secondary objectives are: possible tumor volume regression, secondary respectability, evaluation of transgene biodistribution.

Official Title
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PILOT STUDY OF GENE THERAPY FOR LOCALLY ADVANCED PANCREATIC ADENOCARCINOMA WITH INTRATUMOURAL INJECTION OF JetPEI/DNA COMPLEXES WITH ANTITUMOURAL EFFECT AND CHEMOSENSITIZING ACTIVITY FOR GEMCITABINE

Conditions
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Pancreatic Adenocarcinoma

Intervention / Treatment
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* Genetic: Gene Therapy product CYL-02 = plasmid DNA pre-complexed to linear polyethylenimine encoding sst2 + dck::umk genes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with a pancreatic adenocarcinoma histologically proven and/or a solid pancreatic mass associated with on or multiple metastatis from pancreatic origin (histologically proven) Patient with a non resectable pancreatic adenocarcinoma (on preoperative CT-scan and/or endoscopic ultrasound evaluation) Pancreatic tumor that could be evaluated by endoscopic ultrasound (no digestive stenosis, no gastrectomy) Patient with no contraindication to général anaesthesia. Karnofsky index >= 70% Written informed consent given Exclusion Criteria: - Exclusion period for another clinical trial or research protocol. Patient unable to read or understand information/consent formula or unable to decide alone for his participation to the trial Patient under tutelage Pregnant woman or able to procreate without contraception. Patient with pancreatic cystic tumor or pancreatic pseudocyst. Patient with pancreatic tumor different from adenocarcinoma (endocrine, metastasis). Patient contraindication to Gemzar® : Hypersensitivity to Gemcitabine. Decision of radiotherapy Granulocytes < 1000/mm3 Thrombocytes < 100 000/mm3 Patient not efficiently treated for jaundice (biliary stent or bypass) if present at time of diagnosis Contraindication for fine needle aspiration biopsy under endoscopic ultrasound (hemostasis trouble).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapy<br> | Genetic: Gene Therapy product CYL-02 = plasmid DNA pre-complexed to linear polyethylenimine encoding sst2 + dck::umk genes<br>* Intratumoral injection of the gene therapy product CYL-02 (2,5 ml within the primary tumor under endoscopic ultrasound guidance an under propofol anaesthesia). The intratumor injection of CYL-02 is followed by three IV infusions of Gemcitabine (1000 mg/m2) at 48 hours and then every two weeks. A second Intratumoral injection of the gene therapy product CYL-02 is performed at a same dosage and volume 30 days after the first administration followed by Three infusions of gemcitabine (1000 mg/m2) according the same rhythm (48 hours and every week) and dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasability and security : Number of Participants with Adverse Events | Feasibility, security (pancreas and general) of intratumor injections of the gene therapy product (CYL-02 plasmid DNA pre-complexed to PEI encoding sst2 dck::umk) administered under endoscopic ultrasound guidance and followed by gemcitabine treatment at standard doses. | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumoral effect: secondary resecability, transgenes diffusion | antitumoral effect, secondary resecability, transgenes diffusion (urine and blood) and expression (tumor). | 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene therapy, pancreatic carcinoma, gemcitabine, endoscopic ultrasound