Suicide Plus Immune Gene Therapy for Advanced Melanoma

Study Overview
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Brief Summary
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Safety evaluation of combined immunogene therapy in patients with advanced melanoma.

Detailed Description
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This phase I clinical protocol is proposed to evaluate the safety of combined immunotherapy genetics in humans. This treatment combines the high local cytotoxicity of the suicide gene system (HSV thymidine kinase: HSVt k) / prodrug (ganciclovir: GCV) with the immunostimulation of interleukin2 (hIL2) and immunoamplification of granulocyte and macrophage colony stimulating factor (hGMCSF) in the presence of tumor antigens. The proposed scheme consists in the periodic intra / peritumoral application of plasmid DNA complexes: cationic lipid (lipoplexes) containing the HSVtk gene, co-administered with the prodrug GCV, and subcutaneous injections of a vaccine (LGvax) produced with formolized extracts of allogeneic melanoma combined with lipoplexes carrying the hIL2 and hGMCSF genes.

Official Title
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Phase 1 Suicide Plus Immune Gene Therapy for Advanced Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Suicide plus immunogene therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically and / or cytologically confirmed melanoma. Patients progressed or are intolerant to conventional systemic treatments. Patients that are not candidates for surgery under oncologic criteria (complete resection). Performance status (ECOG) 0 or 1. Patients with life expectancy greater than 6 months. Patients with at least one accessible target lesion for gene inoculation (superficial localizations of the primary tumor, satelitosis, subcutaneous or accessible lymph node metastasis). Patients with measurable disease (according to RECIST 1.1 criteria, irrespective of the target lesion chosen for suicide gene inoculation) Patients with signed informed consent. Exclusion Criteria: Patients with uncontrolled cardiovascular disease Patients with uncontrolled respiratory disease. Patients with uncontrolled immune disease. Patients with glucocorticoids or immunosuppressive drugs or agents with immunomodulatory activity (except non-steroidal anti-inflammatory agents) up to 2 weeks before treatment. Patients performing other experimental therapies. Patients who are pregnant or breastfeeding. Patients undergoing concurrent chemotherapy or radiation therapy. Uncontrolled diabetes. Patients with active diagnosis of other malignant neoplasms. HIV-positive patients. Uncontrolled thyroid abnormality. Patients with significant medical morbidity. Patients with a history of allergic reactions to chemicals or similar to those used in this study. Metastasis in the central nervous system. Laboratory eligibility criteria excluded: Hemoglobin: <8 g / dL, leukocytes: <3,000 / mm3, platelets: <100,000 / mm3, neutrophils: <1000 / mm3, hematocrit: <25%. bilirubin> 2.0 mg / dL, GOT or GPT: 2.5 times> than normal upper institutional limit (ULN), alkaline phosphatase: 2 times> ULN, creatinine> 2.0 mg / dL, creatinine clearence : <60 ml / min / 1.73 m2.

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
Interventional Model Description: Suicide plus immunogene therapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Suicide plus immunogene therapy<br>Intra and peritumoral infiltrates with multiple injections of lipoplexes carrying the HSVtk suicide gene co-administered with GCV and subcutaneous vaccine produced with formolized allogeneic tumor extracts and lipoplexes carrying hIL-2 and hGM-CSF genes. | Biological: Suicide plus immunogene therapy<br>* Intra and peritumoral infiltrates with multiple injections of 0.1 ml/cm2 or 0.2 ml/cm3 of lipoplexes bearing the HSVtk suicide gene (1: 1; 1 mg/ml, according to tumor size), co-administered with GCV (12.5 mg/ml). Patients start with a minimum of 0.5 ml and at the 3rd week, the maximum dose is scaled according to the tumor size up to 2 ml maximum. Treated simultaneously with a subcutaneous vaccine produced with: Formolized allogeneic tumor extracts and, Lipoplexes carrying hIL-2 and hGM-CSF genes (0.5 mg each).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety reported as the number of treatment-related adverse events as assessed by CTCAE v4.03 | Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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melanoma, lipoplexes, plasmid, herpes simplex thymidine kinase, interleukin-2, granulocyte-macrophage colony-stimulating factor, tumor vaccine, suicide gene