Study of Recombinant Adenovirus AdVince in Patients With Neuroendocrine Tumors; Safety and Efficacy

Study Overview
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Brief Summary
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An open-labelled, uncontrolled, single-center Phase I/IIa clinical study to evaluate the safety of repeated infusions of AdVince into the hepatic artery in patients with metastatic neuroendocrine tumors (NETs), and if possible determination of maximum tolerated dose.

Detailed Description
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An open-labelled, uncontrolled, single-center Phase I/IIa clinical study to evaluate the safety of repeated infusions of AdVince into the hepatic artery in patients with metastatic neuroendocrine tumors (NETs), and if possible determination of maximum tolerated dose. Secondary objectives include to evaluate the anti-tumoral efficacy of AdVince infusions on metastatic neuroendocrine tumors, to determine the replication profile of AdVince and to determine the humoral (antibody) and cytokine-mediated immune response to AdVince. Minimum 12 and maximum 35 patients will be included, the number is based on the toxicity observed.

Official Title
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Study of Recombinant Adenovirus (AdVince) in Patients With Neuroendocrine Tumors; Safety and Efficacy

Conditions
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Neuroendocrine Tumors

Intervention / Treatment
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* Drug: AdVince


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject´s written informed consent Histologically and radiologically confirmed progressive neuroendocrine carcinoma of gastrointestinal, pancreatic or bronchial origin with multiple liver metastases. Progression in Clinical symptoms and tumor growth verified over the last 6 months on CT or MRI Cancer that is not considered resectable for potential cure or tumor reduction Patent portal vein and adequate liver perfusion Liver dominant disease with involvement of <60% of liver parenchyma Karnofsky performance status of >=70% Life expectancy of >=6 months >=18 years of age Must use a reliable method of contraception if sexually active and of reproductive potential Plasma creatinine <105 ug/ml Aspartate transaminase (AST), Alanine transaminase (ALT) and Alkaline Phosphatase (ALP) <3.0-fold upper limit of normal Total bilirubin <2.0-fold upper limit of normal Prothrombin time (PT)/International Normalized Ratio (INR) <2.0 and Prothromboplastin time (PTT) within normal limits Neutrophils >1500/ml, hemoglobin >100 g/L, platelets >100 000/ml Patients with functioning NET should have cover by somatostatin analog Exclusion Criteria: Known chronic liver dysfunction Before the development of metastatic cancer (e.g. cirrhosis, chronic hepatitis) Active infection, including documented HIV and hepatitis C Any viral syndrome diagnosed within the previous 2 weeks Chemotherapy within the previous 4 weeks Before the first treatment Radiotherapy to the target tumor site within the last 24 weeks from the baseline CT scan Concomitant malignancy Pregnant or lactating females Prior participation in any research protocol that involved administration of adenovirus vectors Treatment with any other investigational therapy within the last 4 weeks, organ transplantation prior to treatment, severe cardiovascular, metabolic or pulmonary disease Continuing treatment with any other cancer therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: AdVince<br>Dose escalation, minimum 3 patients per dose in Phase I. Dose levels: 10 000 000 000 virus particles 100 000 000 000 virus particles 300 000 000 000 virus particles 1000 000 000 000 virus particles Maximum tolerated dose will be confirmed by 12 additional patients treated at this dose level in Phase IIa. | Drug: AdVince<br>* Virus solution for infusion in intrahepatic artery<br>* Other names: Ad5PeptideTransductionDomain(PTD)(CgA-E1AmiR122);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AE) according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 | AEs probably or possibly related to the study drug or local injuries caused by the administration procedure. If possible identify dose limiting toxicity (DLT), i.e. grade 4 toxicity of any duration or grade 3 toxicity lasting more than 7 days, excluding flu-like symptoms, according to CTCAE v4.03.Clinically significant changes in laboratory parameters (haematology, blood coagulation, liver function, biochemistry and kidney function) and vital signs (body temperature, heart rate, blood pressure, respiratory rate and consciousness according to Reaction Level Scale from 1985 (RLS-85). | From screening visit and through study completion, an average time of 18 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in tumor size | Computer tomography (CT) and/or positron emission tomography (PET) with magnetic resonance imaging (MRI). Assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) or modified RECIST (mRECIST). | Measured within 4 weeks before first treatment and after 80 +/-14 days (evaluation visit 1) | 
| Change in tumor size | Computer tomography (CT) and/or positron emission tomography (PET) with magnetic resonance imaging (MRI). Assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) or modified RECIST (mRECIST). | Measured within 4 weeks before first treatment and after 214 +/- 14 days (evaluation visit 2) | 
| Change in tumor metabolic activity | Change in hormone levels including chromogranin- A (CgA), chromogranin-B (CgB), neuron specific enolase (NSE) and specific hormones. | Baseline value within 24 hrs before first treatment and after 80 +/- 14 days(evaluation visit 1) | 
| Change in tumor metabolic activity | Change in hormone levels including chromogranin- A (CgA), chromogranin-B (CgB), neuron specific enolase (NSE) and specific hormones. | Baseline value within 24 hrs before first treatment and after 214 +/- 14 days (evaluation visit 2) | 
| Progression-free survival (PFS) | Number of patients with progression-free survival (PFS). | Twelve weeks after 80 days from first treatment (4 treatment cycles) or the corresponding time. | 
| Change in replication profile of AdVince | Replication profile determined by quantification of adenovirus genomic copies in patient´s blood by quantitative real-time polymerase chain reaction (QRT-PCR). | Before and 4hrs after each treatment cycle up to a time period of 214 days. | 
| Change in replication profile of AdVince | Replication profile determined by quantification of adenovirus genomic copies in patient´s blood by quantitative real-time polymerase chain reaction (QRT-PCR). | Before and 24hrs after each treatment up to a time period of 214 days. | 
| Change in replication profile of AdVince | Replication profile determined by quantification of adenovirus genomic copies in patient´s blood by quantitative real-time polymerase chain reaction (QRT-PCR). | Before and 72hrs after each treatment cycle up to a time period of 214 days. | 
| Change in the humoral immune response to AdVince | Detection of anti-adenovirus neutralizing antibodies against adenovirus. | At baseline, after 8+2 days, after 50 +/- 7days, optional after 124 +/- 7days and 184 +/- 7 days. | 
| Change in the cytokine-mediated immune response | Measure from patient´s plasma. | At baseline and at 4hrs following each treatment up to a time period of 214 days. | 
| Change in the cytokine-mediated immune response | Measure from patient´s plasma. | At baseline and at 24hrs following each treatment up to a time period of 214 days. | 
| Change in the cytokine-mediated immune response | Measured from patient´s plasma. | At baseline and at 72hrs following each treatment up to a time period of 214 days. |