RADNET: Study of Recombinant Adenovirus AdVince in Patients With Neuroendocrine Tumors; Safety and Efficacy
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: AdVince 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
Virus solution for infusion in intrahepatic artery
Other Names:
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Outcome Measures
Primary Outcome Measures
- Number of Adverse Events (AE) according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 [From screening visit and through study completion, an average time of 18 months.]
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).
Secondary Outcome Measures
- Change in tumor size [Measured within 4 weeks before first treatment and after 80 +/-14 days (evaluation visit 1)]
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).
- Change in tumor size [Measured within 4 weeks before first treatment and after 214 +/- 14 days (evaluation visit 2)]
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).
- Change in tumor metabolic activity [Baseline value within 24 hrs before first treatment and after 80 +/- 14 days(evaluation visit 1)]
Change in hormone levels including chromogranin- A (CgA), chromogranin-B (CgB), neuron specific enolase (NSE) and specific hormones.
- Change in tumor metabolic activity [Baseline value within 24 hrs before first treatment and after 214 +/- 14 days (evaluation visit 2)]
Change in hormone levels including chromogranin- A (CgA), chromogranin-B (CgB), neuron specific enolase (NSE) and specific hormones.
- Progression-free survival (PFS) [Twelve weeks after 80 days from first treatment (4 treatment cycles) or the corresponding time.]
Number of patients with progression-free survival (PFS).
- Change in replication profile of AdVince [Before and 4hrs after each treatment cycle up to a time period of 214 days.]
Replication profile determined by quantification of adenovirus genomic copies in patient´s blood by quantitative real-time polymerase chain reaction (QRT-PCR).
- Change in replication profile of AdVince [Before and 24hrs after each treatment up to a time period of 214 days.]
Replication profile determined by quantification of adenovirus genomic copies in patient´s blood by quantitative real-time polymerase chain reaction (QRT-PCR).
- Change in replication profile of AdVince [Before and 72hrs after each treatment cycle up to a time period of 214 days.]
Replication profile determined by quantification of adenovirus genomic copies in patient´s blood by quantitative real-time polymerase chain reaction (QRT-PCR).
- Change in the humoral immune response to AdVince [At baseline, after 8+2 days, after 50 +/- 7days, optional after 124 +/- 7days and 184 +/- 7 days.]
Detection of anti-adenovirus neutralizing antibodies against adenovirus.
- Change in the cytokine-mediated immune response [At baseline and at 4hrs following each treatment up to a time period of 214 days.]
Measure from patient´s plasma.
- Change in the cytokine-mediated immune response [At baseline and at 24hrs following each treatment up to a time period of 214 days.]
Measure from patient´s plasma.
- Change in the cytokine-mediated immune response [At baseline and at 72hrs following each treatment up to a time period of 214 days.]
Measured from patient´s plasma.
Eligibility Criteria
Criteria
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
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Cancer that is not considered resectable for potential cure or tumor reduction
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Patent portal vein and adequate liver perfusion
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Liver dominant disease with involvement of <60% of liver parenchyma
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Karnofsky performance status of >=70%
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Life expectancy of >=6 months
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=18 years of age
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Must use a reliable method of contraception if sexually active and of reproductive potential
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Plasma creatinine <105 ug/ml
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Aspartate transaminase (AST), Alanine transaminase (ALT) and Alkaline Phosphatase (ALP) <3.0-fold upper limit of normal
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Total bilirubin <2.0-fold upper limit of normal
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Prothrombin time (PT)/International Normalized Ratio (INR) <2.0 and Prothromboplastin time (PTT) within normal limits
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Neutrophils >1500/ml, hemoglobin >100 g/L, platelets >100 000/ml
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Patients with functioning NET should have cover by somatostatin analog
Exclusion Criteria:
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Known chronic liver dysfunction Before the development of metastatic cancer (e.g. cirrhosis, chronic hepatitis)
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Active infection, including documented HIV and hepatitis C
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Any viral syndrome diagnosed within the previous 2 weeks
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Chemotherapy within the previous 4 weeks Before the first treatment
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Radiotherapy to the target tumor site within the last 24 weeks from the baseline CT scan
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Concomitant malignancy
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Pregnant or lactating females
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Prior participation in any research protocol that involved administration of adenovirus vectors
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Treatment with any other investigational therapy within the last 4 weeks, organ transplantation prior to treatment, severe cardiovascular, metabolic or pulmonary disease
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Continuing treatment with any other cancer therapy
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Endocrine Oncology Clinic, Uppsala University Hospital | Uppsala | Sweden | 752 37 |
Sponsors and Collaborators
- Uppsala University
Investigators
- Principal Investigator: Joakim Crona, MD, PhD, Uppsala University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- VIRUSNET201401
- 2014-000614-64