Treatment of neuroendocrine neoplasms with genetically modified adenovirus

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Uppsala University

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Mar 2016 → 9 Jan 2025

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Oncolytic virus fund, Uppsala University

External identifiers

EU CT number

2024-517654-10-00

EudraCT number

2014-000614-64

ClinicalTrials.gov

NCT02749331

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response, Therapy, Pharmacokinetic

The primary objective of this study is to evaluate the safety of repeated infusions of AdVince into the hepatic artery in patients with metastatic NENs and if possible determination of maximum tolerated dose (MTD).

Secondary objectives 3

1. To evaluate the anti-tumoral efficacy of AdVince infusions on metastatic neuroendocrine tumors
2. To determine the replication profile of AdVince
3. To determine the humoral and cytokine-mediated immune responses to AdVince

Conditions and MedDRA coding

Neuroendocrine neoplasms (NENs) is a heterogeneous group with varying symptoms, tumor biology and treatment response. NENs may occur in any organ, most commonly they are observed in the gastroenteropancreatic system and lungs. Most NEN patients are diagnosed at advanced stage, 65% of them will die within 5 years. The only curative treatment is surgery with complete resection of the primary tumor. However, more than 50% of patients exhibit metastatic disease, where there is no cure.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Subject's written informed consent
2. Histologically confirmed NEN of gastrointestinal, pancreatic or bronchial origin
3. Disease progression verified over the last 6 months on CT or MRI using criteria employed in standard practice at the local hospital
4. Disease that is not considered resectable for potential cure or tumor reduction
5. Standard anti-cancer therapy exhausted according to the European Society of Medical Oncology (ESMO) guidelines for GEP-NETs and according to the European Neuroendocrine Tumor Society (ENETS) guidelines for lung carcinoids
6. Adequate liver perfusion ensured e.g. by patent portal vein, patent hepatic veins
7. Liver dominant disease with involvement of < 60% of liver parenchyma
8. Karnofsky performance status of ≥70%
9. Life expectancy of ≥ 6 months
10. ≥ 18 years of age
11. Must use a reliable method of contraception if sexually active and of reproductive potential
12. Plasma creatinine < 105 µg/ml
13. AST, ALT < 5.0-fold upper limit of normal
14. Total bilirubin < 3.0-fold upper limit of normal
15. PT/INR < 2.0 and PTT within normal limits
16. Neutrophils > 1,500/µl, haemoglobin > 100 g/L, platelets > 100,000/µl
17. Patients with functioning NEN should have cover by somatostatin analog

Exclusion criteria 12

1. Known chronic liver dysfunction before the development of metastatic cancer (e.g., cirrhosis, chronic hepatitis)
2. Active infection, including documented HIV and hepatitis C
3. Any viral syndrome diagnosed within the previous 2 weeks
4. Systemic anti-cancer therapy (except for somatostatin analogues) within the previous 4 weeks before the first treatment
5. Radiotherapy to the target tumor site within the last 24 weeks from the baseline CT scan
6. Evidence of clinically significant immunosuppression such as primary immunodeficiency state such as Severe Combined Immunodeficiency Disease
7. Requirement of treatment with corticosteroids (prednisone >10 mg/day or equivalent)
8. Concomitant malignancy
9. Pregnant or lactating females
10. Prior participation in any research protocol that involved administration of adenovirus vectors
11. Treatment with any other investigational therapy within the last 4 weeks, organ transplantation prior to treatment, severe cardiovascular, metabolic or pulmonary disease
12. Continuing treatment with any other cancer therapy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Number of Adverse Events (AE) according to CTCA v 4.03, probably or possibly reated to the study drug, reported from the first study-related procedure until 30 days following the last dose, or local injuries caused by the administration procedure checked at each administration of Advince
2. Identify Dose Limiting Toxicity (DLT) from first until last injection of Advince, if possible
3. Changes in laboratory efficacy and safety parameters, biological serum markers and vital signs over time vs baseline values.

Secondary endpoints 3

1. Tumor size and tumor metabolic activity by: a) Computer tomography (CT) and/or positron emission tomography (PET) and/or magnetic resonance imaging (MRI) before first and after last treatment cycle; b) Hormone level screening (biological markers) from baseline until progressive disease; c) Progression-free survival (PFS) 24 weeks after 4th cycle.
2. Viral replication by adenovirus quantification of in patients’ blood on day 1, 8, 22 and 50; before and 24h after injection, as well as 72h after injection by QRT-PCR.
3. Humoral response by detection of anti-adenovirus neutralizing antibodies at baseline, day 8 and day 50. Cytokine-mediated immune response is determined by cytokine measurement in plasma at baseline, 24h and 72h (optional) following virus injections.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Uppsala University

Sponsor organisation

Uppsala University

Address

Box 256

City

Uppsala

Postcode

751 05

Country

Sweden

Scientific contact point

Organisation

Uppsala University

Contact name

Department of Immunology, Genetics and Pathology (IGP)

Public contact point

Organisation

Uppsala University

Contact name

Department of Immunology, Genetics and Pathology (IGP)

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications