The aim of this prospective proof-of-concept study is to increase the expression of the SSTR2 in NET patients with negative or low expression to levels amenable for somatostatin analogue treatment through the use of epigenetic drugs.
ID
Source
Brief title
Condition
- Neoplastic and ectopic endocrinopathies
- Endocrine neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint will be the percentage of patients that after treatment
will have an uptake of 68Ga-DOTATATE that is at least one point higher on the
Krenning scale.
Secondary outcome
Secondary endpoints include safety monitoring, circulating drug levels,
dosimetric evaluations and leucocyte methylation analysis.
Background summary
Somatostatin receptor type 2 (SSTR2) expressions are of eminent importance for
the staging and treatment of neuroendocrine tumors (NETs). The clinical benefit
obtained by treatment with unlabeled and radiolabeled somatostatin analogues
does not apply to the subset of patients with SSTR2-negative or low expression
tumors. The lack of these anti-tumoral options could be responsible for the
inferior outcome of these patients compared to those with SSTR2-positive
tumors. Recent in vitro data showed the possibility of upregulating SSTR2
expression in pancreatic NET cells through treatment with epigenetic drugs.
Translating these methods into clinic could substantially improve diagnostic
and treatment options for patient with SSTR2-negative or low expression tumors.
Study objective
The aim of this prospective proof-of-concept study is to increase the
expression of the SSTR2 in NET patients with negative or low expression to
levels amenable for somatostatin analogue treatment through the use of
epigenetic drugs.
Study design
Interventional proof-of-concept self-controlled study
Intervention
14 days treatment with valproic acid (30mg/kg body weight/day)
Study burden and risks
We consider the risk of this study to be minor, as both valproic acid is a well
known drug and treatment duration is limited to 14 days. The most commonly
reported toxicity of the study drugs were distal tremor, nausea and drowsiness.
As a safety precaution, patients with impaired kidney function (creatinine
clearance <50ml/min) and liver disease (liver transaminases >3 times upper
normal range) will be excluded. In case of patients reporting toxicity,
individual evaluation concerning dosage reduction or additional treatment will
be undertaken.
After inclusion, blood samples will be drawn at baseline and at the two
consecutive visits (day 7 & day 14), total additional amount of blood taken
will be 3x 20ml.
At day 14, an additional 68Ga-DOTATATE-PET scan will be performed. The
radiation dosage for the additional 68Ga-DOTATATE-PET CT scan is around 5.8
mSv. Given the possible gain of over 5 years progression free survival the
risk-benefit ratio for this study is deemed positive.
Dr. Molenwaterplein 40
Rotterdam 3015 GD
NL
Dr. Molenwaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
• Age >=18 years
• Inoperable or metastasized neuroendocrine tumor with well-differentiated
histology (grade 1, 2 or 3)
• SSTR2 negativity or low uptake on 68Ga DOTATATE PET scan, defined as tumor
uptake on 68Ga-DOTATATE PET CT below that or equal to that (Krenning Score 1 or
2) of the liver
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
• Hypotension, defined as systolic blood pressure <90mmHg
• Heart failure, defined as NYHA III-IV
• Impaired kidney function, defined as creatinine clearance <50ml/min
• Impaired liver function, defined as bilirubin or liver transaminases >3
times upper normal range
• Epilepsy
• Known allergies / intolerances to valproic acid or hydralazine
• Existing drug treatment which cannot be stopped and interacts or interferes
with study drugs
• Inability to provide informed consent
• End of life care
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-004091-35-NL |
| CCMO | NL67891.078.18 |
| Other | NL7726 |