This study has been transitioned to CTIS with ID 2024-513392-40-01 check the CTIS register for the current data. The design will be a prospective, single center phase I feasibility and dose finding study in patients with high-grade glioma, to…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters are to establish the safety, feasibility, and optimal
dosage of Cetuximab-IRDye800CW for fluorescence guided surgery, in comparison
to the standard of care (SOC), 5-ALA fluorescent imaging agent.
Secondary outcome
The identification of DSC MR imaging biomarkers predictive for EGFR
amplification
Background summary
High-grade glioma is a high-grade astrocytoma (grade 4) and the most common
primary malignant central nervous system tumor, accounting for 14.7% of the
primary brain tumors each year, with an annual incidence rate of 3.21/100.000.
High-grade glioma is associated with a low overall survival rate of around 15
months, with a 5-year survival rate of 5.6% post diagnosis.
Because of the (intrinsic) invasive nature of high-grade glioma in the brain,
complete surgical resection will almost never be achieved. Nonetheless,
surgical treatment still plays an important role in the treatment of high-grade
glioma, as extensive surgical resection is a key prognostic factor of better
outcomes. The downside of extensive surgical treatment however, is the
potential increase in surgery related morbidity and a decrease in postoperative
quality of life. Underlying all of this and constraining extensive surgical
resection, is the neurosurgeon*s visual inability to delineate tumorous tissue
from healthy tissue because of a lack of contrast.
Currently, 5-aminolevulinic acid (5-ALA) is used for real-life intraoperative
fluorescent imaging in patients with a high-grade glioma. 5-ALA supports the
neurosurgeon intraoperatively to distinguish tumorous tissue from healthy
tissue. The use of 5-ALA for High Grade Glioma surgery is described to lead to
a longer progression free survival (PFS) and overall survival (OS) after
surgery. However, 5-ALA has intrinsic properties that makes its use undesirable
and unpractical. For example, when using 5-ALA fluorescent signals can be
observed outside tumor margins, possibly leading to higher percentages of
post-operative and surgery- related neurological complications.
There is a clear need for tumor specific agents that can be used during surgery
for HGG to improve tumor delineation, and by that establish a refinement of
margin control and achieve the most complete but non- incapacitating resection.
Several studies have described the use of near infrared (NIR) fluorescent
labeled antibodies for sensitive and specific cancer detection during surgical
oncological resections to guide margin assessment. Optical imaging has several
advantages over current methods for visualizing tumor characteristics: it does
not use ionizing radiation, it provides real-time molecular information, and it
is relatively cheap. Due to the inherent optical properties of NIR fluorescent
dyes, improved tissue penetration is achieved by less absorption of NIR emitted
light by hemoglobin, whereas less autofluorescence and scattering in the NIR
region results in less non-specific fluorescence leading to false-positive
signals. These properties often lead to higher signal-to-background ratios,
improving contrast between healthy and non-healthy tissue.
The Epidermal Growth Factor Receptor (EGFR) gene is a proto-oncogene involved
in cancer pathogenesis and EGFR-gene amplification is known to be present in
40% of high-grade gliomas. Because of the low EGFR expression in surrounding
healthy brain tissue, it has the potential to be used for better tumor
delineation and therefore refinement of the margin assessment compared to
5-ALA. The therapeutic antibody which targets EGFR is cetuximab. In this study,
GMP fluorescent labelled Cetuximab (cetuximab-IRDye800CW) will be investigated
for tumor delineation in high-grade glioma surgery.
Study objective
This study has been transitioned to CTIS with ID 2024-513392-40-01 check the CTIS register for the current data.
The design will be a prospective, single center phase I feasibility and dose
finding study in patients with high-grade glioma, to establish the safety,
feasibility, and optimal dosage of Cetuximab-IRDye800CW for fluorescence guided
surgery, in comparison to the standard of care (SOC), 5-ALA fluorescent imaging
agent.
Study design
The first cohort, receiving a predose of 75 mg Cetuximab followed by 25 mg of
Cetuximab-IRDye800CW, will be expanded until 5 patients have been included in
whom a fluorescent signal is observed intraoperatively or until 10 patients
have been imaged in total. After inclusion of the first cohort is finalized, an
interim analysis will be performed to determine if a TBR of >2 is obtained. If
an adequate TBR is found (TBR of >2), the dose of Cetuximab-IRDye800CW will be
deescalated to 15 mg. If an inadequate TBR (TBR of <2) is found, the study will
be terminated. During the interim analysis, DSC biomarkers obtained from the
patients included in the first cohort will be correlated with EGFR-gene
amplification status. If a clinically relevant predictive imaging marker is
found, this marker will be validated and used for the stratification of
patients with a HGG that are included after the interim analysis.
In the second cohort, receiving a predose of 75 mg Cetuximab followed by 15 mg
of Cetuximab-IRDye800CW, the inclusion will be continued until 5 patients have
been included in whom a fluorescent signal is observed intraoperatively or when
10 patients have been included in cohort 2. An interim analysis will then be
performed to determine if a TBR of >2 is obtained by either intraoperative
fluorescence imaging. If a TBR of >2 found, expansion of the cohort with the
best TBR, either cohort 1 (25 mg) or cohort 2 (15 mg), will take place until 15
fluorescence positive patients have been included or the total number of 21
patients is reached. If no adequate TBR is found (TBR of <2), expansion cohort
1 (25 mg) will take place until 15 fluorescence positive patients have been
included or the total number of 21 patients is reached.
Intervention
Patients will - after written informed consent -receive an intravenous
injection of the predose unlabeled cetuximab and one hour later the fluorescent
tracer cetuximab-IRDye800CW. The injection of cetuximab and
cetuximab-IRDye800CW will be preceded by injection of clemastine 2 mg, to
reduce the chance of allergic reactions. Two to four days later, fluorescence
imaging is performed during surgery and after surgery, at the department of
Pathology. A detailed description of the imaging procedures can be found in
section 8.3. Furthermore, patients can voluntarily participate in the
development of a radiomics tool, for which they will undergo approximately 30
minutes of additional MRI scanning, focused on DSC biomarkers. Additional
informed consent will be obtained for this study aspect.
Study burden and risks
Burden: The burden associated with participation consists of a longer admission
visit because of the tracer administration. Also, the surgical procedure will
be prolonged with approximately 15-30 minutes for taking fluorescence images.
When the participant decides that he/she wants to participate in the voluntary
aspect of the study, i.e. the development of a radiomics model, his/her regular
clinical MRI scanning time will be extended by approximately 30 minutes.
Risks: Risks to study participants are mainly related to the, already present,
risks of the surgical procedure and to the administration of the tracer. No
preclinical or clinical study reported higher than grade 2 adverse events,
moreover, these studies used significant higher doses of the investigational
product. Previous studies with cetuximab-IRDye800CW reported no tracer related
serious events.
Benefit: Patients will have no direct benefit from this study. Surgery will be
planned as usual. During surgery, no decisions will be made based on the
fluorescence imaging with Cetuximab-IRDye800CW.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
- Willing to adhere to the prohibitions and restrictions specified in this
protocol.
- Capable of giving signed informed consent (voluntarily), indicating that the
patient understands the purpose and procedures required for the study and is
willing to comply with the requirements and restrictions listed in the informed
consent form and in this protocol.
- Patients aged >= 18 years inclusive at moment signing informed consent form.
- Established High-grade glioma (astrocytoma grade 4 according to the WHO
classification) and scheduled for surgical intervention.
- Life expectancy of > 12 weeks.
- Karnofsky performance status of at least 70%.
- No clinically significant laboratory abnormalities as determined by the
investigator
o Note: one retest of lab tests is allowed within the screening window
- Female patients should fulfil one of the following criteria:
o At least 1 year post-menopausal (amenorrhea >12 months) at screening
o Surgically sterile (bilateral oophorectomy, hysterectomy, or tubal ligation)
o Women >18 years of age who are fertile, need to agree to use an adequate form
of contraceptives during and till 3 months after the study. Before study
enrollment, a pregnancy test in blood or urine will be performed to rule out a
pregnancy. In the case of an unlikely pregnancy during the study, they accept
the possible maternal/ fetal risk of participation in the study.
Exclusion criteria
General:
- Behavioral or cognitive impairment or psychiatric disease that in the opinion
of the investigator affects the ability of the patient to understand and
cooperate with the study protocol
- Deprived of freedom by an administrative or court order or in an emergency
setting.
- Insufficient venous access for the study procedures.
- Close affiliation with the investigator; e.g. a close relative of the
investigator,
dependent person (e.g. employee or student), employee of the department of
Neurosurgery of the UMCG, or affiliates
- Any finding in the medical examinations or medical history giving, that in
the opinion of the investigator, leads to a reasonable suspicion of a disease
or condition that makes treatment with the investigational drug unadvisable, or
that might affect interpretation of the results of the study or render the
patient at high risk for treatment complications
- Participation in an interventional clinical study within 30 days prior to
tracer administration that involved treatment with any drug (excluding vitamins
and minerals) or medical device
Medical conditions
- Concomitant malignancies, including metastasized colon-, rectal-, breast
carcinoma, non-small cellular lung carcinoma (NSCLC); primary epithelial
ovarian-, fallopian tube-, primary peritoneal- or cervical carcinoma.
- Any abnormalities in the vital signs of the patient, as judged by the
investigator, as a result of which the patient cannot participate
- eGFR (based on plasma-creatinine) outside of normal range at screening or
known renal impairment (<=40 mL/min).
- Current evidence or history of bacterial, viral or fungal infections within 7
days before Cetuximab-IRDye800CW administration, as judged by the Investigator.
o T > = 38.0°C or lab confirmed viral/bacterial/fungal infection (PCR)) or
symptoms suggestive of an infection)
- Any laboratory test which is abnormal, and which is deemed by the
Investigator(s) to be clinically significant
- A history of anaphylaxis, history of allergic reaction(s), known allergy to
one of the drugs or excipients administered as part of this study. Mild
allergies without angio-edema or treatment need can be acceptable if deemed not
to be of clinical significance (including but not limited to allergy to animals
or mild seasonal hay fever)
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 |
|---|---|
| EU-CTR | CTIS2024-513392-40-01 |
| EudraCT | EUCTR2022-002666-32-NL |
| CCMO | NL83364.056.22 |