The main purpose is to establish the intraoperative use of cetuximab-IRDye800CW as a reliable marker for residual tumor in resection margins after surgical removal of HNSCC. The objective is to establish the positive predictive value of cetuximab-…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective Part 1 (dose finding)
To determine the optimal dose of cetuximab-IRDye800CW for intra operative
imaging with the SurgVision F2 open air NIRF imaging system of easily
accessible anatomical areas in the head & neck region, or with a standard
nasopharyngeal endoscope coupled to the SurgVision F2 NIRF imaging system for
difficult accessible anatomical areas in the head & neck region.
Primary objective Part 2 (main study)
The main purpose is to establish the intraoperative use of cetuximab-IRDye800CW
as a reliable marker for residual tumor in resection margins after surgical
removal of HNSCC. The objective is to establish the positive predictive value
of cetuximab-IRDye800CW fluorescence as a marker for a tumor positive resection
margin.
Secondary outcome
To determine the threshold level in vivo of cetuximab-IRDye800CW
fluorescence for reliable intraoperative deep margins assessment with high
sensitivity while ensuring an adequate positive predictive value.
To quantify sensitivity and positive predictive value of
cetuximab-IRDye800CW fluorescence of HNSCC ex vivo using optical molecular
imaging and MDSFR/SFF versus fluorescence microscopy and EGFR
immunohistochemistry.
To obtain information on safety aspects of cetuximab-IRDye800CW
administration by registration of conjugate blood levels, conjugate integrity,
side effects, adverse events (AE), serious adverse events (SAE) and suspected
unexpected serious adverse reactions (SUSAR).
Background summary
Surgery remains a main pillar in the treatment of head and neck squamous cell
carcinoma (HNSCC). The margin status is the main prognostic factor of local
tumor control in surgically treated HNSCC and will determine the postoperative
treatment strategy. A margin of *1 mm of normal tissue is considered a positive
margin and requires either a re-operation or postoperative chemoradiation with
a combination of cisplatin and 5FU, which substantially increases morbidity.
Margins wider than 1 mm require re-operation or, if that is not possible,
post-operative radiotherapy without the concomitant use of chemotherapy.
Currently, no technology is available in the operating room, which reliably
supports tumor excision in terms of margin status. In fact, surgeons can only
combine pre- operative imaging data with tactile and visual information during
surgery for assessing tumor margins with limited accuracy. With the
introduction of molecular imaging techniques using near infrared (NIR)
fluorescent optical contrast agents coupled to targeted compounds, new avenues
have opened up for intra-operative assessment of tumor margins. Tracers are
based on antibodies directed against Vascular Endothelial Growth Factor-A, i.e.
bevacizumab-IRDye800CW, in patients with breast cancer or against Epidermal
Growth Factor Receptor, i.e. cetuximab-IRDye800CW, in patients with HNSCC.
First trials have shown that systemic administration of these compounds is safe
and tumor specific. These findings prompted us to design this innovative
application in a clinical trial for the intraoperative assessment of tumor
margins during surgical treatment of HNSCC using cetuximab-IRDye800CW. The
study is subsidized by the Dutch Cancer Foundation.
Study objective
The main purpose is to establish the intraoperative use of cetuximab-IRDye800CW
as a reliable marker for residual tumor in resection margins after surgical
removal of HNSCC. The objective is to establish the positive predictive value
of cetuximab-IRDye800CW fluorescence as a marker for a tumor positive resection
margin.
Study design
The study is designed as a phase 1-2, single center prospective cross sectional
diagnostic study in patients with HNSCC that require surgical excision. First,
a dose escalation study will be performed in 9 patients using 10, 25 and 50 mg
of cetuximab-IRDye800CW with three patients per dose cohort. Additional, one
to three cohorts will receive a *cold* predosing dose cetuximab. Patients will
receive one hour prior to cetuximab-IRDye800CW (15 or 25 or 50mg) an unlabeled
*cold* unlabeled pre-dose of cetuximab. The dose found to be optimal in the
first and only performed study using cetuximab-IRDye800CW in the detection of
HNSCC was 25mg/m2. We therefore think that a sufficient dose will be found
within this range. The most optimal dose will be used in the second part of the
study which will include a cohort of 70 patients. The choice of
cetuximab-IRDye800CW dose will be a balance between the lowest dose vs. a
clinically usable tumor to background ration (TBR) on the fluorescence images.
During the second phase of the study tumor margins will be studied in a cohort
of 70 patients to determine the positive predictive value of optical imaging to
identify positive margins. Based on historical data retrieved from our HNSCC
database at UMCG we anticipate in a cohort of 70 patients at least 14 (20%)
margin-positive patients and a 90% EGFR overexpression rate. We anticipate a
sensitivity of 90% of the cetuximab-IRDye800CW conjugate based on the EGFR
overexpression rate, which we will be able to measure with sufficient precision
( 95%CI of 60-96%).
Intervention
Tracer administration: patients will visit the hospital four days prior to the
planned surgery of their HNSCC. The cetuximab-IRDye800CW will be injected by
slow infusion and patients will be monitored for potential side effects. The
dose will be either 10, 25 or 50 mg of cetuximab-IRDye800CW which is less or
equal to10% of the dose of cetuximab when used for curative treatment of HNSCC
(usually 400mg/m2 loading dose and 250mg/m2 maintenance dose). In the *cold*
predosing group, patients will receive one hour prior to cetuximab-IRDye800CW
(15 or 25 or 50mg) an unlabeled *cold* unlabeled pre-dose of cetuximab. Prior
to cold-dosing, 2mg clemastine will be given. From these doses one will be
chosen based on the study parameters. The second part of the study will be
performed with one dose of cetuximab-IRDye800CW.
Study burden and risks
Burden - Time investment: Patients need to make one extra visit to the UMCG
four days before their planned surgery that will take approximately 2 hours.
Usually patients are admitted one day prior to the planned surgery. Therefore
the measurements one day before surgery will not require extra time investment
Burden-extra procedures: 1) Intravenous administration of cetuximab-IRDye800CW
and in some cases cetuximab 2) The estimated time for taking fluorescence
images and spectroscopy measurements is approximately 30min. Therefore the time
under general anesthesia will be prolonged. The usual time of surgical
procedures for removal of head & neck squamous cell carcinoma ranges from 2 hrs
to 15 hrs, depending on complexity of the surgical procedure. 3) If
fluorescence is visible in the surgical cavity of at the resection area at the
excised specimen after initial resection, a direct re-resection might be
executed if deemed safe by the attending head and neck surgeon.
Risks: Allergic reactions to cetuximab have been reported but this is
considered a low risk. No preclinical or clinical study reported higher than
grade 2 adverse events. the first study with cetuximab-IRDye800CW no serious
events were reported in six patients.
Benefit: patients will have no benefit from this study directly. Surgery will
be planned as usual. During surgery, no decisions will be made based on the
fluorescence imaging. The benefit of this study will be the establishment of
usefulness of cetuximab-IRDye800CW during surgery to identify margins
containing tumors. The results of these types of study will be at least
beneficial for other patients with cancer in the future. Clinical experience
will be obtained with fluorescent labeled antibody in intra operative margin
assessment during surgery of HNSCC.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
1) Biopsy confirmed diagnosis of primary or recurrent HNSCC and scheduled to
undergo surgical resection as decided by the Multi-Disciplinary Head & Neck
Tumor Board of the UMCG.
2) Age * 18 years
3) Written informed consent
4) Adequate potential for follow up
5) Acceptable hematologic status, kidney function, and liver function, as
standard surgery protocol requires.
Exclusion criteria
1) Medical or psychiatric conditions that compromise the patient*s ability to
give informed consent
2) Concurrent uncontrolled medical conditions.
3) Received an investigational drug within 30 days prior to the dose of
cetuximab-IRDye800CW
4) Tumors at sites of which the surgeon would assess that in vivo imaging would
not be feasible
5) Had within 6 months prior to enrollment: myocardial infarction,
cerebrovascular accident, uncontrolled cardiac heart failure, significant liver
disease, unstable angina
6) Inadequately controlled hypertension with or without current
antihypertensive medications.
7) History of infusion reactions to cetuximab or other monoclonal antibody
therapies
8) Pregnant or lactating women. Documentation of a negative pregnancy test must
be available for women of childbearing potential. Woman of childbearing
potential are premenopausal women with intact reproductive organs and women
less than two years after menopause.
9) Evidence of QT prolongation on pretreatment ECG (greater than 440 ms in
males or greater than 450 ms in females)
10) Lab values that in the opinion of the primary surgeon would prevent
surgical resection
11) Patients receiving Class IA (quinidine, procainamide) or Class III
(dofetilide, amiodarone, sotalol) antiarrhythmic agents.
12) Magnesium, potassium and calcium deviations that might lead to cardiac
rhythm (grade II or higher deviations by CTCAE).
13) Life expectancy < 12 weeks
14) Karnofsky performance status < 70%
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 | EUCTR2016-002726-37-NL |
| ClinicalTrials.gov | NCT03134846 |
| CCMO | NL58585.042.16 |