Trial Title:
Development of a Fluorescent Visualization System for Non-visible Lung Cancer Nodules
NCT ID:
NCT06101394
Condition:
Lung Cancer
Video-assisted Thoracic Surgery
EGFR
Cetuximab
Conditions: Official terms:
Lung Neoplasms
Cetuximab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cetuximab-IRDye800
Description:
Infusion of the study drug will be performed 2-5 days before the surgery: the patients
will receive 100 mg of cetuximab intravenously over 30 minutes and a dose 50 mg of
cetuximab-IRDye800 over 30 minutes to 1 hour.
Arm group label:
cetuximab-IRDye800
Other name:
Cetuximab
Summary:
To date, lung resection and lymphadenectomy remain the best curative option in patients
with early-stage non-small cell lung cancer. Moreover, cancer screening programs have led
to a frequent diagnoses of indeterminate lung lesions, many of which require surgical
biopsy for diagnosis and intervention. Additionally, pre-operative imaging assessment
frequently underestimates lymph-node involvement. Finally, the increase in the
utilization of minimally invasive procedures remains mandatory.
The aim of our project is to verify if Cetuximab-IRDye800 could detect cancer nodules and
lymph node metastases during minimally invasive thoracic surgery. A result favoring the
use of Cetuximab-IRDye800 would permit the use of a minimally invasive approach to a more
significant number of patients, which are presently operable only by a traditional "open"
approach. Consequentially, it would lead to an improvement in surgical outcomes, a
reduction of costs, and an enhanced patient quality of life.
In addition, a result favoring Cetuximab-IRDye800 could consent to correctly remove
mislead metastatic lymph nodes (i.e., unexpected lymph-nodes metastasis) and neoplastic
localization unidentified at pre-operative diagnostic assessments. It would lead to more
accurate cancer staging, and a tailored post-operative treatment. Finally, the
investigators expect to validate using Cetuximab-IRDye800 as an optimal tracker that can
be easily applied intraoperatively during minimally invasive surgical procedures.
Detailed description:
Lung cancer is the leading cause of cancer deaths in the European Union (EU) (267,000
deaths/year) and the fourth most common cancer (321,000 new cases/year). To date, radical
surgery remains the best curative option in patients with early-stage lung cancer.
Moreover, cancer screening programs have led to frequent diagnoses of indeterminate lung
lesions, many requiring surgical biopsy for diagnosis and intervention.
For example, available data showed that 5.9 % of the European population over 15 years of
age consumed at least 20 cigarettes per day (8.4 % in the male population), and around
12.6 % consumed less than 20. The recent lung cancer screening studies documented a
prevalence of indeterminate pulmonary nodules as high as 50% in high-risk smokers, with a
cancer detection rate in the overall screened population of 1%. Fascinatingly, 69% of
screen-detected lung cancers were detected at early stage IA or IB.
Finally, studies on lung cancer screening, like the NELSON trial, showed a 26% reduction
in lung cancer deaths at 10 years. The potential social impact of the present project is
linked to establishing this screening program in Europe. One could estimate that if
applied in the high-risk European population (i.e., high smokers), the screening could
identify 3.5 million indeterminate pulmonary nodules, of which 250,000 are early-stage
lung cancer. [2] Therefore, using the NIR-tracker the investigators propose could consent
to a minimally invasive surgery in this scenario as a diagnostic and therapeutic
procedure. Consequently, it could determine the reduction of time to diagnosis,
morbidity, mortality, and costs of postoperative care associated with more invasive
surgical procedures.
To date, lung anatomical resection with lymphadenectomy remains the best curative option
in patients with early-stage non-small cell lung cancer. Moreover, cancer screening
programs have led to frequent diagnoses of indeterminate lungs, many requiring surgical
biopsy for diagnosis and intervention.
Nevertheless, the increase in the utilization of minimally invasive procedures (e.g.,
video-assisted thoracic surgery -VATS- and robotic-assisted thoracic surgery -RATS- )
remains mandatory in order to reduce the significant morbidity of classic surgery, the
surgical trauma, to preserve organs function and to improve patient's quality of life.
Nevertheless, minimally invasive surgery represents the surgical approach of choice in
less than 40% of lung anatomical resections conducted in Europe. One of the significant
issues that hinder the application of VATS and RATS to most early-stage NSCLC patients is
the difficulty of recognizing lung nodules located deep in the lung parenchyma and,
consequently, not visible with the traditional camera system. Indeed, VATS and RATS do
not consent to manual lung palpation, making localizing the not superficial lung nodule
problematic.
Several approaches have been developed to enhance the localization of indeterminate lung
nodules and decrease the time to diagnosis and rate of conversion to open surgery.
Nevertheless, none of these is 100% sensitive or without complications, also of severe
grade.
Numerous pre-operative methods are being employed, including percutaneous CT-guided
placement techniques, encompassing the use of microcoils, hook-wires, and spiral-wires.
These devices can support nodule localization during minimally invasive lung procedures;
nevertheless, they could be easily displaced during patient transport and positioning,
intraoperative atelectasis, single lung ventilation, and surgeon manipulation. Moreover,
some locations of the lung as the apex, near the diaphragm, and the proximity of
mediastinum and great vessels. Furthermore, all these pre-operative localization
techniques require two different procedures, one for the CT-guided referral placement and
one for surgical treatment. Finally, the rate of pneumothorax, hemorrhage, and
subcutaneous emphysema are not insignificant, and these complications are mandatory to
avoid in several sub-groups of patients. Other pre-operative methods encompass the use of
dye marking by methylene blue or fluorescent. [8] Nevertheless, the accuracy of the
staining of the targeted area is greatly affected by the time between tumor marking and
thoracoscopy. In particular, the significant impact is on the difficulty in dye
visualization during operation, limited information on lesion depth, and rapid diffusion
of dye into surrounding lung parenchyma between the time of injection and surgery. Of
note, methylene blue has limited application in patients with anthracotic pigmentation.
Moreover, also these techniques require two procedures for diagnosis and treatment.
Lastly, these procedures remain complicated by the risk of pneumothorax, hemorrhage, dye
air embolism, and cerebrovascular accident, and cases of lethal anaphylaxis to the dye of
choice.
On the other hand, clinical pre-operative staging and surgical planning are based on
pre-operative images taken before surgery, either by computed tomography (CT), positron
emission tomography (PET), or magnetic resonance imaging (MRI). These pre-operative
imaging assessments frequently underestimate lymph node involvement and secondary
localizations. This results in an upstaging after surgical resection ranging from 9 to 24
% in clinical Stage I lung cancer. [10, 11] Nevertheless, the current system of
intraoperative imaging, based on direct injection of a tracker in the principal tumoral
mass, demonstrated a substantial limitation in lung cancer. This is principally due to
the deeper location of the lymph node, usually profoundly engaged in normal fat tissue,
and to the irregular lymph node drain system in the respiratory region.
In this context, intraoperative fluorescence imaging can enhance the real-time
identification of cancer cells during minimally invasive surgical procedures. This could
overcome the difficulty of finding cancer nodules located deep in the lung parenchyma,
not visible on the surface of normal, uninvolved tissue. The Near-infrared (NIR)
fluorescence (700-1,000 nm) detection avoids the natural background fluorescence
interference of biomolecules, which provides high contrast between the target and
background tissues in small animals. NIR fluorophores have a more comprehensive dynamic
range and minimal background fluorescence because of reduced scattering compared with
visible fluorescence detection. However, the conventional near-infrared (NIR) indocyanine
green (ICG) method demonstrated a significant limitation in deep cancer recognition,
principally due to its intrinsic low-depth tissue penetration. Similarly, the lymph-node
sentinel approach conducted by the ICG method proved to be inefficient, mainly due to the
non-specificity of the tracker and the irregular pathway of pulmonary lymph node
drainage.
The IRDye® 800CW is an indocyanine-type NIR fluorophore with peak absorption at 775 nm
and peak excitation emission at 796 nm. It provides a quantum yield of 9% with an
extinction coefficient of 242,000 M-1cm-1. It has a molecular weight of 962 Da. The
IRDye® 800CW demonstrated enhanced tissue penetration compared to other NIR dyes.
Epidermal growth factor (EGF) is a 53-amino acid cytokine (6.2 kDa) that is secreted by
ectodermic cells, monocytes, kidneys, and duodenal glands. EGF stimulates the growth of
epidermal and epithelial cells. EGF and at least seven other growth factors and their
transmembrane receptor kinases play essential roles in cell proliferation, invasion,
metastasis, neovascularization, adhesion, migration, differentiation, and inhibition of
apoptosis. The EGF receptor (EGFR) family consists of four transmembrane receptors, which
include EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4); and is
commonly overexpressed in lung cancer. Cetuximab is a monoclonal antibody able to inhibit
and degrade the EGFR. Given by intravenous infusion (IV), Cetuximab binds to the EGFR and
stops the binding and activation of the downstream signaling pathways. Moreover, as the
investigators previously published, EGFR mutation is linked with skip-metastasis
phenomena (i.e., pathologically proved mediastinal lymph node involvement in the absence
of intrapulmonary or hilar lymph node disease).
The combination with the clinical approved monoclonal antibody anti-epidermal growth
factor EGFR Cetuximab (Cetuximab-IRDye800) has shown promising results as a specific
tracker in other cancer types (i.e., brain, pancreas, head, and neck). The investigators
hypothesize that using Cetuximab-IRDye800 during minimally invasive surgical procedures
for lung cancer could overcome the limitation demonstrated by ICG and the traditional
localization strategies (e.g., coil, hook, dye intra-tumoral injection). The
investigators expect to validate using an optimal tracker that can be easily applied
intraoperatively during minimally invasive lung surgical procedures. The investigators
expect to define the optimal time window and the optimal dose of administration of the
tracker. The investigators expect to discover neoplastic localization in lymph nodes and
lung parenchyma not predictable pre-operatively.
Criteria for eligibility:
Criteria:
Inclusion criteria:
1. Clinical Stage I non-small cell lung cancer
2.
- Considered candidate to minimally invasive surgical resection after
pre-operative assessment
3. Adequate organ function
4. Performance status (ECOG) ≤2
5. Potentially fertile female subjects must agree to use highly effective contraception
throughout the - study and for three months after the last dose of the study
medication
6. Written informed consent
Exclusion criteria:
1. Previous systemic treatments for lung cancer
2. Previous radiotherapy on lung or mediastinum
3.
- Concomitant disorders that compromise the ability to adhere to the procedures
of the Protocol
4. Hemoglobin < 9 gm/dL
5. Platelet count < 100,000/mm³
6. Leukocyte count < 3000/mm³
7. Absolute neutrophil count < 1500/mm³
8. Magnesium, potassium, and calcium < the lower limit of normal per institution normal
lab values
9. Thyroid-stimulating hormone (TSH) > 13 micro international units/mL
10. Received an investigational drug within 30 days or 5 half-life prior to the first
dose of cetuximab IRDye800
11. Within 6 months prior to enrollment, myocardial infarction; cerebrovascular
accident; uncontrolled congestive heart failure; significant liver disease; or
unstable angina
12. History of infusion reactions to cetuximab or other monoclonal antibody therapies
13. Evidence of QT prolongation on pretreatment electrocardiogram (ECG) (greater than
440 ms in males or greater than 450 ms in females)
14. Hypersensitivity to Cetuximab-IRDye800, Cetuximab, or any of the excipients.
15. Receiving class IA (quinidine, procainamide) or class III (dofetilide, amiodarone,
sotalol) antiarrhythmic agents
16. Pregnancy, assessed by a pregnancy serum test (βhCG), or breastfeeding
Gender:
All
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino
Address:
City:
Torino
Zip:
10126
Country:
Italy
Status:
Not yet recruiting
Contact:
Last name:
Francesco Guerrera, M.D., Ph.D.
Email:
fguerrera@cittadellasalute.to.it
Facility:
Name:
S.C. Chirurgia Toracica U, Città della Salute e della Scienza di Torino
Address:
City:
Torino
Zip:
10126
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Francesco Guerrera, MD, Phd
Email:
francesco.guerrera@unito.it
Start date:
January 2024
Completion date:
December 2025
Lead sponsor:
Agency:
University of Turin, Italy
Agency class:
Other
Collaborator:
Agency:
A.O.U. Città della Salute e della Scienza
Agency class:
Other
Source:
University of Turin, Italy
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06101394
