To assess the feasibility of simultaneous use of ICG and SGM-101 for intraoperative imaging of colorectal liver metastases.
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Metastases
- Hepatobiliary therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main endpoint is feasibility of the simultaneous use of ICG and SGM-101. It
is deemed feasible when it meets all of the following criteria:
1. A positive score on practical workability measured with survey A *practical
workability during surgery*, defined as an average score of at least neutral.
2. A positive score on the patient*s experience measured with survey B *patient
experience*, defined as an average score of at least neutral.
3. SGM-101: at least 80% sensitivity, measured as follows:
- For capsular lesions, that are visible in white light are counted positive if
TBR >= 1.5 in vivo.
- For subcapsular lesions that are not visible in white light will be counted
as positive if:
A: TBR >= 1.5 in vivo, OR
B: TBR >= 1.5 ex vivo on whole specimen or on bread loafs
All the above measurements are performed with the Quest Open Camera System
4. No cross-interference of fluorescent signal of both dyes within the two
different excitation and emission channels. Cross-Interference is deemed
insignificant if at macroscopic bread loaf imaging with the Quest spectrum
System:
A: At the 800nm channel the rim signal (ICG, 800nm) to tumour (possibly due to
SGM-101, 700nm) ratio (STR) >= 1.5
B: At the 700nm channel the tumour (SGM, 700nm) to rim signal (ICG, 800nm)
ratio (TRR) >= 1.5 in SGM-101 positive tumours (defined in bullet point 3).
Feasibility is reached when we get a positive result on all four items.
Secondary outcome
Secondary study parameters/endpoints (if applicable) 1. The accuracy of ICG,
SGM-101 or both to demonstrate an irradical resection. The accuracy comprises
of the rate of true positives, true negatives, false positives and false
negative with accompanied sensitivity, specificity, positive predictive value
and negative predictive value. An irradical resection may be demonstrated by:
a. A fluorescent hotspot in the wound bed of either ICG, SGM-101 or both. If
this results in a reresection of the hotspot in the wound bed this is
correlated to the pathology outcome. When the surgeon was not able to perform a
reresection of the wound bed then the assumed corresponding site at the ex-vivo
specimen will be marked to correlate it to pathology. A margin of <1mm is
classified as R1. Additionally, when the surgeon performs a reresection based
on white light only (SGM-101 and ICG negative), this will be noted and
correlated to pathology. b. A fluorescent hotspot on the ex-vivo specimen of
either ICG, SGM-101 or both. This hotspot will be marked with a stitch and
correlated to pathology. Likewise, the possible reresection will be correlated
to pathology. 2. Concordance rate of ICG, SGM-101, ICG and SGM-101 combined
(both fluorescent) or ICG and SGM-101 combined (for which only one is
fluorescent), to histopathological result (lesion benign vs malignant). The
concordance rate comprises of the rate of true positives, true negatives, false
positives and false negative with accompanied sensitivity, specificity,
positive predictive value and negative predictive value. a. In-vivo: An in-vivo
SBR (ICG)/TBR (SGM-101) of >=1,5 is determined as positive for both SGM-101 as
ICG. b. ex-vivo: this will be performed with the Quest open imaging system. An
ex-vivo SBR/TBR of >=1,5 is noted as positive for both SGM-101 as ICG. c.
Ex-vivo bread loafs: This will be performed with both the ex-vivo Quest open
imaging system as with the Pearl imaging system. A TBR/SBR of >=1,5 is noted as
positive for both SGM-101 as ICG. 3. For every lesion a TBR (SGM-101) /SBR
(ICG) will be calculated in vivo (Quest open camera), ex vivo whole specimen
(Quest open camera, Pearl system) and ex vivo bread loafs (Quest open camera,
Pearl system). 4. Modification of operative plan due to imaging (e.g. extension
of resection margins, additional resection, preservation of tissue) and the
correlation to histopathology. 5. Survey C *surgeon*s satisfaction and judged
potency* questionnaire (see section 8.1.4) will be handed to all the surgeons
at the end of the trial that have at minimum operated 3 times within this
trial. Outcomes will be analysed. 6. To assess the correlation between lesion
CEA expression, performed using immunohistochemistry staining, to bread loaf
TBR (SGM-101) measured with the Pearl system. Hereby also correlating the
effect of: a. Immunohistochemical score for CEA to bread loaf TBR. The amount
of CEA expression is determined by immunohistochemistry and quantified using
the immunoreactive score (IRS). b. Percentage of tumour comprising of vital
tumour cells to bread loaf TBR 7. Effect of tumour depth on fluorescent status
of ICG/SGM-101 will be calculated in three ways a. Distance between tumour to
liver surface assessed by pre-operative CT or MRI b. Distance between tumour to
liver surface as assessed by post-operative pathology c. Distance between
tumour to closest resection margin as assessed by post-operative pathology
Exploratory endpoints 1. To evaluate the feasibility of minimally invasive
diagnostic approach for the early detection of colorectal cancer through
circulating tumor cells and extracellular vesicles. 2. To evaluate the
feasibility of using CTCs and EVs in the blood of CRC patients as biomarkers
for early detection of recurrence/metastasis. 3. To evaluate the feasibility of
using CTCs and EVs from peripheral blood for disease monitoring and early
cancer detection.
Background summary
25-30% of patients with colorectal cancer develop colorectal liver metastases
(CRLM). Cornerstone for optimal survival is achieving radical surgical
resections of all metastases . To asisst the surgeon in achieving this, the use
of intra-operative ICG for fluorescent tumour delineation has widely been
adopted as standard of care. Multiple international trials have demonstrated
that the use of ICG increases the rate of radical resections and result in the
detection of additional malignant lesions invisible to the naked eye. However,
the rate of false positives is still high and although it has increased the
number of radical resections, even in a minimal invasive cohort the unintended
R1 rate is still as much as 8%. Therefore, we are in need of an additional
real-time intra-operative tool to detect R1 resections, especially in patients
with a priori high risk for R1. To illustrate, in a large shared database of
the Erasmus University Medical Center we found that patients that either
received neoadjuvant chemotherapy, underwent a resection for >3 CRLM or
patients that had a locally recurrent liver metastasis were independently
associated with high R1 rates, ranging between 23-29%. Therefore, we propose
the addition of SGM-101, a tumour targeted (carcinoembryonic antigen, CEA)
NIR-fluorescence probe to ICG in patients scheduled for a resection with high
risk of R1, ultimately to reduce the R1 ratio. This is the first trial testing
the feasibility of working simultaneously with the two fluorescent dyes. If
feasibility is met in this trial, this is a step-up towards a powered trial
with primary objective to reduce the rate of R1 resections. An additional
exploratory objective of this study is to investigate the feasibility of
SGM-101*s potential to isolate circulating tumour cells (CTCs) and
tumour-derived extracellular vesicles (EVs) as biomarkers for CRC. The load of
CTCs and EVs in the circulation is strongly associated with poor clinical
outcomes. Studies have shown that they contain information about the molecular
profile of the tumour. The administration of SGM-101 may enable the detection
of CEA positive CTCs and EVs.
Study objective
To assess the feasibility of simultaneous use of ICG and SGM-101 for
intraoperative imaging of colorectal liver metastases.
Study design
This is an open-label, single dose, exploratory study in the Leiden University
Medical Center (LUMC).
Intervention
Administration of SGM-101: 4 (+/-1) days prior to surgery, the patient will be
hospitalized. Written informed consent will be obtained prior to any
study-related procedure. SGM-101 administration takes 30 minutes. After the
injection, patients will remain in the hospital for at least 2 hours for
observation. They will complete survey B "patient experience.
During surgery, fluorescence will be imaged with the Quest spectum camera
system.
Study burden and risks
NIR fluorescence imaging using ICG results in improved detection of CRLM,
although improvements could still be made. By using a tumour-specific
fluorophore, SGM-101, which could be visualized on another wavelength channel,
we aim to improve the intraoperative detection of CRLM and thus the rate of R0
resections. This is directly correlated with an improved overall survival. As
ICG currently standard of care during oncologic liver surgery, participation in
this study only requires an additional visit 4 days before surgery. SGM-101 has
already shown great potential in phase I/II studies and proven to be safe and
effective. No DLT have occurred. An extensive risk analysis is described in
Chapter 13. The potential benefits and risks of intra-operative
NIR-Fluorescence imaging during curative-intent surgical resection of CRLM
using SGM-101: Potential benefits: - Potential improved intra-operative
visualization of local tumor status and extent, and surgical plane, potentially
resulting in: * Lesion removal with greater precision; higher chance of
achieving an R0 resection. Patients participating in this study will undergo
intraoperative NIR-fluorescence imaging after injection of a single dose of
ICG, which is standard-of-care in the LUMC, and SGM-101. NIR-Fluorescence
imaging is a clinical technology that requires administration of a
fluorescence-imaging agent that can be excited at near-infrared (NIR)
wavelengths of ~700-800*nm. Upon illuminating tissue surfaces with penetrating
NIR light to excite the imaging agent within the tissues, the generated
fluorescence is collected to form a two-dimensional (2D) image demarking the
tissue deposition of the imaging agent. Intraoperative NIR-fluorescence imaging
is an additional intra-operative tool for surgeons which could provide them
with real-time visual enhancement and guidance during open and minimally
invasive (laparoscopic/robotic) interventions. NIR-fluorescence imaging with
SGM-101 is used in conjunction with and as addition to standard white-light
visual inspection (WLI), IOUS inspection and NIR-fluorescence ICG inspection
and will not substitute standardized perioperative clinical. The potential
benefits of NIR-Fluorescence imaging with SGM-101 on top of ICG during
resection of CRLM need to be sought within the additional visual information it
generates for the surgeon. The scheduled resection will be carried out
according to standardized principles, besides white-light visual inspection
(WLI), palpation, IOUS and NIR-fluorescence ICG imaging, NIR-fluorescence
SGM-101 imaging will be used to inspect the target lesion(s), infiltration,
radicality and to screen for new (liver) lesions as described in section 8.3.1.
In the recent SGM-101 phase 2 trial, comprising of patients with locally
advanced rectal cancer or locally recurrent rectal cancer, it was found that in
19% of patients, SGM-101 led to more complete tumour tissue removal by
highlighting tumour tissue that was not detected by the naked eye, and thereby
reduced the R0 rate (12). It is therefore that we suspect that the addition of
SGM-101 to ICG in patients with CRLM has the potential to increase the R0 rate.
Therefore, in the case NIR fluorescence imaging shows: 1) additional extent of
the lesion in the surgical plane, or 2) a fluorescent hotspot in the wound bed
suggesting incomplete tumor removal or 3) a fluorescent hotspot on the back
table - suggesting limited marges or incomplete tumor removal- the surgeon
could decide to resect this additional tissue when it is safe and surgically
feasible. All lesions that are suspect on standard of care assessment will be
resected (WL, ICG, IOUS, pre-operative imaging), independent of fluorescent
status of SGM-101. When a lesion is not suspect/visible with standard of care
but SGM-101 positive then an excision biopsy will be performed. A lesion that
is not suspect in WL, ICG and SGM-101 will not be resected. During the standard
follow-up of 6 months this lesion will be monitored and issued as malignant
when it turns out to be malignant at the follow-up. Lastly, in case of doubt,
the surgeon is able to perform a small fresh frozen biopsy (FFS) and send this
to pathology for real-time analysis. Depending on the pathological result on
this FFS the surgeon can decide how to judge the fluorescence. Post-operative,
additionally to the standard histopathological analyses, the pathologist will
evaluate the additional (FLI+, WLI-) biopsies/tissue that have been resected
separately for presence of malignant tissue. In case, pathological examination
shows that the additionally (FLI+, WLI-) resected tissue is 'true positive'
i.e. tumor+, this could result in an (oncological) benefit for the patient. In
case pathological examination shows that the additionally (FLI+, WLI-) resected
tissue is 'false positive', there will be no (oncological) benefit. The
additional resected tissue is minimal compared to the magnitude of the planned
surgery, the likelihood of harm caused by potential tissue removal based on a
false positive signal could be graded minimal. Therefore, the potential harm
for the patient is estimated to be negligible compared to the potential benefit
of a more complete removal of the CRLM. This study drug (SGM-101) and study
design have been used previously in colorectal and pancreatic cancer patients
(phase II), without significant drug-related events, as well as no significant
changes in vital signs, ECG or laboratory analysis were observed. Although,
when administrating an investigational product, it is possible that unknown
side effects or (hyper)sensitivity reactions occur. Based on experience with
other fluorescent tracers, such reactions are generally mild and transient in
nature. The risk of damage in this study related to administration of this
compound is considered negligible. Currently several clinical studies (Phase II
and III) are enrolling patients with colorectal cancer for evaluation of
SGM-101. The multicenter national phase II trial on locally advanced rectal
cancer and recurrent rectal cancer (L19-069, NL69838.056.19), still open for
inclusion aims to reduce the R1 rate, similar as in the proposed study. The
international multicentric phase 3 trial in colorectal cancer is currently in
progress in 10 clinical centers and aims for FDA approval (P19.004 and EudraCT
2018-000151-40). In over >300 patients so far, SGM-101 has proven to be well
tolerated and safe. All study drug administrations will be done in the clinic
under medical supervision. The patients receiving any study drug will remain in
the clinic after the administration of the study drug. Thus, the patients can
be closely monitored for any adverse signs during the treatment. Therefore,
providing the protocol is adhered to, careful observation and medical
management will minimize any associated risk in this study. Issues of possible
concern with the use of the SGM-101 and accompanying imaging system are: •
Adverse reactions to SGM-101. • Presence and functioning of a Near-Infrared-
Fluoresence camerasystem in the operating room; • Nonspecificity of
localization; • Phototoxicity from the light source; • Fading of the
chromophore (photobleaching); • Inability to excite SGM-101 or to record
emission; As proven with extensive knowledge of the Leiden University Medical
Center, the presence of a camera system in the operating room is not novel and
should create little problem with maintaining a sterile field. The Quest
Spectrum Platform Camera will be used initially prior to surgical excision to
record the localization of tumors and post-excision to document the status. As
such, it needs not be intrusive during the procedure. Standard hospital
procedures to ensure sterilization or masking of the equipment will be
employed. There is limited potential for phototoxicity from any light source
drie octoberstraat 15a
Leiden 2313zl
NL
drie octoberstraat 15a
Leiden 2313zl
NL
Listed location countries
Age
Inclusion criteria
In total 10 patients will be included who are scheduled for resection of
colorectal liver metastases and meet at least one of the following criteria: 1.
Scheduled for resection of >3 CRLM or, 2. Completed neo-adjuvant
chemotherapy, of which the last course was completed within 3 months before
surgery or, 3. Scheduled for surgery because of a locally recurrent liver
metastasis.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
1. Patients with contraindications for SGM-101
a. History of any anaphylactic shock;
b. Patients pregnant or breastfeeding (pregnancy should be ruled out by a
pregnancy test within two weeks prior to administration of the conjugate);
c. Known positive test for human immunodeficiency virus (HIV), hepatitis B
surface antigen (HBsAG) or hepatitis C virus (HCV) antibody or patients with
untreated serious infections;
d. Previous administration of SGM-101
2. Patients with contraindications for Indocyanine green:
a. Allergy for shells and/or clamps
b. Hyperthyroidism
c. Known allergy for ICG
3. Any condition that the investigator considers to be potentially jeopardizing
the patient*s well-being or the study objectives
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
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 |
|---|---|
| CCMO | NL84605.058.23 |