The primary objective of this clinical trial is to assess the performance of SGM-101 in theintraoperative detection of resection margins and metastases in patients undergoing curativesurgery for colorectal cancer. SGM-101 will be administered as a…
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Brief title
Condition
- Gastrointestinal conditions NEC
Synonym
Research involving
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Intervention
Outcome measures
Primary outcome
Primary efficacy endpoint P1 (detection rate):
The detection rate is agregated at the patient level and corresponds to the
rate of patients who have
at least one zone of interest identified under NIR only (not detectable under
WL) and pathologically
confirmed as cancer [WL negative, NIR positive, pathology positive].
Key secondary efficacy endpoint P2 (conservative surgery benefit):
The key secondary efficacy endpoint is agregated at the patient level and
corresponds to the rate of
patients who have more [WL positive, NIR negative, pathology negative lesions]
(NIR true negatives)
than [WL negative, NIR positive, pathology negative] (NIR false positive)
lesions, i.e. a net benefit in
numbers of negative lesions wrongly resected.
Secondary outcome
Assessment at the zone of interest level: For each zone of interest, a
*fluorescence outcome* will
be derived as either
• positive (if the use of fluorescence led to a change in the surgical plan or
post-surgery
management of the patient that was beneficial, e.g. identification and
resection of a
metastatic lesion not visible with normal light, i.e. [WL negative, NIR
positive, pathology
positive], identification of R2 margins*)
• negative (if the use of fluorescence led to a change in the surgical plan
that was potentially
deleterious, e.g. resection of some fluorescent tissue that was considered as
normal with
normal light and is confirmed as non-tumorous by pathology, i.e. [WL negative,
NIR positive,
pathology negative])
• neutral (if the use of fluorescence did not result in a change in the
surgical plan, or if it
induced a change in the plan that was neither beneficial nor detrimental).
Background summary
Technological advances have been made in cancer diagnostics and therapeutics
during the last years
to compensate for the high rate of death due to cancer over the world. Although
modern surgical
advancements have improved surgical oncology, adequate tumor visualization
remains a limitation
preventing total removal of cancer tissue. Surgeons rely primarily on white
light reflectance, which
limits the differentiation between healthy tissue and tumor and can lead to
residual cancer cells
inadvertently left behind [1]. Oncologic surgeons agree that advances in
fluorescence imaging using
targeted probes to enhance the visual capability of the operating surgeon
beyond that of white-light
reflectance would provide a major opportunity to improve outcomes [2]. The goal
of administration
of SGM-101 is to provide oncologic surgeons with an intraoperative imaging tool
that will offer them
pseudo-color distinction between tumor and adjacent normal tissue thus allowing
them to visualize
and delineate tumors overexpressing CEA, particularly colorectal tumors and
their metastases.
Study objective
The primary objective of this clinical trial is to assess the performance of
SGM-101 in the
intraoperative detection of resection margins and metastases in patients
undergoing curative
surgery for colorectal cancer. SGM-101 will be administered as a single
intravenous dose, at the
optimal dose and according to the schedule determined in the Phase I/II studies.
To analyze the clinical benefit
resulting from the use of
Fluorescence Guided Surgery (FGS)
during the surgical procedure, with
SGM-101 as the intraoperative
imaging agent, in terms of additional
cancer lesions resected.detected
with the goal to achieving R0
resection
Study design
This is a randomized, multicenter, semi-blinded parallel-group, Phase III study
on the performance of
SGM-101, a fluorochrome-labeled anti-carcino-embryonic antigen (CEA) monoclonal
antibody, for
the delineation of primary tumor, recurrent disease and metastases in patients
undergoing curative
surgery for colorectal cancer.
The focus of this trial is on the evidence needed for an indication of improved
visualization based on
the concordance between histopathology and tissue fluorescence. The control is
standard operating
conditions or what can be called white light surgery, and each patient in the
SGM-101 arm is his own
control. Indeed surgeons will have the possibility to turn the near-infrared
camera on and off when
they need during the procedure, several times if necessary. Moreover there is
no possibility to blind
the surgeons in such an imaging procedure as they will know immediately if the
patient has received
SGM-101 when turning-on the near-infrared light.
300 patients will be randomized with an unbalanced randomization ratio of 4:1
(SGM-101 guided
surgery: saline injection and standard surgical treatment). The randomization
will be stratified
according to two stratification variables:
• tumor location-and-type with the following five categories:
o cT4 colon cancer
o cT3/4 rectal cancer
o recurrent colon cancer
o recurrent rectal cancer
o peritoneal metastasized colorectal cancer
• geographical region with two categories
o USA
o Europe.
The objective of the control arm is to assess the influence of the fluorescence
on the surgical
approach and thus on the safety of each patient. Indeed, for clear ethical
reasons, no surgeon shall
deliberately minimize the initial resection knowing that the SGM-101
fluorescence would constitute
a back-up security on visible defects. Nor shall he be more aggressive in the
presence of
fluorescence. There will be very clear instructions to follow standard of care
tumor assessment (that
has to be done in white light at the beginning of every surgical intervention).
In the SGM-101 arm
the surgeons will have the possibility to assess the presence of additional
tumor lesions by use of
fluorescence but in no case shall they modify their initial global evaluation
routine. Documentation
of patients* short-term outcome in both arms shall give sufficient information
on a possible
surgeons* bias to use an overly-aggressive approach (too much resection) caused
by fluorescence.
Intervention
Eligible and consenting patients will be randomized 4:1 to one of two groups (A
and B).
• Group A: SGM-101 injection followed by conventional then fluorescence tumor
assessment.
• Group B: Saline injection followed by standard surgical treatment -
conventional tumor
assessment
SGM-101 is a CEA-specific chimeric antibody conjugated with a NIR emitting
fluorochrome,
developed as an intraoperative imaging agent for the delineation and/or
detection of tumors.
The SGM-101 active ingredient is a covalent conjugate of the SGM-Ch511 anti-CEA
chimeric
monoclonal antibody with the fluorochrome BM-104 (Figure 1). The BM-104
fluorochrome is
conjugated to free amino groups of the antibody via a stable heterobifunctional
linker and an amide
bond.
Study burden and risks
The issues of possible concern with the use of the SGM-101 and accompanying
imaging system are:
• Presence of a camera in the operating room;
• Phototoxicity from the light source;
• Nonspecificity of localization;
• Failure to bind to receptors;
• Fading of the chromophore (photobleaching);
• Inability to excite SGM-101 or to record emission;
• Adverse reactions to SGM-101;
• Adverse events resulting from unnecessary tissue resection.
To maintain a sterile field, the camera will be used initially prior to
surgical excision to record the
localization of tumors and post-excision to document the status and does not
interfere with sterility
requirements. Standard hospital procedures to ensure sterilization or masking
of the equipment will
be employed.
There is a potential for phototoxicity from any light source. The degree of
risk is related to the power
of the beam and the extent of exposure. Controls will be in place to ensure
exposure is limited to
what is necessary to capture the images needed.
While SGM-101 appears to specifically localize to colorectal carcinomas, there
is a possibility that
some patients will have CEA-negative tumors and will not benefit from the use
of this agent. The CEA
expression of CRC may not be known before surgery but most patients (>90%) will
have CEA
expressing tumors. In the case where the tumor would not express CEA, SGM-101
would be
eliminated with no risk for the patient.
There is no evidence to date of a failure of SGM-101 to bind to CEA in
pre-clinical models, so this
remains a theoretical concern. Possible mechanisms would be competitive
antagonism with another
ligand or a change in the molecule or receptor resulting in altered binding.
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Listed location countries
Age
Inclusion criteria
1. Patients aged over 18 years old;
2. Patients should be scheduled for curative colorectal cancer surgery of
primary cT4 colon cancer or primary cT3/4 rectal cancer, recurrent colorectal
cancer or peritoneal metastasized colorectal cancer;
3. Female patients should not be of child-bearing potential (i.e., women with
functioning ovaries who have a documented tubal ligation or hysterectomy,
ovariectomy or women who are post-menopausal) nor breastfeeding. Women of
child-bearing potential, including women with a documented tubal ligation, will
be
included provided that they have a negative highly sensitive urine pregnancy
test or a negative
serum pregnancy test at the day of the injection and agree to practice adequate
contraception
for 30 days prior to administration of investigational product, and 3090 days
after completion
of injection. A postmenauposal state is defined as no menses for 12 months
without an
alternative medical cause. A high follicle stimulating hormone (FSH) level in
the postmenopausal
range may be used to confirm a post-menopausal state in women not using hormonal
contraception or hormonal replacement therapy. However, in the absence of 12
months of
amenorrhea, a single FSH measurement is insufficient.
Acceptable forms of highly effective contraception methods are methods that can
achieve a failure
rate of less than 1% per year when used consistently and correctly are
considered as highly
effective birth control methods. Such methods include:
• Combined (estrogen and progestogen containing) hormonal contraception
associated with
inhibition of ovulation:
o Oral;
o Intravaginal;
o Transdermal.
• Progestogen-only hormonal contraception associated with inhibition of
ovulation:
o Oral;
o Injectable;
o Implantable.
• Intrauterine device (IUD) 2;
• Intrauterine hormone-releasing system (IUS) 2;
• Bilateral tubal occlusion 2;
5. STUDY POPULATION
5.1. INCLUSION CRITERIA
SGM-CLIN03 Version <4.1> - The Netherlands
SurgiMab 08/02/2023
40
• Male sterilization (with the appropriate post-vasectomy documentation of the
absence of
sperm in the ejaculate). For female subjects on the study, the vasectomized
male partner
should be the sole partner for that subject.
• True abstinence: When this is in line with the preferred and usual lifestyle
of the subject and
only if defined as refraining from heterosexual intercourse during the entire
period of risk
associated with the study treatments. Periodic abstinence (e.g. calendar,
ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of
contraception
4. Patients should be capable and willing to give informed consent before study
specific procedures.
Exclusion criteria
1. Other malignancies, either currently active or diagnosed in the last 5 years,
except for adequately treated in situ carcinoma of the cervix and basal or
squamous cell skin carcinoma;
2. Primary appendiceal cancer;
3. Laboratory abnormalities defined as:
- Aspartate AminoTransferase, Alanine AminoTransferase, Gamma
Glutamyl Transferase) or Alkaline Phosphatase levels above 5 times the
ULN or;
- Total bilirubin above 2 times the ULN or;
- Serum creatinine above 1.5 times the ULN or;
- Platelet count below 100 x 109/L or;
- Hemoglobin below 4 mmol/L (females) or below 5 mmol/l (males);
4. 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;
5. Use of another investigational drug during 4 weeks before the Injection Day.
6. Any condition that the investigator considers it would potentially
jeopardize the patient*s well-being or the study objectives, such as severe
anaphylactic reaction in medical history, previous allergic reaction to SGM-101
or to any excipient present in the product or known hypersensitivity to murine
proteins.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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 |
|---|---|
| EudraCT | EUCTR2018-000151-40-NL |
| CCMO | NL68489.058.18 |