Primary objective:1. To evaluate the safety and tolerability of the [18F]fluoro-PEG-folate PET tracer2. To determine the pharmacokinetics (protein binding, biodistribution, clearance rate) of the [18F]fluoro-PEG-folate PET tracerSecondary objectives…
ID
Source
Brief title
Condition
- Ovarian and fallopian tube disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the study will be to evaluate the safety, tolerability
and pharmacokinetics of the [18F]fluoro-PEG-folate tracer.
Tolerability assessments (blood pressure (mmHg), pulse rate (bpm), peripheral
oxygen saturation, respiratory rate, temperature will be recorded at regular
intervals (every 15 minutes) starting directly before administration and
continued up to two hours after dosing. Following the [18F]fluoro-PEG-folate
PET/CT scan, an ECG (PR, QRS, QT) will be performed. Additionally, (serious)
adverse events and the concomitant use of other medications throughout the
study period (defined as up to six weeks after the administration of the
[18F]fluoro-PEG-folate tracer) will be recorded.
Furthermore, pharmacokinetics will be determined. Manual blood samples will be
used to determine the arterial input curve and to calibrate and correct it for
plasma-to-whole blood concentration ratios and labelled protein binding
fractions, thereby generating a protein binding corrected, arterial plasma
input function. Full-kinetic quantitative analysis will be performed using
1-tissue and both irreversible and reversible 2-tissue compartment models, all
with an additional blood volume fraction parameter consisting of whole-blood
activity. Pharmacokinetic parameters will be extracted, such as the volume of
distribution (VT). Furthermore, several simplified uptake metrics will be
derived, such as several semiquantitative parameters (standardized uptake
values). In this way, we are able to determine which model best describes the
kinetics of the radiotracer and which simplified and/or semiquantitative
parameter correlates best for accurate quantification of [18F]fluoro-PEG-folate
uptake in whole-body PET/CT scans.
Secondary outcome
The secondary objective of the study is to investigate the sensitivity and
specificity of the [18F]fluoro-PEG-folate PET/CT scan for the detection of
metastatic disease in epithelial ovarian cancer. This will independently be
determined qualitatively as well as quantitatively by two nuclear medicine
physicians, using the Peritoneal Cancer Index (PCIPET/CT). This PCI indicates
the presence of large (> 5 cm), moderate (0.5-5 cm), small (< 0.5 cm) or no
involvement in 13 abdominal regions. The assessment of para-aortic and pelvic
lymph nodes is not included in the PCI, but will be added to the CRF.
Semiquantitative parameters will be obtained by semi-automatic tumor
segmentation based on, for example, a threshold value method. Regions of
interest (ROIs) determination will be performed by an investigator who is
blinded for the results of immunohistochemical data. In addition, the
conventional CT-scan made during routine clinical work-up will be scored by two
independent radiologists, also using the PCI (PCICT). Preoperative PET-positive
lesions and routine conventional CT findings will be compared on the basis of
the PCI and a per-lesion based analysis. Postoperative histological findings
will be regarded as the gold standard for presence, magnitude and localization
of metastatic lesions. Imaging signal and histologically proven malignancy will
be scored as a dichotomous variable (yes/no, 2x2 table). The number of true
positive, true negative, false positive and false negative lesions will be
reported. If feasible, whole mount tissue sections will be obtained to
correlate immunohistochemical FR expression to [18F]fluoro-PEG-folate uptake in
the primary tumor as seen on the FR-targeted PET/CT images.
The sensitivity is defined as the proportions of [18F]fluoro-PEG-folate PET
positive lesions to the total number of histologically confirmed EOC lesions
(with a 95% confidence interval). The specificity is defined as the proportions
of [18F]fluoro-PEG-folate PET negative lesions to the total number of lesions
without tumor involvement (with a 95% confidence interval). The location and
magnitude of these lesions will be taken into account. Positive predictive
value (PPV), negative predictive value (NPV) and diagnostic accuracy will be
calculated as far as possible in this small study population.
Background summary
Clinical relevance
Epithelial ovarian cancer (EOC) is the leading cause of death from
gynecological cancer in developed countries. In the Netherlands, there are
annually 1300 newly diagnosed ovarian cancers and 1100 women die from this
disease. The high mortality rate in EOC is due to the fact that 75% of women
present with advanced stage disease. In these women, treatment consists of
cytoreductive surgery, either preceded by neoadjuvant chemotherapy (NACT), and
subsequently followed by adjuvant chemotherapy. Completeness of surgery is the
most significant prognostic variable for survival. Cytoreductive surgery
therefore aims to achieve resection of all visible lesions. During surgery
however, gynecologic oncologists must rely on naked eye visual inspection and
palpation, potentially leading to inaccurate cancer resections.
Whether NACT is administered prior to cytoreductive surgery in patients with
advanced stage EOC is determined on the basis of the patient*s performance
status and surgical resectability as estimated on computed tomography (CT)
scan. Despite the fact that the overall sensitivity of a CT scan is 85-93%, it
is merely 11-37% for the detection of tumors located in the subdiaphragmatic
space, omentum, root of mesentery and serosal surface of the small bowel. It is
the involvement of these sites that signify irresectability. Consequently,
33-39% of patients undergo unnecessary laparotomy. Diagnostic laparoscopy prior
to cytoreductive surgery has shown to lower this rate to 10%, but this method
is invasive and its utility is hampered by bulky tumors and adhesions. Lastly,
diffusion-weighted magnetic resonance imaging (DW-MRI) seems promising, but
further research is needed before this modality can routinely be used.
Molecular imaging using agents that specifically target EOC will allow for
improved preoperative tumor detection. A suitable target for tumor-targeted
molecular imaging of metastatic lesions in EOC is folate receptor (FR). FR is
overexpressed in 90-95% of EOCs and their corresponding peritoneal, omental and
lymph node metastases. In the majority of normal tissues its expression is
absent. We previously showed that the use of a folate analogue conjugated to a
fluorescent dye in the near-infrared range (OTL38, * = 700-900 nm) led to the
detection of 29% additional metastatic lesions that would otherwise not have
been detected during cytoreductive surgery.
FR-targeted positron emission tomography (PET) imaging using the
18F]fluoro-PEG-folate PET tracer can aid in the preoperative assessment of
metastatic tumor load in patients with advanced stage EOC and may ultimately
help selecting patients for either primary cytoreductive surgery or NACT
followed by interval cytoreductive surgery. It may thereby ensure that patients
will be offered customized treatment and reduce the number of unnecessary
laparotomies. Before FR-targeted PET/CT imaging can be implemented in routine
clinical work-up in patients with EOC, more information is needed on the
safety, tolerability and the biodistribution of the [18F]fluoro-PEG-folate PET
tracer as well as the sensitivity and specificity of [18F]fluoro-PEG-folate
PET/CT imaging for the detection of metastatic lesions derived from EOC. The
current study aims to examine these parameters.
Study objective
Primary objective:
1. To evaluate the safety and tolerability of the [18F]fluoro-PEG-folate PET
tracer
2. To determine the pharmacokinetics (protein binding, biodistribution,
clearance rate) of the [18F]fluoro-PEG-folate PET tracer
Secondary objectives:
To examine the sensitivity and specificity of [18F]fluoro-PEG-folate PET/CT
imaging for the detection of metastatic lesions in patients with advanced stage
EOC.
Study design
A phase I study will be conducted. An exact sample size is not applicable for
this study. A total of 15 patients with advanced stage EOC scheduled to undergo
cytoreductive surgery will be included at the LUMC. This number is feasible, as
each year approximately twelve to fifteen patients with advanced stage EOC will
undergo cytoreductive surgery.
After inclusion, 185 MBq of [18F]fluoro-PEG-folate will be intravenously
administered. Immediately following injection, an FR-targeted PET/CT scan will
be performed. During the PET/CT scan nineteen arterial blood samples (97 mL in
total) are taken for pharmacokinetic analyses. Vital signs will be measured.
PET images will be independently scored by two nuclear medicine physicians
using the Peritoneal Cancer Index (PCIPET/CT). This PCI indicates the presence
of large (> 5 cm), moderate (0.5-5 cm), small (< 0.5 cm) or no involvement in
13 abdominal regions. The assessment of para-aortic and pelvic lymph nodes is
not included in the PCI, but will be added to the case report form (CRF). The
conventional CT-scan made during routine clinical work-up will be scored by two
independent radiologists, also using the PCI (PCICT). Within three weeks
following the FR-targeted PET/CT, patients will undergo cytoreductive surgery.
During surgery, the gynecologic oncologists will determine the PCI (PCIsurgery)
using the CRF without knowledge of the results of the FR-targeted PET/CT scan.
The PET/CT findings will be presented after initial exploratory laparotomy but
before cytoreductive surgery to allow for a *second look*. The suspect lesions
on the FR-targeted PET/CT will be identified and marked on the CRF. The
PET-positive lesions that were neither detected by the conventional CT scan nor
by initial exploration during cytoreductive surgery will remain in situ. These
non-resected PET-positive lesions will be reported on the CRF as being
clinically suspected of malignancy (yes/no). All suspect lesions identified by
the conventional CT scan and/or cytoreductive surgery will be excised, when
surgically feasible (standard care). These resected suspect lesions will be
reported on the CRF as being PET-positive (yes/no). The resected lesions will
then be examined on tumor status by a pathologist specialized in gynecologic
oncology. Immunohistochemical staining for FR expression on the resected
tissues will be performed. FR-targeted PET/CT results will be compared to
postoperative histopathology (gold standard; if applicable) and the previously
made routine conventional CT scan.
Intervention
• A screening visit including ECG prior to the performance of the
[18F]fluoro-PEG-folate PET/CT scan
• Intravenous administration of [18F]fluoro-PEG-folate prior to the
[18F]fluoro-PEG-folate PET/CT scan
• An ascites drainage if a large amount of ascites is present
• Performance of the [18F]fluoro-PEG-folate PET/CT scan
• An extra iv to take blood samples (max. 108 mL in total) and an ECG following
the [18F]fluoro-PEG-folate PET/CT scan
• A short phone call two and six weeks following the [18F]fluoro-PEG-folate
PET/CT scan, respectively
Study burden and risks
Patients participating in this study will undergo PET/CT imaging and will thus
be exposed to radiation. Additionally, although the investigational product has
already been used in humans, it is possible that unknown side effects occur.
For complete pharmacokinetic analysis and protein binding analysis, arterial
blood sampling (97 mL) will be performed. The additional burden of patients is
acceptable as only one visit, twice an electrocardiography (ECG) and extra
blood sampling is required (max. 108 mL in total) to participate in this study.
The extent of risks associated with participation in this study is considered
relatively low. .
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
Patients with radiologically FIGO stage IIIB/IIIC EOC based on the conventional
CT scan who are
• scheduled to undergo primary cytoreductive surgery and
a) in whom EOC is histologically proven, or
b) in whom EOC is cytologically suspected and a serum CA125/CEA ratio > 25 is
found
or
• treated with neoadjuvant chemotherapy (NACT) and are scheduled to undergo
interval cytoreductive surgery and
a) in whom EOC is histologically proven, or
b) in whom EOC is cytologically suspected and a serum CA125/CEA ratio > 25 was
found before NACT
c) and with radiologically FIGO stage IIIB/IIIC EOC based on the response
evaluation CT scan after NACT
Exclusion criteria
1. Women younger than 30 years of age (in accordance with the guidelines of the
Netherlands Commission on Radiation Dosimetry, as the total radiation dose will
be 7.2 mSv)
2. Patients who previously underwent primary laparotomy and in whom complete or
optimal cytoreduction was not considered feasible.
3. Contraindication for PET (pregnancy, lactating or severe claustrophobia)
4. Thrombocytopenia (platelet count < 100 x 10^9/L) and/or INR > 2
5. Impaired renal function (defined as eGFR < 50 mL/1.73 m2)
6. Impaired liver function (ALT, AST or total bilirubin > 3x upper limit of
normal)
7. Clinically significant abnormalities on ECG and/or clinically laboratory
test
8. Inability to tolerate lying supine for the duration of a PET/CT examination
(~110 minutes)
9. Patients with concomitant malignancy (except basal cell carcinoma of the
skin) or any condition that in the opinion of the investigators could
potentially jeopardize the health status of the patient
10. Patients not able to comply with the study procedures
11. Patients who did not give informed consent
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
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 | EUCTR2020-000112-29-NL |
| CCMO | NL72618.058.20 |