The main objective of this study is to define the optimal dose of fluorescent tracer for intraoperative detection of tumor delineation during breast cancer surgery.
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
- Breast therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tumor to Background Ratios (TBR) calculated from images taken intraoperatively
and ex vivo from bread loaf slices of the excised specimen.
Secondary outcome
• Assess the safety of the second generation conjugate at all doses tested.
• Compare conventional histopathological margin assessment with margin
assessment using the fluorescent signal
• Confirm if fluorescent signal corresponds to tumor tissue
• Explore fluorescence intensity ex vivo in tumor and surrounding tissue
Background summary
Breast conserving surgery (BCS) has become the standard treatment as part of
breast conserving therapy (BCT) for early stage breast tumors 3,4. In BCS the
tumor tissue is removed while healthy breast tissue is preserved, which is
beneficial for improving patient recovery and breast cosmesis as compared to
total mastectomy. However this procedure is accompanied by a risk of incomplete
tumor resection. Whether all tumor tissue is removed can only be determined
after the surgery is completed through pathological analysis of the excised
tissue. Tumor free surgical margins are critical in BCS; the risk of local
recurrence (LR) of the primary tumor increases significantly with positive
resection margins 4,5. A meta-analysis done by Kreike in 2008 revealed that in
30 of 34 reviewed studies that persistent microscopic or macroscopic inadequate
surgical margins were highly significant for LR compared with negative margins
6. Positive margins are defined as tumor cells at or near the cut edge of the
surgical specimen. The prevalence of positive margins in histological analysis
varies between 5 - 82%, while most studies report positive resection margins
between 20 - 40% 6-11. In cases of incomplete resection, the treatment plan may
need to be adjusted, which often results in the decision to perform re-excision
surgery which in turn increases the risk of co-morbidities, causes extra
psychological burden, reduces cosmesis and increases healthcare costs 10,12,13.
Although the tumor can often be localized with various imaging techniques prior
and also during surgery, the intraoperative feedback enabling the surgeon to
distinguish healthy tissue from tumor tissue are still limited to visual
observation and palpation alone. It is expected that the results of BCS improve
significantly when the surgeon is able to better delineate the tumor from the
healthy tissue intraoperatively with potentially a lower rate of positive
margins.
A need for further investigation for fluorescence image-guided surgery in
breast conserving surgery (BCS) has arisen following the results obtained from
a phase I feasibility breast cancer trial (BIRDYE study: ABR NL 37479.042011)
executed at the UMCG and UMCU. The BIRDYE study investigated the visualization
of breast cancer tissue intraoperatively using a fluorescent tracer,
Bevacizumab-IRDye800CW, in combination with a specially designed imaging
platform. This study demonstrated that the tracer-uptake was tumor specific
since a fluorescent signal could be detected in all specimens ex vivo. However,
the signal was not sufficient for margin assessment intraoperatively.
Currently, both the sensitivity of the intraoperative near-infrared
multispectral fluorescence camera system as well as the quantum yield of the
tracer are optimized. These optimizations are expected to improve the
intraoperative detection of fluorescent signals. Additionally an increase in
dose of the tracer is expected to improve the signal. The aim of this study is
to define the optimal dose of the fluorescent tracer for intraoperative
delineation of breast cancer tissue using the improved and optimized
fluorescent tracer and camera system.
Study objective
The main objective of this study is to define the optimal dose of fluorescent
tracer for intraoperative detection of tumor delineation during breast cancer
surgery.
Study design
This is a two center interventional exploratory open label dose escalation
trial consisting of two parts. In part 1 four groups of three patients each
will be included in four escalating doses of the tracer, respectively 4.5mg,
10mg, 25mg, 50mg. Before continuing to the next dose level, tumor-to-background
analyses will be performed and the DSMB will review the safety of the tracer.
Three patients in each group does not generate sufficient data points to decide
which dose can be selected for a subsequent phase 3 study. In part 2, the two
best performing dose groups of part 1 will be expanded to a total of 10
patients per group. This means that 20-26 patients will be included.
Intervention
Three days prior to surgery a single bolus injection of the fluorescent tracer
Bevacizumab-IRDye800CW will be administered. Intra-operatively a near infrared
camera system will be used to detect fluorescent signals. Patients are followed
up till 2 weeks after the administration of the tracer.
Study burden and risks
The risk related to tracer exposure is regarded minimal. The tracer is
administered as a single dose that is over 100x less than the therapeutic dose
for Bevacizumab (Avastin). Furthermore, previous clinical experience did not
reveal any adverse events related to the imaging compound
bevacizumab-IRDye800CW. Participants have one extra visit to the hospital for
tracer administration. At this visit a blood sample may be taken to check
patient*s levels of potassium, sodium and calcium before infusion of the
tracer, if this data is not evident from the patient record and recently (<3
months) obtained. An ECG will be taken twice before and after tracer
administration in order to determine the QTc interval. The patient will stay
for one hour after tracer administration at the ward for safety monitoring. The
scheduled surgery 3 days after injection may take up to a maximum of 30 minutes
longer related to the intraoperative imaging collection. If fluorescent signals
are still present in the surgical cavity after routine resection, additional
tissue samples will be taken from this fluorescent tissue. No direct benefits
are expected for study subjects.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
1. Females aged >= 18 years.
2. Confirmed diagnosis of breast cancer by means of histology or cytology and eligible for breast cancer surgery.
3. Tumor size >= 5 mm (0, 5 cm) diameter according to anatomical imaging data.
4. WHO performance score 0-2.
5. Life expectancy greater than 12 weeks
6. Written informed consent has been obtained
7. In the Investigator*s opinion, patient is able and willing to comply with all trial requirements
8. A negative serum pregnancy test within 2 weeks prior to receiving the second generation tracer
9. Willing to ensure that she or her partner uses effective contraception during the trial and for 3 months thereafter.
Exclusion criteria
1. Medical or psychiatric conditions that compromise the patient*s ability to give informed consent
2. Breast prosthesis in the target breast
3. History of infusion reactions to Bevacizumab or other monoclonal antibody therapies
4. Concurrent anticancer therapy (chemotherapy, radiotherapy, vaccines, immunotherapy) delivered within the last 6 weeks prior to the start of the treatment
5. Unresolved chronic non-hematological toxicity higher than NCI-CTC grade 2
6. Participation in a clinical study involving an investigational drug or device within 30 days prior to the start of treatment
7. Significant renal or hepatic impairment.
8. Scheduled elective surgery, with the exception of the breast surgical procedure, or other procedures requiring general anesthesia during the trial.
9. Inadequately controlled hypertension with or without current antihypertensive medications.
10. History of myocardial infarction (MI), TIA, CVA, pulmonary embolism, uncontrolled congestive heart failure (CHF), significant liver disease, unstable angina within 6 months prior to enrollment.
11. Patients receiving anticoagulant therapy with vitamin K antagonists.
12. Patients receiving Class IA (e.g. Quinidine, Procanamide) or Class III (e.g. Dofetilide, Amiodarone, Sotalol) antiarrhythmic agents.
13. Evidence of QT prolongation on pre-treatment ECG (Males >440 ms, Females >450 ms).
14. Magnesium, potassium and calcium levels below LLN which is regarded clinically relevant with regards to study participation.
15. Preoperatively undetectable lymphnodes using 99m-TC SPECT-scan that leads to the need of using Patent Blue intraoperatively.
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 | EUCTR2015-000535-33-NL |
| Other | ingediend: nummer volgt |
| CCMO | NL52447.042.15 |