FLuoresence image guided surgery with A VEGF-targeted tracer in soft-tissue Sarcomas in Humans

There is a need for better visualization of resection margins during surgery
for soft tissue sarcomas. Optical molecular imaging of sarcoma associated
biomarkers is a promising technique to accommodate this need. The biomarker
Vascular Endothelial Growth Factor (VEGF-A) is overexpressed in soft tissue
sarcomas versus normal tissue and has proven to be a valid target for
molecular imaging. We hypothesize that bevacizumab-800CW accumulates in VEGF
expressing cancer, enabling sarcoma visualization using a NIR intraoperative
camera system. In this pilot intervention study we will determine the optimal
dosage of bevacizumab-800CW (10, 25 or 50mg) to detect soft tissue sarcoma
intraoperatively

Part 1
1. Determine if accumulation of the fluorescent tracer bevacizumab-800CW can be
detected for identification of soft tissue sarcoma during surgery.
2. Identify two doses of bevacizumab-800CW that provide the best visualization
of tumour tissue during surgery.
3. Obtain information on safety aspects of the tracer, side effects, adverse
events (AE), serious adverse events (SAE) and suspected unexpected serious
adverse reactions (SUSAR).

Part 2
Define which of the two doses of Bevacizumab-800CW identified in part 1 is the
optimal dose for further development in a phase II trial.

This is an interventional exploratory dose escalation trial. Studying the
fluorescence signal in soft tissue sarcomas after administration of
bevacizumab-800CW in patients with clinical suspicion of a soft tissue sarcoma
who are scheduled to undergo surgical intervention. The main objective of this
study is to determine if accumulation of the fluorescent tracer
bevacizumab-800CW can be detected to identify soft tissue sarcoma tissue during
surgery. The secondary objective is to define the optimal dose of the tracer to
visualize the tumour delineation intraoperatively. For this purpose the study
will comprise of two parts. In part 1 small cohorts of three patients will
receive increasing doses of the tracer: 10mg, 25mg, and 50mg subsequently.
After completion of each cohort efficacy data will be reviewed by determining
the fluorescent signal and safety reports. In part 1 the two doses with optimal
performance will be defined. In part 2 the sample size for the two doses in
part 1 will be increased to 10 patients for each of the two dose groups, to
achieve a sufficient sample size to conclusively decide which dose of the
tracer has to be used for further development in a phase II trial

In part one, a maximum of 9 patients will receive a single bolus injection of
bevacizumab-800CW three days before surgery. During surgery three imaging
moments are defined in which the near infrared intraoperative camera system
will detect the fluorescent signal. The two most optimal dosages will be
identified by determining the fluorescent signals. In part two these two
cohorts will be extended to ten patients each to define which of the doses is
the optimal dose for further development in a phase II trial.

Time investment for study participants
Soft tissue sarcoma patients who are scheduled for surgery with curative intent
at the UMCG are asked to participate in this trial. Once written informed
consent is obtained the patient has one study specific visit for administration
of the tracer. In addition to the surgical procedure the study related
procedures are expected to take up to 15 minutes extra as compared to regular
practice.

Risk for study participants
Risks to study participants are mainly related to the, already present, risks
of the surgical procedure and to the administration of the tracer in increasing
dosages. A data safety monitoring board (DSMB) will not be installed as in more
than 110 patients receiving bevacizumab-800CW, no (serious) adverse events were
observed.

For patients who are on combination therapy with Bevacizumab for the treatment
of cancer, it is commonly accepted that the patient can safely undergo surgery
6 weeks after termination of the Bevacizumab therapy: i.e. at this time the
anti-angiogenetic effects have diminished sufficiently to assure there is no
increased risk of bleeding or post-operative complications. The through plasma
levels after 6 weeks wash out of the drug equal the peak plasma levels after a
160mg IV dose (communication and calculations by the Hospital Pharmacy and the
department of Medical Oncology at the UMCG). Furthermore, Starlinger et al
investigated that even after a cessation time of 6 weeks Bevacizumab is fully
active and blocks circulating and local VEGF at the time of liver resection,
but no increase in perioperative morbidity is recorded1. Since the
Bevacizumab-800CW will be used in a dose far below 160mg it will therefore
cause no additional complication risk, as also evaluated in more than 110
patients after receiving bevacizumab-800CW.

Benefits for study participants
The addition of the near infrared fluorescent imaging agent and camera system
during soft tissue sarcoma surgery does not have direct benefits for the
participating patients. Interference with standard clinical care is not
expected since the surgeons are to follow their normal standard of care during
tumour resection surgery. If fluorescent signals are detected during surgery in
parts that are not part of the surgical specimen, a maximum of 3 biopsies per
fluorescent area may be taken to confirm ex vivo analyses if the fluorescent
signals represent cancer tissue.