Optical PD-L1 imaging using Quantitative Fluorescence Endoscopy in locally advanced esophageal cancer using durvalumab-680LT: a phase I multicenter feasibility and safety study

Treatment of patients with locally advanced esophageal cancer (EC) is
multidisciplinary and consists of neoadjuvant therapy followed by surgical
removal of the esophageal tumor and potentially tumor positive lymph nodes. The
beneficial effect of the addition of immunotherapy to improve response rates to
current treatment strategies has been investigated response to, since only 16
to 43% of EC patients achieve a pathological complete response (pCR) after
neoadjuvant therapy and a pCR is associated with better long-term outcomes.
Unfortunately, not all patients respond to immunotherapy and the knowledge
about biomarkers that predict response to therapy are required. A promising
novel parameter is tumor programmed death-ligand 1 (PD-L1) expression, one of
the immune checkpoints targeted by cancer immunotherapy. Studies performed in
patients with various solid tumors demonstrate improved response to
immunotherapy and survival benefit in patients with higher PD-L1 expression.
Nonetheless, not all patients with high PD-L1 expression show benefit and some
without expression do. Moreover, mostly biopsy-based tests are used to assess
PD-L1 status, although these tests are prone to errors, partly due to
heterogeneity in tissue expression. Novel methods are needed to gain more
insight in the PD-L1 expression in order to better select patients who are
likely to benefit from immunotherapy. We hypothesize that quantitative
fluorescence endoscopy using the tracer durvalumab-680LT targeting PD-L1 is a
promising technique to investigate the heterogeneity of PD-L1 expression.

This study has been transitioned to CTIS with ID 2024-517258-85-00 check the CTIS register for the current data.

The primary objective of this study is to determine the feasibility and safety
of quantitative fluorescence endoscopy using the fluorescent tracer
durvalumab-680LT to get insight in the PD-L1 expression before and after
neoadjuvant therapy in patients with locally advanced EC.

The study design is similar to the previously approved study for molecular
fluorescence endoscopy of patients with EC using bevacizumab-800CW as a tracer
(NL65856.042.18). The current study is a non-randomized, non-blinded,
prospective, multicenter feasibility, safety study in patients with locally
advanced EC. Thirty-one patients with non-metastatic locally advanced EC will
be included in this study. Patients will undergo two fluorescence endoscopy
procedures for in vivo analysis, that are scheduled before and after
neoadjuvant therapy, after receiving a single intravenous dose of 4.5 mg
durvalumab-680LT. After the fluorescence endoscopy, extensive ex vivo analyses
will be performed to correlate fluorescence signals with histology, and to gain
more insight in tissue distribution of the tracer. An interim analysis will be
conducted when study procedures have been performed in 5 patients before
neoadjuvant therapy. In case of insufficient fluorescent signal, the tracer
dose will be increased. Additionally, a maximum of 5 *blanco* control patients
will be included who will not receive durvalumab-680LT.

Tracer administration: The PD-L1-targeted fluorescent tracer durvalumab-680LT
will be administered intravenously 2-4 days prior to the endoscopy at the UMCG.
Afterwards, patients will be monitored for one hour by measurements of vital
parameters (i.e. heartrate, blood pressure and temperature) for potential
side-effects, such as infusion-related reactions. In addition, blood will be
drawn before, 1 hour after and 2-4 days after tracer administration.
Endoscopy procedure: Patients will undergo two endoscopies, before and after
neoadjuvant therapy. Two to four days before each gastroscopy/endoscopic
ultrasound, tracer injection takes place. Both endoscopies will be performed by
a dedicated ultrasound endoscopists. First, routine high-definition white-light
(HD-WL) inspection is used. Quantification of fluorescence using multi-diameter
single fiber reflectance/single fiber fluorescence (MDSFR/SFF) spectroscopy
will be performed both in vivo and ex vivo. Subsequently, fluorescence
molecular endoscopy (FME) and endoscopic ultrasound (EUS) will be performed.
FME allows in vivo fluorescence inspection and during EUS the depth of tissue
invasion and regional lymph nodes involvement can be visualized. Furthermore,
EUS enables single fiber reflectance/single fiber fluorescence (SFR/SFF)
spectroscopy measurements via fine needle aspiration (FNA) to gain insight in
the drug distribution throughout the tumor. Additionally, biopsies will be
obtained: from the tumor (max. 6), from non-cancerous tissue (max. 2) and from
additional suspected lesions when present (max. 2). In addition, cytology will
be obtained through FNA: from the tumor area (max. 3) and from (suspected)
lymph nodes (max. 2).

Time investment: Three extra visits to the UMCG on the day of tracer
administration which takes about two hours are needed for patients involved in
this study. The first fluorescent procedures are performed during the
diagnostic endoscopy before initiation of neoadjuvant treatment, which is part
of normal clinical practice. The second endoscopy will be planned 2-4 weeks
after neoadjuvant therapy, since this would be the optimal window to initiate
immunotherapy in the future. To minimize the time investment required to attend
the appointments associated with the study, when possible, said appointments
will be combined with regular hospital care visits.
Risks:
The intravenous injection and the use of a cannula are known to carry a small
risk of infection and hematoma. Theoretically, a possible SAE for injection of
durvalumab-680LT could be an allergic or anaphylactic reaction. Therefore,
anti-histamines, adrenalin and prednisone will always be present at the site of
the injection. However, this is considered a very low risk and was not seen in
previously injected patients. Although there is no clinical experience with
durvalumab-680LT in vivo, our research group has extensive clinical experience
with bevacizumab-800CW, cetuximab-800CW and vedoluzimab-800CW. We administered
these tracers in more than 250 patients. In addition, the toxicity of the
unlabeled antibodies is known. Since the durvalumab tracer will be administered
in the clinical trials at a microdose level of 4.5 mg, the risk of adverse
events is estimated as negligible. Furthermore, there is extensive clinical
experience with durvalumab since it has been used as a therapeutic agent for
several years.
The study procedures will prolong a standard endoscopy with
approximately 15 minutes, due to spectroscopy, fluorescence imaging and
biopsies. The risks of the investigational endoscopy procedures are comparable
to the minimal risks of a standard clinical endoscopy as the fibers used for
imaging can be inserted through the working channel of the HD-WL endoscope. The
superficial biopsies that will be taken pose a very small risk of bleeding
which often can be treated by the gastroenterologist. Performing FNA in
combination with SFR/SFF spectroscopy poses a remote chance of loss of
sterility of the SFR/SFF spectroscopy fiber and breaking of the fiber. To
prevent measurements be taken in a non-sterile environment or in case of
contamination, a new fiber will be attached to the system.

Benefit: Patients will not benefit from this study directly. Surgery will be
planned and performed according to standard clinical care. No decisions will be
made based on the fluorescence analysis. The benefit of this study will be the
establishment of usefulness of durvalumab-680LT during endoscopy.