Blood-borne assessment of stromal activation in esophageal
adenocarcinoma to guide tocilizumab therapy: a randomized
phase II proof-of-concept study

Esophageal cancer continues to have a poor prognosis despite intensive
treatment regimes of chemoradiation and resection. The tumor stroma has
increasingly been found to harbor tumor-promoting properties. Recently, serum
ADAM12 has been found as a marker for active stroma. In a recent preclinical
study, active stroma was found to confer resistance to chemoradiation in
esophageal adenocarcinoma via IL-6 production. Therefore, stroma-derived IL-6
provides an interesting new target for improvement of treatment. Tocilizumab is
a IL6R inhibitor used in rheumatoid artritis and cytokine-release syndrome. We
aim to combat stromal induced therapy resistance in a personalized way by using
ADAM12 as a marker for stromal activation.

This study has been transitioned to CTIS with ID 2023-509458-77-00 check the CTIS register for the current data.

The primary objective of the study of this study is to demonstrate that
stroma-targeting by tocilizumab in esophageal adenocarcinoma patients with
highly activated stroma increases efficacy of chemoradiotherapy measured by
pathological response according to the Mandard criteria. Patients will be
grouped for ADAM12, a non-invasive blood-borne marker of stromal activation.

This is a randomized proof-of-concept study with tocilizumab (T) and standard
of care paclitaxel (P), carboplatin (C) and radiation (RT) followed by surgical
resection of the oesophagus for patients with surgically resectable
adenocarcinomas of the oesophagus or oesophageal junction.
Patients will be grouped for serum ADAM12 with a cutoff of 203 ng/mL. Patients
in both groups will be randomized to receive tocilizumab or not in addition to
paclitaxel, carboplatin and radiation. Surgery will be planned approximately in
week 13-15, which is 8 to 10 weeks after the end of chemoradiation.

Tocilizumab will be given intravenously at a dose of 8 mg/kg with a maximum of
800 mg per gift. Patients will receive an infusion every 2 weeks for 3 cycles
during administration of chemotherapy. After 8-10 weeks in week 13-15 a
resection will take place.

Administration of tocilizumab costs 1,5 h extra for 3 outpatient clinic visits.
Patients have to hand in faeces 3 times and register their food intake for 3
days beforehand.
A venapuncture and applying an iv can be painful and cause a subcutaneous
hemorrhage. Taking blood samples for BASALT will be combined with regular blood
withdrawal.
The extra endoscopy can in rare cases cause bleeding, aspiration pneumonia or a
perforation.
Tocilizumab can also cause side effects. Allergic reactions during or after
infusion can occur

Very common (incidence > 10%)
• upper respiratory tract infections with typical symptoms such as cough,
blocked nose, runny nose, sore throat and headache • high blood fat
(cholesterol) levels.

Common (incidence 1-10 %)
• lung infection (pneumonia) • shingles (herpes zoster) • cold sores (oral
herpes simplex), blisters • skin infection (cellulitis) sometimes with fever
and chills • rash and itching, hives • allergic (hypersensitivity) reactions •
eye infection (conjunctivitis) • headache, dizziness, high blood pressure •
mouth ulcers, stomach pain • fluid retention (oedema) in the lower legs, weight
increase • cough, shortness of breath • low white blood cell counts shown by
blood tests (neutropenia, leucopenia) • abnormal liver function tests
(increased transaminases) • increased bilirubin shown by blood tests • low
fibrinogen levels in the blood (a protein involved in blood clotting).

Uncommon (< 1%)
• diverticulitis (fever, nausea, diarrhoea, constipation, stomach pain) • red
swollen areas in the mouth • high blood fat (triglycerides) • stomach ulcer •
kidney stones • underactive thyroid.

Although not expected based on literature side effects due to the combination
of tocilizumab and chemoradiotherapy can also occur.