The primary objective of this study is to demonstrate that stroma-targeting by tocilizumab in patients with adenocarcinoma of the esophagus or gastroesophageal junction 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.
Randomized phase II proof-of-concept study with tocilizumab and standard of care paclitaxel, carboplatin and radiation 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 8mg/kg on day 1, 15 and 29 or not in addition to paclitaxel 50mg/m2, carboplatin dosed with area under the curve (AUC) 2 on day 1, 8, 15, 22 and 29 and radiation 41.4 Gy in 23 fractions. Surgery will be planned approximately in week 13-15, which is 8 to 10 weeks after the end of chemoradiation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
41
tocilizumab 8 mg/kg with a maximum of 800 mg intravenously on day 1, 15 and 29 of standard of care neoadjuvant chemoradiation
Paclitaxel 50 mg/m2 will be given intravenously on days 1, 8, 15, 22 and 29
Carboplatin AUC = 2 will be given intravenously on days 1, 8, 15, 22 and 29
External beam radiotherapy will be delivered to a total dose of 41.4 Gy in 23 fractions of 1.8 Gy, 5 fractions per week starting the first day of the first cycle of chemotherapy
Academic Medical Center, Medical Oncology
Amsterdam, Netherlands
Efficacy defined as pathological response to chemoradiotherapy according to the Mandard criteria
The primary outcome is efficacy of tocilizumab in patients with high and low stroma activation defined as pathological response according to the Mandard criteria
Time frame: 34 months
R0 resection rate
Percentage of R0 resection at surgery
Time frame: 34 months
Progression free survival
Average time to progression of disease
Time frame: 34 months
Overall survival
average time to date of death
Time frame: 34 months
Interleukin 6- Signal Transducer and Activator of Transcription 3 (IL6-STAT3) pathway inhibition measured by gene expression analysis
Analysis of gene expression to measure level of inhibition of IL6-STAT3 pathway
Time frame: 36 months
IL6-STAT3 pathway inhibition measured by immunohistochemistry
Phosphorylated STAT3 and stromal abundance measured by immunohistochemistry in formalin-fixed paraffin-embedded tumor tissue
Time frame: 36 months
Levels of ADAM12 in tumor biopsies and serum
average levels of ADAM12 in tumor biopsies and serum
Time frame: 36 months
Incidence and severity of toxicity
Incidence of treatment-emergent adverse events according to CTCAE v5.0
Time frame: 34 months
Incidence and severity of radiation toxicity
Incidence of treatment-emergent adverse events according to Radiation Oncology Group (RTOG) criteria
Time frame: 34 months
Incidence and severity of post-operative complications
Incidence and severity of post-operative complications according to the Clavien - Dindo classification
Time frame: 36 months
Feasibility completion
Percentage completion of chemotherapy and radiation treatment
Time frame: 34 months
Feasibility withdrawal rate
Percentage withdrawal rate from surgery due to tocilizumab related complications
Time frame: 34 months
Feasibility delay
Percentage delay of surgery due to tocilizumab related complications
Time frame: 36 months
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