Blood-borne Assessment of Stromal Activation in Esophageal Adenocarcinoma to Guide Tocilizumab Therapy

NCT04554771 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: NL74310.018.202020-002909-25
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Esophageal Adenocarcinoma; Oesophageal Adenocarcinoma; Resectable Carcinoma

Keywords

Resectable; Esophageal adenocarcinoma; Neoadjuvant chemoradiation; Tocilizumab; Stroma activation

Outcome Measures

Primary Outcomes (1)

• 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

  34 months

Secondary Outcomes (12)

• R0 resection rate

  34 months

• Progression free survival

  34 months

• Overall survival

  34 months

• Interleukin 6- Signal Transducer and Activator of Transcription 3 (IL6-STAT3) pathway inhibition measured by gene expression analysis

  36 months

• IL6-STAT3 pathway inhibition measured by immunohistochemistry

  36 months

Other Outcomes (1)

• Predictive biomarkers using oa RNA sequencing

  54 months

Study Arms (4)

ADAM12 high with tocilizumab and standard of care

EXPERIMENTAL

Patients have serum ADAM12 higher than 203ng/mL. Patients will receive tocilizumab 8 mg/kg with a maximum of 800 mg intravenously on day 1, 15 and 29 in addition to paclitaxel 50mg/m2 and carboplatin AUC 2 intravenously on day 1, 8, 15, 22 and 29. External beam radiation of 41.4 Gy will be given in 23 fractions. Surgery will be planned approximately in week 13-15, which is 8 to 10 weeks after the end of chemoradiation.

Drug: Tocilizumab 20 Mg/mL Intravenous Solution; Drug: Paclitaxel; Drug: Carboplatin; Radiation: External beam radiotherapy

ADAM12 high with standard of care

ACTIVE COMPARATOR

Patients have serum ADAM12 higher than 203ng/mL. Patients will receive paclitaxel 50mg/m2 and carboplatin AUC 2 intravenously on day 1, 8, 15, 22 and 29. External beam radiation of 41.4 Gy will be given in 23 fractions. Surgery will be planned approximately in week 13-15, which is 8 to 10 weeks after the end of chemoradiation.

Drug: Paclitaxel; Drug: Carboplatin; Radiation: External beam radiotherapy

ADAM12 low with tocilizumab and standard of care

EXPERIMENTAL

Patients have serum ADAM12 lower than 203ng/mL. Patients will receive tocilizumab 8 mg/kg with a maximum of 800 mg intravenously on day 1, 15 and 29 in addition to paclitaxel 50mg/m2 and carboplatin AUC 2 intravenously on day 1, 8, 15, 22 and 29. External beam radiation of 41.4 Gy will be given in 23 fractions. Surgery will be planned approximately in week 13-15, which is 8 to 10 weeks after the end of chemoradiation.

Drug: Tocilizumab 20 Mg/mL Intravenous Solution; Drug: Paclitaxel; Drug: Carboplatin; Radiation: External beam radiotherapy

ADAM12 low with standard of care

ACTIVE COMPARATOR

Patients have serum ADAM12 lower than 203ng/mL. Patients will receive paclitaxel 50mg/m2 and carboplatin AUC 2 intravenously on day 1, 8, 15, 22 and 29. External beam radiation of 41.4 Gy will be given in 23 fractions. Surgery will be planned approximately in week 13-15, which is 8 to 10 weeks after the end of chemoradiation.

Drug: Paclitaxel; Drug: Carboplatin; Radiation: External beam radiotherapy

Interventions

Tocilizumab 20 Mg/mL Intravenous Solution DRUG

tocilizumab 8 mg/kg with a maximum of 800 mg intravenously on day 1, 15 and 29 of standard of care neoadjuvant chemoradiation

Also known as: RoActemra, L04AC07

ADAM12 high with tocilizumab and standard of care; ADAM12 low with tocilizumab and standard of care

Paclitaxel DRUG

Paclitaxel 50 mg/m2 will be given intravenously on days 1, 8, 15, 22 and 29

Also known as: L01CD01

ADAM12 high with standard of care; ADAM12 high with tocilizumab and standard of care; ADAM12 low with standard of care; ADAM12 low with tocilizumab and standard of care

Carboplatin DRUG

Carboplatin AUC = 2 will be given intravenously on days 1, 8, 15, 22 and 29

Also known as: L01XA02

ADAM12 high with standard of care; ADAM12 high with tocilizumab and standard of care; ADAM12 low with standard of care; ADAM12 low with tocilizumab and standard of care

External beam radiotherapy RADIATION

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

ADAM12 high with standard of care; ADAM12 high with tocilizumab and standard of care; ADAM12 low with standard of care; ADAM12 low with tocilizumab and standard of care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proven adenocarcinoma of the esophagus or gastroesophageal junction.
• Surgical resectable (\<T4b, N0 or N+, M0), as determined by Endoscopic UltraSound (EUS) and/or CT scan of neck, thorax and abdomen. Tumors that cannot be passed with an endoscope for endoscopic ultrasound are eligible if all other criteria are fulfilled.
• T1N+ tumors are eligible.
• If the tumor extends below the gastroesophageal (GE) junction into the proximal stomach, the bulk of the tumor must involve the esophagus or GE junction.
• Age ≥ 18.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate hematological, renal and hepatic functions defined as:
• neutrophiles ≥ 1.5 x 109/L
• platelets ≥ 100 x 109/L
• hemoglobin ≥ 5.6 mmol
• total bilirubin ≤ 1.5 x upper normal limit
• creatinine clearance (Cockroft) \> 60 ml/min
• Written, voluntary informed consent
• Patients must be accessible to follow up and management in the treatment center

You may not qualify if:

• Past (within 5 years) or current history of malignancy other than entry diagnosis interfering with prognosis of esophageal cancer, not including superficial and adequately treated skin and cervical malignancies.
• Previous chemotherapy, radiotherapy and/or treatment with Interleukin-6 (IL6) receptor blockers for esophageal cancer
• Previous radiation to the mediastinum precluding full dose radiation of the currently present esophageal tumor.
• Previous chemotherapy and/or treatment with targeted agents and/or IL6 receptor blockers for other forms of cancer within the last six months.
• Invasion of the tracheobronchial tree or presence of tracheoesophageal fistula.
• T1N0 tumors or in situ carcinoma.
• Pregnancy (positive serum pregnancy test), planning to become pregnant, and lactation.
• Patient (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment.
• Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) precluding major surgery.
• Pulmonary fibrosis and/or severely impaired lung function precluding major surgery.
• Serious underlying medical condition which would impair the ability of the patient to receive the planned treatment, including prior allergic reactions to drugs containing Cremophor, such as teniposide or cyclosporine.
• Dementia or altered mental status that would prohibit the understanding and giving of informed consent
• Inadequate caloric- and/or fluid intake despite consultation of a dietician and/or tube feeding.
• Requires systemic treatment with IL6 receptor blockers or IL-6 antagonists, Tumor Necrosis Factor (TNF)-alpha blockers or other biologicals within the last six months before the first dose of trial treatment.
• Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• Noordwest Ziekenhuisgroep: collaborator

Study Sites (1)

Academic Medical Center, Medical Oncology

Amsterdam, 1100 DD, Netherlands

Location

MeSH Terms

Conditions

Adenocarcinoma Of Esophagus

Interventions

tocilizumab; Paclitaxel; Carboplatin

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes

Study Officials

• Hanneke WM van Laarhoven, MD, PhD, PhD

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: prof. dr. H.W.M. van Laarhoven

Model Details: 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 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 Record Dates

• First Submitted: August 18, 2020
• First Posted: September 18, 2020
• Study Start: January 27, 2021
• Primary Completion: October 10, 2022
• Study Completion (Estimated): April 10, 2028
• Last Updated: July 29, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)