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

NCT ID: NCT04554771

Last Updated: 2024-07-29

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-27
• Study Completion Date: 2028-04-10

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.

Detailed Description

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.

Conditions

Esophageal Adenocarcinoma; Oesophageal Adenocarcinoma; Resectable Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

ADAM12 high with tocilizumab and standard of care

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.

Group Type: EXPERIMENTAL

Tocilizumab 20 Mg/mL Intravenous Solution

Intervention Type: DRUG

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

Paclitaxel

Intervention Type: DRUG

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

Carboplatin

Intervention Type: DRUG

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

External beam radiotherapy

Intervention Type: 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

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.

Group Type: ACTIVE_COMPARATOR

Paclitaxel

Intervention Type: DRUG

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

Carboplatin

Intervention Type: DRUG

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

External beam radiotherapy

Intervention Type: 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 low with tocilizumab and standard of care

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.

Group Type: EXPERIMENTAL

Tocilizumab 20 Mg/mL Intravenous Solution

Intervention Type: DRUG

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

Paclitaxel

Intervention Type: DRUG

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

Carboplatin

Intervention Type: DRUG

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

External beam radiotherapy

Intervention Type: 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 low with standard of care

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.

Group Type: ACTIVE_COMPARATOR

Paclitaxel

Intervention Type: DRUG

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

Carboplatin

Intervention Type: DRUG

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

External beam radiotherapy

Intervention Type: 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

Interventions

Tocilizumab 20 Mg/mL Intravenous Solution

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

Intervention Type: DRUG

Paclitaxel

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

Intervention Type: DRUG

Carboplatin

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

Intervention Type: DRUG

External beam radiotherapy

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

Intervention Type: RADIATION

Other Intervention Names

RoActemra; L04AC07; L01CD01; L01XA02

Eligibility Criteria

Inclusion Criteria

• 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.
• Tumor length longitudinal ≤ 10 cm; if larger than 10 cm, inclusion should be discussed with the principal investigator.
• 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

Exclusion Criteria

• 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.
• Has an active infection requiring systemic therapy which has not resolved 3 days (simple infection such as cystitis) to 7 days (severe infection such as pyelonephritis) prior to the first dose of trial treatment.
• Has a total cholesterol > 6.5 mmol/L despite adequate treatment with lipid-lowering agents.
• Has evidence of (latent) tuberculosis infection in patient history.
• Receiving a live or live weakened vaccine during treatment with tocilizumab
• Has evidence of acute or chronic infection with hepatitis B
• Patients with prior allogeneic stem cell or solid organ transplantation.
• Pre-existing motor or sensory neurotoxicity greater than World Health Organization (WHO) grade 1.
• Known allergy for tocilizumab or one of its excipients (sucrose, polysorbate 80, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dehydrate)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Noordwest Ziekenhuisgroep

OTHER

Sponsor Role: collaborator

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

OTHER

Sponsor Role: lead

Responsible Party

Hanneke W. M. van Laarhoven

prof. dr. H.W.M. van Laarhoven

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hanneke WM van Laarhoven, MD, PhD, PhD

Role: PRINCIPAL_INVESTIGATOR

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

Locations

Academic Medical Center, Medical Oncology

Amsterdam, , Netherlands

Countries

Netherlands

Other Identifiers

2020-002909-25

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL74310.018.20

Identifier Type: -

Identifier Source: org_study_id