Blood-borne Assessment of Stromal Activation in Esophageal Adenocarcinoma to Guide Tocilizumab Therapy: a Randomized Phase II Proof-of-concept Study
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 41
- 试验地点
- 1
- 主要终点
- Efficacy defined as pathological response to chemoradiotherapy according to the Mandard criteria
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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
排除标准
- •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
- •Known allergy for tocilizumab or one of its excipients (sucrose, polysorbate 80, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dehydrate)
研究组 & 干预措施
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.
干预措施: Tocilizumab 20 Mg/mL Intravenous Solution (Drug)
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.
干预措施: Paclitaxel (Drug)
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.
干预措施: Carboplatin (Drug)
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.
干预措施: External beam radiotherapy (Radiation)
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.
干预措施: Paclitaxel (Drug)
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.
干预措施: Carboplatin (Drug)
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.
干预措施: External beam radiotherapy (Radiation)
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.
干预措施: Tocilizumab 20 Mg/mL Intravenous Solution (Drug)
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.
干预措施: Paclitaxel (Drug)
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.
干预措施: Carboplatin (Drug)
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.
干预措施: External beam radiotherapy (Radiation)
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.
干预措施: Paclitaxel (Drug)
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.
干预措施: Carboplatin (Drug)
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.
干预措施: External beam radiotherapy (Radiation)
结局指标
主要结局
Efficacy defined as pathological response to chemoradiotherapy according to the Mandard criteria
时间窗: 34 months
The primary outcome is efficacy of tocilizumab in patients with high and low stroma activation defined as pathological response according to the Mandard criteria
次要结局
- IL6-STAT3 pathway inhibition measured by immunohistochemistry(36 months)
- Incidence and severity of post-operative complications(36 months)
- Incidence and severity of radiation toxicity(34 months)
- Feasibility completion(34 months)
- R0 resection rate(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)
- Levels of ADAM12 in tumor biopsies and serum(36 months)
- Feasibility delay(36 months)
- Progression free survival(34 months)
- Incidence and severity of toxicity(34 months)
- Feasibility withdrawal rate(34 months)
研究者
Hanneke W. M. van Laarhoven
prof. dr. H.W.M. van Laarhoven
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)