Neoadjuvant CCRT With/Without Bevacizumab for Locally Advanced ESCC

NCT02812641 | Unknown Phase 2 DMC

• 1 other identifier: 201511008MINC
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Esophageal squamous cell carcinoma (ESCC) is one of the ten leading cancers in Taiwanese male. The prognosis is poor with a five-year overall survival rate of 10 to 30 %. Randomized clinical trials have demonstrated that trimodality therapy (TMT), consisted of neoadjuvant concurrent chemoradiation (CCRT) and radical esophagectomy, improves the overall survival for patients with locally advanced disease. Despite of the advancement, the outcome remained unsatisfactory with the median progression-free survival around 20 to 25 months and median overall survival around 30 months. It is know that the most important prognostic factor is whether a pathological complete response can be achieved after neoadjuvant CCRT. However, the use of new generation chemotherapeutic agent taxanes and epidermal growth factor inhibitors (such as Cetuximab) failed to significantly improve prognosis comparing to the standard platinum-fluorouracil (PF) regimen. As a consequence, it is mandatory to develop new chemotherapeutic regimen for CCRT. In previous prospective studies, investigators used proximal ligation assay technology to identify serum VEGF-A in correlation with the pathological response and prognosis for patients receiving neoadjuvant CCRT plus radical esophagectomy for locally advanced ESCC. Other investigators also showed high VEGF expression correlating to poor outcome. Therefore, investigators generate the hypothesis that adding vascular endothelial growth factor (VEGF) monoclonal antibody, Bevacizumab, to standard neoadjuvant CCRT may improve outcome for patients with ESCC. Meanwhile, several prospective clinical studies have shown the feasibility, safety, and activity of adding Bevacizumab to chemotherapy, CCRT, or combined modality therapy including surgery, either in head and neck cancer, esophageal cancer, or esophagogastric junction adenocarcinoma. However, its efficacy should be further investigated in larger prospective trials and little is known about the activity and toxicity of Bevacizumab in ESCC due to small number of reported cases. In the present clinical trial, investigators plan to investigate whether incorporation of Bevacizumab into standard neoadjuvant PF-CCRT will improve treatment response and increase pathological complete response rate. Investigators will also evaluate associated biomarkers in relation to prognosis. By the present research, investigators expect to develop a new TMT regimen for this poor prognostic disease.

Conditions

Stage III Esophageal Squamous Cell Carcinoma

Keywords

Concurrent chemoradiation; Esophageal squamous cell carcinoma; Vascular endothelial growth factor

Outcome Measures

Primary Outcomes (2)

• Dose-limiting toxicity (run-in phase)

  Number of participant in the run-in phase with life-threatening adverse event or death, which is probable or definitely associated with bevacizumab

  30 days after radical esophagectomy

• Pathological complete response rate (randomized phase)

  Number of participant achieved pathological complete response, which is defined as complete surgical resection of all gross tumours without residual microscopic invasive carcinoma at primary tumor location and dissected lymph nodes.

  8 weeks

Secondary Outcomes (8)

• Acute toxicity

  From date of CCRT until 90 days after CCRT starts

• Late toxicity

  From 90 days after CCRT starts until the date of death from any cause, up to 60 months

• Patient reported outcome (Quality of Life questionnaire of cancer patients)

  At baseline, 2, 4 weeks after CCRT, before surgery, 1 month after surgery, and every 3 month thereafter until unequivocal progression, hospice care, or death, assessed up to 24 months

• Patient reported outcome (Quality of Life questionnaire of esophageal cancer patients)

  At baseline, 2, 4 weeks after CCRT, before surgery, 1 month after surgery, and every 3 month thereafter until unequivocal progression, hospice care, or death, assessed up to 24 months

• Image response

  at baseline and before surgery (8 weeks)

Other Outcomes (1)

• Serum biomarker (VEGF-A)

  At baseline, after CCRT, before and after surgery, and documented disease progression, assessed up to 100 months

Study Arms (3)

BPF-CCRT (Run-in Phase)

EXPERIMENTAL

Neoadjuvant CCRT with Bevacizumab, Cisplatin and 5-fluorouracil Chemotherapy: Bevacizumab(B): 10 mg/kg on day 1 Cisplatin(P): 75 mg/m2 on day 1 5-fluorouracil(F): 24 hours continuous infusion of 1,000 mg/m2 on days 1-4 Radiotherapy: 40 Gy/20 fractions: days 1-5, weeks 1-4

Drug: BPF-CCRT (run-in)

BPF-CCRT (Randomized Phase)

EXPERIMENTAL

Neoadjuvant CCRT with Bevacizumab, Cisplatin and 5-fluorouracil Chemotherapy: Bevacizumab(B): 10 mg/kg on day 1 Cisplatin(P): 75 mg/m2 on day 1 5-fluorouracil(F): 24 hours continuous infusion of 1,000 mg/m2 on days 1-4 Radiotherapy: 40 Gy/20 fractions: days 1-5, weeks 1-4

Drug: BPF-CCRT (randomized)

PF-CCRT (Randomized Phase)

ACTIVE COMPARATOR

Neoadjuvant CCRT with Cisplatin and 5-fluorouracil Chemotherapy: Cisplatin(P): 75 mg/m2 on day 1 5-fluorouracil(F): 24 hours continuous infusion of 1,000 mg/m2 on days 1-4 Radiotherapy: 40 Gy/20 fractions: days 1-5, weeks 1-4

Drug: PF-CCRT (randomized)

Interventions

BPF-CCRT (run-in) DRUG

Six patients will be enrolled in run-in phase. If \<= 1 patient developed dose-limiting toxicity, the trial will be continued to randomized phase. If \> 1 patients developed dose-limiting toxicities, the protocol will be discontinued.

Also known as: Bevacizumab, Cisplatin, 5-Fluorouracil, Radiation

BPF-CCRT (Run-in Phase)

BPF-CCRT (randomized) DRUG

Twenty-two patients will be planned to assign to the experimental arm

Also known as: Bevacizumab, Cisplatin, 5-Fluorouracil, Radiation

BPF-CCRT (Randomized Phase)

PF-CCRT (randomized) DRUG

Twenty-two patients will be planned to assign to the active control arm

Also known as: Cisplatin, 5-Fluorouracil, Radiation

PF-CCRT (Randomized Phase)

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proved squamous cell carcinoma of esophagus
• Locoregional advanced stage III disease, which are defined by Tumor, Nodes, Metastases (TNM) system of American Joint Committee on Cancer (AJCC) Cancer Staging System (7th edition) in 2010, fulfilling one of the following criteria:
• T1-2 N2-3 M0
• T3 N1-3 M0
• Medical fit for curative surgery
• Age ≥ 20 years
• Karnofsky Performance Status ≥ 60%
• Adequate bone marrow reserves within 2 weeks prior to registration, defined as:
• white blood cells (WBC) ≥ 4,000/µl or neutrophil count (ANC) ≥ 2,000/µl
• platelets ≥ 100,000/µl
• hemoglobin ≥ 9.0 g/dl
• Adequate liver function reserves within 2 weeks prior to registration, defined as:
• hepatic transaminases ≤ 2.5 x upper limit of normal (ULN)
• serum total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Adequate renal function within 2 weeks prior to registration: Creatinine ≤1.5 mg/dL

You may not qualify if:

• Prior radiotherapy to head and neck, chest, or abdomen
• Tumor invasion to adjacent structures (T4 lesion)
• Presence of distant metastasis
• Adenocarcinoma of gastroesophageal junction.
• Synchronously or metachronously diagnosed squamous cell carcinoma of aerodigestive way, other than oesophageal cancer
• Prior invasive malignancy
• Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows:
• Uncontrolled active infection requiring intravenous antibiotics at the time of registration
• Transmural myocardial infarction ≤ 6 months prior to registration
• Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
• Life-threatening uncontrolled clinically significant cardiac arrhythmias
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
• Uncontrolled psychiatric disorder
• On full-dose anticoagulants (e.g., Warfarin or low molecular weight heparin) or medications known to inhibit platelet function (e.g. aspirin, dipyramidole, ticlopidine, clopidogrel, cilostazol, or NSAIDs)

Sponsors & Collaborators

• National Taiwan University Hospital: lead

Study Sites (1)

National Taiwan University Hospital

Taipei, 100, Taiwan

RECRUITING

MeSH Terms

Conditions

Esophageal Squamous Cell Carcinoma

Interventions

Bevacizumab; Cisplatin; Fluorouracil; Radiation; Random Allocation

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Esophageal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Physical Phenomena; Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Jason Chia-Hsien Cheng

  National Taiwan University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Feng-Ming Hsu

CONTACT

+886-2-23123456; hsufengming@ntuh.gov.tw

Jason Chia-Hsien Cheng

CONTACT

+886-2-23123456

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2016
• First Posted: June 24, 2016
• Study Start: June 1, 2016
• Primary Completion: December 1, 2019
• Study Completion: December 1, 2021
• Last Updated: March 11, 2019

Record last verified: 2019-03

Data Sharing

• IPD Sharing: Will not share

Locations

TW (1)