Neoadjuvant CCRT With/Without Bevacizumab for Locally Advanced ESCC

A Randomized Trial of Adding Bevacizumab to Neoadjuvant Platinum-Fluorouracil Concurrent Chemoradiation in Locally Advanced Esophageal Squamous Cell Carcinoma

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.

Study Overview

• Status: Unknown
• Conditions: Stage III Esophageal Squamous Cell Carcinoma
• Intervention / Treatment: Drug: BPF-CCRT (run-in); Drug: BPF-CCRT (randomized); Drug: PF-CCRT (randomized)

Detailed Description

This study is a randomized trial to compare the outcomes between patients receiving neoadjuvant PF-CCRT plus Bevacizumab (BPF-CCRT) or PF-CCRT alone. Investigators design to enrol 6 patients in the run-in phase, and 44 patients in the randomized phase (22 patients in each group) to develop the preliminary evidence for using Bevacizumab in ESCC.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 100
    • Recruiting
    • National Taiwan University Hospital
    • Contact: Jason Chia-Hsien Cheng; Phone Number: 66696 +886-2-23123456; Email: jasoncheng@ntu.edu.tw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

To be eligible for inclusion, patients must fulfill the following criteria:

1. Histologically proved squamous cell carcinoma of esophagus

2. 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:

   1. T1-2 N2-3 M0
   2. T3 N1-3 M0
3. Medical fit for curative surgery
4. Age ≥ 20 years
5. Karnofsky Performance Status ≥ 60%

6. Adequate bone marrow reserves within 2 weeks prior to registration, defined as:

   1. white blood cells (WBC) ≥ 4,000/µl or neutrophil count (ANC) ≥ 2,000/µl
   2. platelets ≥ 100,000/µl
   3. hemoglobin ≥ 9.0 g/dl

7. Adequate liver function reserves within 2 weeks prior to registration, defined as:

   1. hepatic transaminases ≤ 2.5 x upper limit of normal (ULN)
   2. serum total bilirubin ≤ 1.5 x upper limit of normal (ULN)
8. Adequate renal function within 2 weeks prior to registration: Creatinine ≤1.5 mg/dL
9. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN within 2 weeks prior to registration
10. Women of childbearing potential and male participants must practice adequate contraception
11. Patients must be able to comply with the study protocol and follow-up schedules and provide study-specific informed consent

Exclusion criteria Patients fulfill any of the following criteria will be excluded from this trial

1. Prior radiotherapy to head and neck, chest, or abdomen
2. Tumor invasion to adjacent structures (T4 lesion)
3. Presence of distant metastasis
4. Adenocarcinoma of gastroesophageal junction.
5. Synchronously or metachronously diagnosed squamous cell carcinoma of aerodigestive way, other than oesophageal cancer
6. Prior invasive malignancy

7. 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:

   1. Uncontrolled active infection requiring intravenous antibiotics at the time of registration
   2. Transmural myocardial infarction ≤ 6 months prior to registration
   3. Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
   4. Life-threatening uncontrolled clinically significant cardiac arrhythmias
   5. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
   6. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
   7. Uncontrolled psychiatric disorder
8. 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)
9. Prior history of hypertensive crisis or blood pressure at baseline > 150/100 mmHg
10. Hepatic insufficiency resulting in coagulation defects
11. History of a non-healing wound, ulcer, or bone fracture within 90 days (3 months) prior to registration
12. Any hemorrhage/bleeding event CTCAE, ver. 4 grade 3 or greater within 30 days prior to registration
13. Gross hemoptysis or hematemesis (defined as bright red blood of 1 teaspoon or more or frank clots within minimal or no phlegm per coughing episode) within 4 weeks prior to registration; patients with incidental blood mixed with phlegm are not excluded.
14. Major surgical procedure or significant traumatic injury within 28 days prior to registration (with the exception of jejunostomy or port-A insertion)
15. Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BPF-CCRT (Run-in Phase); 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); 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.; Other Names: Radiation; Cisplatin; Bevacizumab; 5-Fluorouracil
EXPERIMENTAL: BPF-CCRT (Randomized Phase); 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); Twenty-two patients will be planned to assign to the experimental arm; Other Names: Radiation; Cisplatin; Bevacizumab; 5-Fluorouracil
ACTIVE_COMPARATOR: PF-CCRT (Randomized Phase); 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); Twenty-two patients will be planned to assign to the active control arm; Other Names: Radiation; Cisplatin; 5-Fluorouracil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute toxicity	Common Toxicity Criteria for Adverse Events version 4	From date of CCRT until 90 days after CCRT starts
Late toxicity	Common Toxicity Criteria for Adverse Events version 4	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)	EORTC Quality of Life-Core 30 questionnaire module	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)	EORTC Quality of Life-Oesophagus(OES) 18 questionnaire module	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	Response Evaluation Criteria In Solid Tumors version 1.1	at baseline and before surgery (8 weeks)
Metabolic Image response	Positron Emission Tomography Response Criteria in Solid Tumors version 1.0	at baseline and before surgery (8 weeks)
Progression-free survival	Number of participant with disease progression	From date of enrolment until the date of first documented disease progression or date of death from any cause, whichever came first, assessed up to 60 months
Overall survival	Number of participant alive	From date of enrollment until the date of death from any cause, assessed up to 60 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum biomarker (VEGF-A)	Serum VEGF-A concentration measured by ELISA	At baseline, after CCRT, before and after surgery, and documented disease progression, assessed up to 100 months

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Jason Chia-Hsien Cheng, National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (ANTICIPATED): December 1, 2019
• Study Completion (ANTICIPATED): December 1, 2021

Study Registration Dates

• First Submitted: June 13, 2016
• First Submitted That Met QC Criteria: June 21, 2016
• First Posted (ESTIMATE): June 24, 2016

Study Record Updates

• Last Update Posted (ACTUAL): March 11, 2019
• Last Update Submitted That Met QC Criteria: March 7, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Vascular endothelial growth factor; Esophageal squamous cell carcinoma; Concurrent chemoradiation
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Esophageal Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Cisplatin; Fluorouracil; Bevacizumab
• Other Study ID Numbers: 201511008MINC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO