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Neoadjuvant CCRT With/Without Bevacizumab for Locally Advanced ESCC

Primary Purpose

Stage III Esophageal Squamous Cell Carcinoma

Status

Unknown status

Phase

Phase 2

Locations

Taiwan

Study Type

Interventional

Intervention

BPF-CCRT (run-in)

BPF-CCRT (randomized)

PF-CCRT (randomized)

About this trial

This is an interventional treatment trial for Stage III Esophageal Squamous Cell Carcinoma focused on measuring Concurrent chemoradiation, Esophageal squamous cell carcinoma, Vascular endothelial growth factor

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria

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

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:
1. T1-2 N2-3 M0
2. 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:
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
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)
Adequate renal function within 2 weeks prior to registration: Creatinine ≤1.5 mg/dL
International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN within 2 weeks prior to registration
Women of childbearing potential and male participants must practice adequate contraception
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

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:
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
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)
Prior history of hypertensive crisis or blood pressure at baseline > 150/100 mmHg
Hepatic insufficiency resulting in coagulation defects
History of a non-healing wound, ulcer, or bone fracture within 90 days (3 months) prior to registration
Any hemorrhage/bleeding event CTCAE, ver. 4 grade 3 or greater within 30 days prior to registration
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.
Major surgical procedure or significant traumatic injury within 28 days prior to registration (with the exception of jejunostomy or port-A insertion)
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

Sites / Locations

National Taiwan University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

BPF-CCRT (Run-in Phase)

BPF-CCRT (Randomized Phase)

PF-CCRT (Randomized Phase)

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

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.

Secondary Outcome Measures

Acute toxicity

Common Toxicity Criteria for Adverse Events version 4

Late toxicity

Common Toxicity Criteria for Adverse Events version 4

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

EORTC Quality of Life-Core 30 questionnaire module

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

EORTC Quality of Life-Oesophagus(OES) 18 questionnaire module

Image response

Response Evaluation Criteria In Solid Tumors version 1.1

Metabolic Image response

Positron Emission Tomography Response Criteria in Solid Tumors version 1.0

Progression-free survival

Number of participant with disease progression

Overall survival

Number of participant alive

Full Information

NCT ID

NCT02812641

First Posted

June 13, 2016

Last Updated

March 7, 2019

Sponsor

National Taiwan University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02812641

Brief Title

Neoadjuvant CCRT With/Without Bevacizumab for Locally Advanced ESCC

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Unknown status

Study Start Date

June 2016 (undefined)

Primary Completion Date

December 2019 (Anticipated)

Study Completion Date

December 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Taiwan University Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Stage III Esophageal Squamous Cell Carcinoma

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

BPF-CCRT (Run-in Phase)

Arm Type

Experimental

Arm Description

Arm Title

BPF-CCRT (Randomized Phase)

Arm Type

Experimental

Arm Description

Arm Title

PF-CCRT (Randomized Phase)

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

BPF-CCRT (run-in)

Other Intervention Name(s)

Bevacizumab, Cisplatin, 5-Fluorouracil, Radiation

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

BPF-CCRT (randomized)

Other Intervention Name(s)

Bevacizumab, Cisplatin, 5-Fluorouracil, Radiation

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

PF-CCRT (randomized)

Other Intervention Name(s)

Cisplatin, 5-Fluorouracil, Radiation

Intervention Description

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

Primary Outcome Measure Information:

Title

Dose-limiting toxicity (run-in phase)

Description

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

Time Frame

30 days after radical esophagectomy

Title

Pathological complete response rate (randomized phase)

Description

Time Frame

8 weeks

Secondary Outcome Measure Information:

Title

Acute toxicity

Description

Common Toxicity Criteria for Adverse Events version 4

Time Frame

From date of CCRT until 90 days after CCRT starts

Title

Late toxicity

Description

Common Toxicity Criteria for Adverse Events version 4

Time Frame

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

Title

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

Description

EORTC Quality of Life-Core 30 questionnaire module

Time Frame

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

Title

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

Description

EORTC Quality of Life-Oesophagus(OES) 18 questionnaire module

Time Frame

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

Title

Image response

Description

Response Evaluation Criteria In Solid Tumors version 1.1

Time Frame

at baseline and before surgery (8 weeks)

Title

Metabolic Image response

Description

Positron Emission Tomography Response Criteria in Solid Tumors version 1.0

Time Frame

at baseline and before surgery (8 weeks)

Title

Progression-free survival

Description

Number of participant with disease progression

Time Frame

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

Title

Overall survival

Description

Number of participant alive

Time Frame

From date of enrollment until the date of death from any cause, assessed up to 60 months

Other Pre-specified Outcome Measures:

Title

Serum biomarker (VEGF-A)

Description

Serum VEGF-A concentration measured by ELISA

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria To be eligible for inclusion, patients must fulfill the following criteria: 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 International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN within 2 weeks prior to registration Women of childbearing potential and male participants must practice adequate contraception 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 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) Prior history of hypertensive crisis or blood pressure at baseline > 150/100 mmHg Hepatic insufficiency resulting in coagulation defects History of a non-healing wound, ulcer, or bone fracture within 90 days (3 months) prior to registration Any hemorrhage/bleeding event CTCAE, ver. 4 grade 3 or greater within 30 days prior to registration 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. Major surgical procedure or significant traumatic injury within 28 days prior to registration (with the exception of jejunostomy or port-A insertion) 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Feng-Ming Hsu

Phone

+886-2-23123456

Ext

67061

hsufengming@ntuh.gov.tw

First Name & Middle Initial & Last Name or Official Title & Degree

Jason Chia-Hsien Cheng

Phone

+886-2-23123456

Ext

66696

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jason Chia-Hsien Cheng

Organizational Affiliation

National Taiwan University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Taiwan University Hospital

City

Taipei

ZIP/Postal Code

100

Country

Taiwan

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jason Chia-Hsien Cheng

Phone

+886-2-23123456

Ext

66696

jasoncheng@ntu.edu.tw

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Neoadjuvant CCRT With/Without Bevacizumab for Locally Advanced ESCC

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