Simultaneous Integrated Boost Radiotherapy and Concurrent Nimotuzumab or Chemotherapy for Esophageal Carcinoma

Prospective, Non-randomised Phase Ⅱ Study of Simultaneous Integrated Boost Radiotherapy and Concurrent Nimotuzumab or Chemotherapy for Locally Advanced Esophageal Carcinoma

This prospective, non-randomized phase II study aims to compare radiotherapy and concurrent nimotuzumab with concurrent chemoradiotherapy to obtain a non-inferior pCR rate and pathological lymph node metastases rate in premise of lower toxicities in locally advanced esophageal cancer.

Study Overview

• Status: Unknown
• Conditions: Esophageal Neoplasms
• Intervention / Treatment: Radiation: IMRT simultaneous integrated boost; Drug: Nimotuzumab; Procedure: Esophagectomy; Drug: Paclitaxel; Drug: Nedaplatin

Detailed Description

In the era of IMRT and concurrent chemoradiotherapy, the 5-year overall survival of esophageal cancer increase from 10% to about 20%-40%, recurrence rate decrease from 80% to 50%-60%, and local recurrence remains to be the most important type of failure. What called for is to enhance local control without increasing toxicity to improve survival. The investigators have found effective and safe regimen of simultaneously integrated boost radiotherapy in previous study, which can achieve high dose in tumor area with avoid of normal tissues. However, a recent prospective study reported that neoadjuvant chemoradiotherapy resulted in much higher toxicities compares to neoadjuvant chemotherapy (46% vs. 15%, p= 0.04). Although chemoradiotherapy reached a higher pCR rate (28% vs. 9%, p=0.002), patients did not differ in survival in two groups.

Nimotuzumab is an humanized monoclonal antibody against EGFR. Radiotherapy combines Nimotuzumab reveals synergistic effect in head and neck cancers with lower toxicities as compared to concurrent chemoradiotherapy. Our previous study showed that EGFR expression rate were similar in esophageal cancer and head and neck cancers. Based on above results, the investigators design this study which aims to obtain a non-inferior pCR rate and pathological lymph node metastases rate in premise of lower toxicities.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zefen Xiao, MD; Phone Number: 8610-87787643; Email: xiaozefen@sina.com
• Study Contact Backup: Name: Wei Deng, MD; Phone Number: +8618813019080; Email: sherrydw@126.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100021
      • Recruiting
      • Zefen Xiao
      • Contact: Zefen Xiao, MD; Phone Number: 8610-87787643; Email: xiaozefen@sina.com
      • Contact: Wei Deng, MD; Phone Number: +8618813019080; Email: sherrydw@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of clinical stage T1-4aN0-1M1a untreated squamous esophageal carcinoma
• KPS≥70
• Adequate organ function
• No known history of drug allergy

Exclusion Criteria:

• Known drug allergy
• Insufficient hepatorenal function
• Severe cardiovascular diseases, diabetes with uncontrolled blood sugar, mental disorders, uncontrolled severe infection, active ulceration which need intervention.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant nimotuzumab; Radiation：Patients undergo radiotherapy once daily 5 days a week for an average of 4.5 weeks in the absence of disease progression or unacceptable toxicity. IMRT simultaneous integrated boost is used to achieve a prophylactic dosage and radical dosage of 1.8Gy and 2.14Gy once respectively. Concurrent nimotuzumab: Patients may receive nimotuzumab 400mg per week which start from 1 week before radiotherapy and in the following 4 weeks after enrollment in the absence of disease progression or unacceptable toxicity. Assessment of surgery: Patients eligible for surgery after multiple disciplinary consultation will receive esophagectomy after a 4-6 weeks break after chemoradiation in the absence of any contraindication.	Radiation: IMRT simultaneous integrated boost; To achieve a prophylactic dosage and radical dosage of 1.8Gy and 2.14Gy once respectively; Drug: Nimotuzumab; nimotuzumab 400mg per week which start from 1 week before radiotherapy and in the following 4 weeks; Procedure: Esophagectomy; Radical esophagectomy 4-6 weeks after neoadjuvant therapy
Active Comparator: Neoadjuvant chemotherapy; Radiation：Patients undergo radiotherapy once daily 5 days a week for an average of 4.5 weeks in the absence of disease progression or unacceptable toxicity. IMRT simultaneous integrated boost is used to achieve a prophylactic dosage and radical dosage of 1.8Gy and 2.14Gy once respectively. Concurrent chemotherapy: Patients may receive a dosage range of Paclitaxel from 45 to 60 mg/m2 and Nedaplatin 25mg/m2 per week which start from 1 week before radiotherapy and in the following 4 weeks after enrollment in the absence of disease progression or unacceptable toxicity. Assessment of surgery: Patients eligible for surgery after multiple disciplinary consultation will receive esophagectomy after a 4-6 weeks break after chemoradiation in the absence of any contraindication.	Radiation: IMRT simultaneous integrated boost; To achieve a prophylactic dosage and radical dosage of 1.8Gy and 2.14Gy once respectively; Procedure: Esophagectomy; Radical esophagectomy 4-6 weeks after neoadjuvant therapy; Drug: Paclitaxel; Paclitaxel from 45 to 60 mg/m2 per week which start from 1 week before radiotherapy and in the following 4 weeks; Other Names: Taxol; Drug: Nedaplatin; Nedaplatin 25mg/m2 per week which start from 1 week before radiotherapy and in the following 4 weeks
Experimental: Radical nimotuzumab; Radiation：Patients undergo radiotherapy once daily 5 days a week for an average of 5.5 weeks in the absence of disease progression or unacceptable toxicity. IMRT simultaneous integrated boost is used to achieve a prophylactic dosage and radical dosage of 1.8Gy and 2.14Gy once respectively. Concurrent nimotuzumab: Patients may receive nimotuzumab 400mg per week which start from 1 week before radiotherapy and in the following 4 weeks after enrollment in the absence of disease progression or unacceptable toxicity.	Radiation: IMRT simultaneous integrated boost; To achieve a prophylactic dosage and radical dosage of 1.8Gy and 2.14Gy once respectively; Drug: Nimotuzumab; nimotuzumab 400mg per week which start from 1 week before radiotherapy and in the following 4 weeks
Active Comparator: Radical chemotherapy; Radiation：Patients undergo radiotherapy once daily 5 days a week for an average of 5.5 weeks in the absence of disease progression or unacceptable toxicity. IMRT simultaneous integrated boost is used to achieve a prophylactic dosage and radical dosage of 1.8Gy and 2.14Gy once respectively. Concurrent chemotherapy: Patients may receive a dosage range of Paclitaxel from 45 to 60 mg/m2 and Nedaplatin 25mg/m2 per week which start from 1 week before radiotherapy and in the following 4 weeks after enrollment in the absence of disease progression or unacceptable toxicity.	Radiation: IMRT simultaneous integrated boost; To achieve a prophylactic dosage and radical dosage of 1.8Gy and 2.14Gy once respectively; Drug: Paclitaxel; Paclitaxel from 45 to 60 mg/m2 per week which start from 1 week before radiotherapy and in the following 4 weeks; Other Names: Taxol; Drug: Nedaplatin; Nedaplatin 25mg/m2 per week which start from 1 week before radiotherapy and in the following 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pathological response rate	Up to 1 year
Pathological lymph node metastases rate	Up to 1 year
R0 resection rate	Up to 1 year
Adverse events	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Disease-free survival (DFS)	Up to 2 years
Overall survival (OS)	Up to 2 years
Recurrence rate	Up to 2 years

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; Peking University First Hospital; Fujian Cancer Hospital; Henan Cancer Hospital; Tianjin Medical University Cancer Institute and Hospital; Beijing Hospital; Affiliated Hospital of Hebei University; Hebei Medical University Fourth Hospital; The Affiliated Hospital of Inner Mongolia Medical University; Beijing Army General Hospital

Publications and helpful links

General Publications

• Ajani JA, D'Amico TA, Almhanna K, Bentrem DJ, Besh S, Chao J, Das P, Denlinger C, Fanta P, Fuchs CS, Gerdes H, Glasgow RE, Hayman JA, Hochwald S, Hofstetter WL, Ilson DH, Jaroszewski D, Jasperson K, Keswani RN, Kleinberg LR, Korn WM, Leong S, Lockhart AC, Mulcahy MF, Orringer MB, Posey JA, Poultsides GA, Sasson AR, Scott WJ, Strong VE, Varghese TK Jr, Washington MK, Willett CG, Wright CD, Zelman D, McMillian N, Sundar H; National comprehensive cancer network. Esophageal and esophagogastric junction cancers, version 1.2015. J Natl Compr Canc Netw. 2015 Feb;13(2):194-227. doi: 10.6004/jnccn.2015.0028.
• van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. doi: 10.1056/NEJMoa1112088.
• Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, Gebski V; Australasian Gastro-Intestinal Trials Group. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011 Jul;12(7):681-92. doi: 10.1016/S1470-2045(11)70142-5. Epub 2011 Jun 16.
• Kranzfelder M, Schuster T, Geinitz H, Friess H, Buchler P. Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer. Br J Surg. 2011 Jun;98(6):768-83. doi: 10.1002/bjs.7455. Epub 2011 Apr 4.
• Harari PM, Huang SM. Combining EGFR inhibitors with radiation or chemotherapy: will preclinical studies predict clinical results? Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):976-83. doi: 10.1016/j.ijrobp.2003.09.097.
• Ramos-Suzarte M, Lorenzo-Luaces P, Lazo NG, Perez ML, Soriano JL, Gonzalez CE, Hernadez IM, Albuerne YA, Moreno BP, Alvarez ES, Callejo IP, Alert J, Martell JA, Gonzalez YS, Gonzalez YS, Astudillo de la Vega H, Ruiz-Garcia EB, Ramos TC. Treatment of malignant, non-resectable, epithelial origin esophageal tumours with the humanized anti-epidermal growth factor antibody nimotuzumab combined with radiation therapy and chemotherapy. Cancer Biol Ther. 2012 Jun;13(8):600-5. doi: 10.4161/cbt.19849. Epub 2012 Jun 1.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Anticipated): November 1, 2019
• Study Completion (Anticipated): November 1, 2021

Study Registration Dates

• First Submitted: July 30, 2016
• First Submitted That Met QC Criteria: August 5, 2016
• First Posted (Estimate): August 8, 2016

Study Record Updates

• Last Update Posted (Actual): July 26, 2019
• Last Update Submitted That Met QC Criteria: July 25, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Locally advanced esophageal cancer; Radiotherapy and nimotuzumab; Concurrent chemoradiotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Paclitaxel; Nimotuzumab; Nedaplatin
• Other Study ID Numbers: 16-082/1161

Plan for Individual participant data (IPD)

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