Erbitux Combined With Chemo-radiotherapy in Esophageal Squamous Cell Carcinoma

Esophageal Cancer Clinical Trial

— EXCEL  

Official title:

An Open-labeled Study to Evaluate Efficacy of Combining Erbitux Plus Concurrent Chemo-radiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma (ESCC)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00815308
• Other study ID #: SDRTC-0901
• Status: Completed
• Phase: Phase 2
• First received: December 29, 2008
• Last updated: February 4, 2011
• Start date: January 2009
• Est. completion date: July 2010

Study information

• Verified date: July 2009
• Source: Shandong Cancer Hospital and Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Ethics CommitteeChina: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether the treatment of locally advanced esophageal squamous cell carcinoma (ESCC)with cetuximab in combination with paclitaxel, cisplatin and radiation improve clinical outcomes.

Description:

Esophageal cancer is the sixth leading cause of cancer death worldwide.

Over the past 2 decades, well-designed clinical trials have documented the clinical benefits of combination of chemotherapy and radiation for localized esophageal cancer, either as primary therapy or in neoadjuvant setting.

Paclitaxel, a radiation sensitizer, has important single-agent activity in esophageal cancer. Paclitaxel-based chemoradiation has been the framework for the recent Radiation Therapy Oncology Group (RTOG) trials of nonoperative management of esophageal cancer.

Accumulating clinical evidence suggests that epidermal growth factor receptor (EGFR) represents a viable target in the treatment of esophageal cancer. EGFR expression is associated with poor prognosis. Cetuximab, a monoclonal antibody, binds specifically to EGFR on both normal and tumor cells and competitively inhibits the binding of EGF and other ligands, such as transforming growth factor (TGF)-α.

Preclinical models have suggested synergy between cetuximab, paclitaxel, cisplatin and radiation. For patients with locally advanced head and neck cancer, the combination of cetuximab and radiation has demonstrated both response and survival benefit.

With all these, the investigators hypothesize that treatment of locally advanced esophageal squamous cell carcinoma (ESCC)with cetuximab in combination with paclitaxel, cisplatin and radiation may further improve clinical outcomes. This trial results will be important as it may support further studies for setting the new treatment standard for ESCC.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: July 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Inpatients or outpatients, = 18 years of age

• Histologically confirmed primary (non-recurrent) ESCC fulfilling one of the following criteria (AJCC Staging System)

• cervical esophageal carcinoma, stage ?-?

• upper thoracic esophageal carcinoma, stage ?-?, or mid-thoracic esophageal carcinoma, stage ?-?,which is medically unfit for surgery, surgery been refused and patient medically able to tolerate chemo-radiation.

• Evidence of unidimensional measurable disease as per Response Evaluation Criteria in Solid Tumours (RECIST).

• ECOG Performance status of 0-1

• Effective contraception for both male and female patients if the risk of conception exists

• Adequate bone marrow reserves: neutrophil (ANC) count = 1500 /mm^3, platelet count = 100,000 /mm^3, hemoglobin = 9 g/dl

• Adequate renal function: serum creatinine = 1.5 mg/dl and/or calculated creatinine clearance = 60 ml/min

• Adequate hepatic function: bilirubin level = 1.5 x ULN, ASAT & ALST = 1.5 x ULN

• Tumor tissue available for KRAS biomarker test

• Signed written informed consent prior to study entry

Exclusion Criteria:

• Previous chest radiotherapy, systemic chemotherapy, and major esophageal surgery

• Concurrent chronic systemic immune therapy, targeted therapy not indicated in this study protocol

• Multiple primary carcinomas of the esophagus

• Pregnancy (confirmed by serum or urine ß-HCG) or lactation period;

• Uncontrolled diabetes, hypertension, and severe cardiac or pulmonary disease

• Unable to comprehend the study requirements or who are not likely to comply with the study parameters;

• Distant metastasis

• Second malignancy, except for curable non-melanoma skin cancer, cervical cancer in situ, or malignant disease, free for = 5 years

• Known grade 3 or 4 allergic reaction to any of the study treatment

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Squamous Cell
• Esophageal Cancer
• Esophageal Neoplasms

Intervention

Drug:
• cetuximab (Erbitux)
Cetuximab,injection,loading dose400 mg/m^2,(Day1 in Week1) followed by 250 mg/m^2(Day1, every week for Weeks 2-8)
• Paclitaxel
Paclitaxel,injection,loading dose 45 mg/m^2,(Day1 in every week for Weeks 2-8)
• Cisplatin
Cisplatin,injection,loading dose 20 mg/m^2,(Day1 in every week for Weeks 2-8)

Radiation:
• Radiation
Radiation, External beam therapy, total 59.4 Gy , 33 fractions, 1.8 Gy per fraction.(Day 1-Day 5 in every week 2-week 8).

Locations

Country	Name	City	State
China	Department of Radiation Oncology, Shandong Cancer Hospital and Institute	Jinan	Shandong

Sponsors (8)

Lead Sponsor	Collaborator
Shandong Cancer Hospital and Institute	Beijing Cancer Hospital, Chinese Academy of Medical Sciences, Hebei Fourth Hospital, Jiangsu Cancer Institute & Hospital, RenJi Hospital, The Affiliated Cancer Hospital of Zhengzhou University, West China Hospital

Country where clinical trial is conducted

China, 

References & Publications (8)

Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Eng — View Citation

Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, Lozach P, Ollier JC, Pavy JJ, Mercier M, Sahmoud T. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med. 1997 Jul 17;337( — View Citation

Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992 Jun 11;32 — View Citation

Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998 Dec 31;339(27) — View Citation

Langer CJ. Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):991-1002. Review. — View Citation

Raben D, Helfrich B, Bunn PA Jr. Targeted therapies for non-small-cell lung cancer: biology, rationale, and preclinical results from a radiation oncology perspective. Int J Radiat Oncol Biol Phys. 2004;59(2 Suppl):27-38. Review. — View Citation

Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001 Jan 15;19(2):305-13. — View Citation

Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996 Aug 15;335(7):462-7. Erratum in: N Engl J Med 1999 Jul 29;341(5):384. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Overall Response Rate (RR)	The overall response rate was defined as the numbers of patients with a complete response (CR) or partial response (PR). CR was defined as no target lesion at follow-up computed tomography scan and barium swallow examination 3-6 weeks after completion of chemo-radiation. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	1 to 3 month after therapy	Yes
Secondary	Number of Participants With Toxicity	All patients were regularly monitored for possible adverse events, which were graded according to National Cancer Institute Common Toxicity Criteria version 3.0.	Every week during treatment and 1 month after therapy	Yes
Secondary	Participants With Overall Survival (OS) at 1 Year		1 year from the date of diagnosis	No
Secondary	Participants With Overall Survival (OS) at 3 Year		3 year from the date of diagnosis	No
Secondary	Participants With Progression Free Survival (PFS)		Recurrence or metastasis from the date of diagnosis	No
Secondary	Number of Participants With K-ras Gene Mutation	DNA was extracted from tumor specimens.Screened for the presence of KRAS codon 12 and 13 mutations using a PCR clamping and melting curve technique. PCR amplification of the wild-type KRAS sequence was suppressed in this process by the incorporation in the reaction mix of a locked nucleic-acid oligomer16 spanning codons 12 and 13 of the KRAS gene. Post-PCR hybridization and melting curve analysis using fluorescently tagged oligonucleotides incorporated in the original PCR reaction permitted the identification and discrimination of distinct KRAS codon 12 and 13 missense mutations.	07/29/2010-09/30/2010	No