Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Drugs used in chemotherapy, such as epirubicin, cisplatin, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab may kill more tumor cells.

PURPOSE: This randomized phase II/III trial is studying the side effects and how well giving combination chemotherapy together with bevacizumab works compared with combination chemotherapy alone in treating patients with previously untreated stomach cancer, gastroesophageal junction cancer or lower oesophageal cancer that can be removed by surgery.

Further Study Information

OBJECTIVES:

Primary

• Assess the safety and efficacy of neoadjuvant and adjuvant chemotherapy comprising epirubicin hydrochloride, cisplatin, and capecitabine with or without bevacizumab in patients with previously untreated, resectable gastric, gastroesophageal junction or lower oesophageal cancer.

OUTLINE: This is a multicenter, randomized, open-label, controlled study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive epirubicin hydrochloride IV and cisplatin IV over 4 hours on day 1 and capecitabine orally twice daily on days 1-21. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo surgery 5-6 weeks after completion of chemotherapy. Patients then receive 3 additional courses of chemotherapy beginning 6-10 weeks after surgery.

• Arm II: Patients receive bevacizumab IV over 30-90 minutes, epirubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1 and capecitabine orally twice daily on days 1-21. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo surgery 5-8 weeks after completion of chemotherapy. Patients then receive 3 additional courses of chemotherapy and bevacizumab beginning 6-10 weeks after surgery. Patients then receive maintenance therapy comprising bevacizumab IV over 30-90 minutes on day 1. Maintenance therapy repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, during treatment, and during the follow-up period.

After completion of study treatment, patients are followed at 9, 18, and 27 weeks after the start of course 4, 1 year post surgery, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,100 patients will be accrued for this study.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed gastric or type I, II or III gastroesophageal junction adenocarcinoma or lower oesophageal

Gastric and Type III junctional tumours should be Stage Ib (T1 N1, T2a/b N0), II, III or stage IV (T4 N1 or N2) with no evidence of distant metastases (M0)

Lower oesophageal and Type I and II junctional tumours should be Stage II to Stage IVa (T1 N1, T2 N1, T3 N0-1, but not T2N0). T4 (N0 or N1) tumours are also eligible providing that they involve only the crura OR invade only the mediastinal pleura. Patients with nodal disease affecting the origin of the left gastric and splenic artery or coeliac axis (staged as M1a) are also eligible.

• Resectable disease

• Previously untreated disease

PATIENT CHARACTERISTICS:

• WHO performance status 0 or 1

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 9 g/dL (can be post transfusion)

• WBC ≥ 3,000/mm^3

• Glomerular filtration rate ≥ 60 mL/min

• Proteinuria ≤ 1 g by 24-hour urine collection

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

• ALT and AST ≤ 2.5 times ULN

• Alkaline phosphatase ≤ 3 times ULN (in the absence of liver metastases)

• INR ≤ 1.5

• PTT ≤ 1.5 times ULN

• FEV_1 ≥ 1.5 L

• Cardiac ejection fraction ≥ 50% by MUGA scan or echocardiogram

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Must be fit enough to receive protocol treatment

• No other malignancies within the past 5 years except for curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix

• No prior or concurrent significant medical conditions, including any of the following:

• Cerebrovascular disease (including transient ischemic attack and stroke) within the past year

• Cardiovascular disease, including the following:

• Myocardial infarction within the past year

• Uncontrolled hypertension while receiving chronic medication

• Unstable angina

• New York Heart Association class II-IV congestive heart failure

• Serious cardiac arrhythmia requiring medication

• Major trauma within the past 28 days

• Serious nonhealing wound, ulcer, or bone fracture

• Evidence of bleeding diathesis or coagulopathy

• Recent history of any active gastrointestinal inflammatory condition (e.g., peptic ulcer disease, diverticulitis, or inflammatory bowel disease)

• If patients have a known diagnosis of any of the above, evidence of disease control is required by negative endoscopy within the past 28 days

• No severe tinnitus

• No lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication

• No known peripheral neuropathy ≥ 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible)

• No known dihydropyrimidine dehydrogenase deficiency

• No known allergy to any of the following:

• Chinese hamster ovary cell proteins

• Other recombinant human or humanized antibodies

• Any excipients of bevacizumab formulation or platinum compounds

• Any other components of the study drugs

Due to an increase in perforations associated with self-expandable metal stents in patients with colorectal cancer receiving bevacizumab, patients with an oesophageal or gastric stent (metal or biodegradable) in situ are ineligible for the study.

PRIOR CONCURRENT THERAPY:

• No prior anthracycline

• More than 28 days since prior major surgery or open biopsy

• More than 10 days since prior thrombolytic therapy

• No concurrent thrombolytic therapy

• No concurrent dipyridamole or allopurinol

• No concurrent capecitabine or sorivudine (or sorivudine analogues [e.g., brivudine])

• No chronic, daily high-dose acetylsalicylic acid (> 325 mg/day) or nonsteroidal anti-inflammatory drugs

• No chronic corticosteroids (≥ 10 mg/day methylprednisolone equivalent)

• Inhaled steroids allowed

• No other concurrent cytotoxic agents

• No other concurrent investigational drugs

• No concurrent radiotherapy

• Low molecular weight heparin allowed

Trial Contact Information

Trial Lead Organizations/Sponsors

Professor David Cunningham

David Cunningham

Study Chair

United Kingdom
England
	Bournemouth
	Royal Bournemouth Hospital
		Tom Geldart	Ph: 44-1202-726-088
	Bradford
	Bradford Royal Infirmary
		Sue Cheeseman, MD	Ph: 44-1274-542-200
	Bristol
	Bristol Haematology and Oncology Centre
		Stephen J. Falk, MD	Ph: 44-117-928-3074
			Email: stephen.falk@ubht.nhs.uk
	Cambridge
	Addenbrooke's Hospital
		Hugo Ford, MD	Ph: 44-1223-245-151
	Carlisle
	Cumberland Infirmary
		Jonathan J. Nicoll, MD	Ph: 44-122-881-4688
			Email: jonathan.nicoll@ncumbria-acute.nhs.uk
	Doncaster
	Doncaster Royal Infirmary
		Jonathan Wadsley	Ph: 44-1302-366-666
	Guildford
	St. Luke's Cancer Centre at Royal Surrey County Hospital
		Gary W. Middleton	Ph: 44-1483-570-122
			Email: gmiddleton@royalsurrey.nhs.uk
	Huddersfield, West Yorks
	Huddersfield Royal Infirmary
		Jo Dent	Ph: 44-1484-342-000
	Leeds
	Leeds Cancer Centre at St. James's University Hospital
		Matthew T. Seymour, MA, MD, FRCP	Ph: 44-113-206-6400
	Lincoln
	Lincoln County Hospital
		Zuzana Stokes	Ph: 44-1522-512-512
	Liverpool
	Aintree University Hospital
		David Smith, MD	Ph: 44-151-525-5980
	London
	Saint Bartholomew's Hospital
		Sarah Slater, MD	Ph: 44-20-7601-8391
	St. George's Hospital
		Tim Benepal, MD	Ph: 44-208-725-2995
	St. Mary's Hospital
		Danielle Power, MD	Ph: 44-20-7886-7690
			Email: danielle.power@st-marys.nhs.uk
	Maidstone
	Mid Kent Oncology Centre at Maidstone Hospital
		Justin Waters, MD	Ph: 44-1622-729-000
	Manchester
	Christie Hospital
		Was Mansoor, MD	Ph: 44-845-226-3000
	Merseyside
	Clatterbridge Centre for Oncology
		David Smith, MD	Ph: 44-151-334-1155
			Email: david.smith@ccotrust.nhs.uk
	Newcastle-Upon-Tyne
	Northern Centre for Cancer Treatment at Newcastle General Hospital
		Fareeda Coxon, MD	Ph: 44-191-256-3551
			Email: fareeda.coxon@nuth.nhs.uk
	Plymouth
	Derriford Hospital
		Sarah Pascoe, MD	Ph: 44-175-277-7111
	Poole Dorset
	Dorset Cancer Centre
		Richard Osborne, MD, FRCP	Ph: 44-1-202-448-265
	Reading
	Berkshire Cancer Centre at Royal Berkshire Hospital
		Joss Adams, MD	Ph: 44-118-322-7878
	Rochdale
	Rochdale Infirmary
		Khurshid Akhtar, MD	Ph: 44-170-637-7777
	Salisbury
	Salisbury District Hospital
		Tim J. Iveson, MD	Ph: 44-1722-336-262 ext. 4688
	Slough, Berkshire
	Wexham Park Hospital
		Marcia Hall, MD	Ph: 44-1753-634-364
			Email: marcia.hall@nhs.net.uk
	Southampton
	Southampton General Hospital
		Tim J. Iveson, MD	Ph: 44-23-8079-6802
			Email: t.iveson@soton.ac.uk
	Sutton
	Royal Marsden - Surrey
		David Cunningham, MD	Ph: 44-20-8661-3279
			Email: david.cunningham@rmh.nhs.uk
Scotland
	Aberdeen
	Aberdeen Royal Infirmary
		Russell Petty, MD	Ph: 44-84-5456-6000
Wales
	Cardiff
	Velindre Cancer Center at Velindre Hospital
		Tom Crosby, MD	Ph: 44-29-2031-6292

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00450203
Information obtained from ClinicalTrials.gov on January 30, 2012

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