Chemotherapy With or Without Bevacizumab or Lapatinib to Treat Operable Oesophagogastric Cancer (ST03)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Medical Research Council
Sponsor:
Collaborators:
Cancer Research UK
Roche Pharma AG
GlaxoSmithKline
Information provided by (Responsible Party):
Professor David Cunningham, Medical Research Council
ClinicalTrials.gov Identifier:
NCT00450203
First received: March 20, 2007
Last updated: September 10, 2014
Last verified: September 2014
  Purpose

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, and small molecule tyrosine kinase inhibitors, such as lapatinib, 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. Lapatinib targets a specific growth receptor, HER-2. Chemotherapy together with bevacizumab or lapatinib, in HER-2 positive tumours, 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. The feasibility study is studying the safety of adding lapatinib to chemotherapy in patients with HER-2 positive previously untreated stomach cancer, gastroesophageal junction cancer or lower oesophageal cancer that can be removed by surgery. The feasibility study will also assess the feasibility of timely HER-2 testing and estimate the HER-2 positivity rate in this patient population.


Condition Intervention Phase
Oesophagogastric Cancer
Biological: bevacizumab
Drug: capecitabine
Drug: cisplatin
Drug: Epirubicin
Procedure: adjuvant therapy
Procedure: conventional surgery
Procedure: neoadjuvant therapy
Drug: Lapatinib
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomised Phase II/III Trial of Peri-Operative Chemotherapy With or Without Bevacizumab in Operable Oesophagogastric Adenocarcinoma and A Feasibility Study Evaluating Lapatinib in HER-2 Positive Oesophagogastric Adenocarcinomas and (in Selected Centres) MRI and PET/CT Sub-studies

Resource links provided by NLM:


Further study details as provided by Medical Research Council:

Primary Outcome Measures:
  • Safety [ Time Frame: at the end of phase II and phase III ] [ Designated as safety issue: Yes ]
  • Efficacy [ Time Frame: end of trial ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: end of trial ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Feasibility [ Time Frame: end of trial ] [ Designated as safety issue: No ]
  • Treatment-related morbidity [ Time Frame: end of trial ] [ Designated as safety issue: No ]
  • Response rates to pre-operative treatment [ Time Frame: at phase II review and at end of trial ] [ Designated as safety issue: No ]
  • Surgical resection rates [ Time Frame: end of trial ] [ Designated as safety issue: No ]
  • Disease-free survival [ Time Frame: end of trial ] [ Designated as safety issue: No ]
  • Quality of life [ Time Frame: end of trial ] [ Designated as safety issue: No ]
  • Cost-effectiveness [ Time Frame: end of trial ] [ Designated as safety issue: No ]
  • HER-2 Positivity Rate [ Time Frame: End of trial ] [ Designated as safety issue: No ]
  • Feasibility of centralised HER-2 testing [ Time Frame: After 60 patients tested and then after 110 patients tested and then at end of trial ] [ Designated as safety issue: No ]

Estimated Enrollment: 1103
Study Start Date: October 2007
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ECX + Bevacizumab
ECX + Bevacizumab
Biological: bevacizumab
7.5mg/kg IV Day 1 of each 21 cycle of chemotherapy (6 cycles) plus day 1 of each maintenance dose every 21 days for 6 doses.
Drug: capecitabine
dose banded as based on patient BSA. Oral dose given twice a day during each 21 day cycle of chemotherapy (6 cycles in total)
Drug: cisplatin
60mg/m2 IV day one of each 21 day cycle of chemotherapy (6 cycles in total)
Drug: Epirubicin
50mg/m2 IV day one of each 21 day cycle of chemotherapy (6 cycles in total)
Procedure: adjuvant therapy
3 cycles of ECX chemotherapy post operatively
Procedure: conventional surgery
Surgery undertaken after 3 cycles of pre-operative chemotherapy. Followed by 3 cycles of chemotherapy.
Procedure: neoadjuvant therapy
3 cycles of pre-operative ECX chemotherapy.
Active Comparator: Epirubicin, Cisplatin and Capecitabine
ECX chemotherapy
Drug: capecitabine
dose banded as based on patient BSA. Oral dose given twice a day during each 21 day cycle of chemotherapy (6 cycles in total)
Drug: cisplatin
60mg/m2 IV day one of each 21 day cycle of chemotherapy (6 cycles in total)
Drug: Epirubicin
50mg/m2 IV day one of each 21 day cycle of chemotherapy (6 cycles in total)
Procedure: adjuvant therapy
3 cycles of ECX chemotherapy post operatively
Procedure: conventional surgery
Surgery undertaken after 3 cycles of pre-operative chemotherapy. Followed by 3 cycles of chemotherapy.
Procedure: neoadjuvant therapy
3 cycles of pre-operative ECX chemotherapy.
Experimental: ECX + Lapatinib
ECX + Lapatinib
Drug: capecitabine
dose banded as based on patient BSA. Oral dose given twice a day during each 21 day cycle of chemotherapy (6 cycles in total)
Drug: cisplatin
60mg/m2 IV day one of each 21 day cycle of chemotherapy (6 cycles in total)
Drug: Epirubicin
50mg/m2 IV day one of each 21 day cycle of chemotherapy (6 cycles in total)
Procedure: adjuvant therapy
3 cycles of ECX chemotherapy post operatively
Procedure: conventional surgery
Surgery undertaken after 3 cycles of pre-operative chemotherapy. Followed by 3 cycles of chemotherapy.
Procedure: neoadjuvant therapy
3 cycles of pre-operative ECX chemotherapy.
Drug: Lapatinib
1250mg/day Day 1-21 of each cycle of chemotherapy (6 cycles) plus day 1-21 of each maintenance course every 21 days for 6 doses.
Other Name: Tyverb

Detailed Description:

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.
  • Assess the safety of neoadjuvant and adjuvant chemotherapy comprising epirubicin hydrochloride, cisplatin, and capecitabine with or without lapatinib in patients with HER-2 positive 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 4 treatment arms.

  • Arm I and II: 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.

  • Arm IV: Patients receive lapatinib orally once daily, 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 lapatinib beginning 6-10 weeks after surgery. Patients then receive maintenance therapy comprising lapatinib orally once daily on days 1-21. 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 1063 patients were recruited to the bevacizumab comparison of the study (now closed to recruitment) and 40 patients with HER-2 positive tumours will be recruited into the ST03 feasibility study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

This is a combined eligibility criteria for both bevacizumab comparison and the lapatinib feasibility study. Please note the bevacizumab comparison closed to recruitment on 28th March 2014.

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 history of interstitial lung disease or radiological evidence of lung fibrosis
  • 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
  • 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
  • More than 7 days since prior CYP3A4 inhibitor therapy
  • More than 14 days since prior CYP3A4 inducer therapy
  • More than 6 months since prior amiodarone therapy
  • More than 14 days since prior St John's Wort, modafinil, ginkgo biloba, kava, grape seed, valerian, ginseng, echinacea and evening primrose oil
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00450203

Contacts
Contact: Claire Robb 0207 670 4804 c.robb@ucl.ac.uk
Contact: Rahela Choudhury 0207 670 4801 rahela.choudhury@ucl.ac.uk

Locations
United Kingdom
Royal Bournemouth Hospital Recruiting
Bournemouth, England, United Kingdom, BH7 7DW
Contact: Tom Geldart    44-1202-726-088      
Bradford Royal Infirmary Recruiting
Bradford, England, United Kingdom, BD9 6RJ
Contact: Sue Cheeseman, MD    44-1274-542-200      
Bristol Haematology and Oncology Centre Recruiting
Bristol, England, United Kingdom, BS2 8ED
Contact: Stephen J. Falk, MD    44-117-928-3074    stephen.falk@ubht.nhs.uk   
Addenbrooke's Hospital Recruiting
Cambridge, England, United Kingdom, CB2 2QQ
Contact: Hugo Ford, MD    44-1223-245-151      
Cumberland Infirmary Recruiting
Carlisle, England, United Kingdom, CA2 7HY
Contact: Jonathan J. Nicoll, MD    44-122-881-4688    jonathan.nicoll@ncumbria-acute.nhs.uk   
Doncaster Royal Infirmary Recruiting
Doncaster, England, United Kingdom, DN2 5LT
Contact: Jonathan Wadsley    44-1302-366-666      
St. Luke's Cancer Centre at Royal Surrey County Hospital Recruiting
Guildford, England, United Kingdom, GU2 7XX
Contact: Gary W. Middleton    44-1483-570-122    gmiddleton@royalsurrey.nhs.uk   
Huddersfield Royal Infirmary Recruiting
Huddersfield, West Yorks, England, United Kingdom, HD3 3EA
Contact: Jo Dent    44-1484-342-000      
Leeds Cancer Centre at St. James's University Hospital Recruiting
Leeds, England, United Kingdom, LS9 7TF
Contact: Matthew T. Seymour, MA, MD, FRCP    44-113-206-6400      
Lincoln County Hospital Recruiting
Lincoln, England, United Kingdom, LN2 5QY
Contact: Zuzana Stokes    44-1522-512-512      
Aintree University Hospital Recruiting
Liverpool, England, United Kingdom, L9 7AL
Contact: David Smith, MD    44-151-525-5980      
St. Mary's Hospital Recruiting
London, England, United Kingdom, W2 1NY
Contact: Danielle Power, MD    44-20-7886-7690    danielle.power@st-marys.nhs.uk   
Saint Bartholomew's Hospital Recruiting
London, England, United Kingdom, EC1A 7BE
Contact: Sarah Slater, MD    44-20-7601-8391      
St. George's Hospital Recruiting
London, England, United Kingdom, SW17 0QT
Contact: Tim Benepal, MD    44-208-725-2995      
Mid Kent Oncology Centre at Maidstone Hospital Recruiting
Maidstone, England, United Kingdom, ME16 9QQ
Contact: Justin Waters, MD    44-1622-729-000      
Christie Hospital Recruiting
Manchester, England, United Kingdom, M20 4BX
Contact: Was Mansoor, MD    44-845-226-3000      
Clatterbridge Centre for Oncology Recruiting
Merseyside, England, United Kingdom, CH63 4JY
Contact: David Smith, MD    44-151-334-1155    david.smith@ccotrust.nhs.uk   
Northern Centre for Cancer Treatment at Newcastle General Hospital Recruiting
Newcastle-Upon-Tyne, England, United Kingdom, NE4 6BE
Contact: Fareeda Coxon, MD    44-191-256-3551    fareeda.coxon@nuth.nhs.uk   
Derriford Hospital Recruiting
Plymouth, England, United Kingdom, PL6 8DH
Contact: Sarah Pascoe, MD    44-175-277-7111      
Dorset Cancer Centre Recruiting
Poole Dorset, England, United Kingdom, BH15 2JB
Contact: Richard Osborne, MD, FRCP    44-1-202-448-265      
Berkshire Cancer Centre at Royal Berkshire Hospital Recruiting
Reading, England, United Kingdom, RG1 5AN
Contact: Joss Adams, MD    44-118-322-7878      
Rochdale Infirmary Recruiting
Rochdale, England, United Kingdom, 0L12 0NB
Contact: Khurshid Akhtar, MD    44-170-637-7777      
Salisbury District Hospital Recruiting
Salisbury, England, United Kingdom, SP2 8BJ
Contact: Tim J. Iveson, MD    44-1722-336-262 ext. 4688      
Wexham Park Hospital Recruiting
Slough, Berkshire, England, United Kingdom, SL2 4HL
Contact: Marcia Hall, MD    44-1753-634-364    marcia.hall@nhs.net.uk   
Southampton General Hospital Recruiting
Southampton, England, United Kingdom, SO16 6YD
Contact: Tim J. Iveson, MD    44-23-8079-6802    t.iveson@soton.ac.uk   
Royal Marsden - Surrey Recruiting
Sutton, England, United Kingdom, SM2 5PT
Contact: David Cunningham, MD    44-20-8661-3279    david.cunningham@rmh.nhs.uk   
Aberdeen Royal Infirmary Recruiting
Aberdeen, Scotland, United Kingdom, AB25 2ZN
Contact: Russell Petty, MD    44-84-5456-6000      
Velindre Cancer Center at Velindre Hospital Recruiting
Cardiff, Wales, United Kingdom, CF14 2TL
Contact: Tom Crosby, MD    44-29-2031-6292      
Sponsors and Collaborators
Professor David Cunningham
Cancer Research UK
Roche Pharma AG
GlaxoSmithKline
Investigators
Study Chair: David Cunningham, MD Royal Marsden NHS Foundation Trust
  More Information

Additional Information:
Publications:
Responsible Party: Professor David Cunningham, ST03 Chief Investigator, Professor David Cunningham, Medical Research Council
ClinicalTrials.gov Identifier: NCT00450203     History of Changes
Other Study ID Numbers: CDR0000536013, MRC-ST03, EU-20710, ISRCTN46020948, 2006-000811-12, 00316/0221/001
Study First Received: March 20, 2007
Last Updated: September 10, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Medical Research Council:
adenocarcinoma of the stomach
adenocarcinoma of the gastro oesophageal junction
adenocarcinoma of the lower oesophagus

Additional relevant MeSH terms:
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Bevacizumab
Capecitabine
Lapatinib
Cisplatin
Epirubicin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on September 22, 2014