Chemotherapy With or Without Bevacizumab or Lapatinib to Treat Operable Oesophagogastric Cancer

Oesophagogastric Cancer Clinical Trial

— ST03  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00450203
• Other study ID #: CDR0000536013
• Secondary ID: MRC-ST03EU-20710
• Status: Recruiting
• Phase: Phase 2/Phase 3
• First received: March 20, 2007
• Last updated: November 30, 2016
• Start date: October 2007
• Est. completion date: December 2017

Study information

• Verified date: November 2016
• Source: Medical Research Council
• Contact: Nicholas Kleovoulou
• Phone: 0207 670 4801
• Email: n.kleovoulou[@]ucl.ac.uk
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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, 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1103
• Est. completion date: December 2017
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adenocarcinoma
• Oesophagogastric Cancer

Intervention

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)
• cisplatin
60mg/m2 IV day one of each 21 day cycle of chemotherapy (6 cycles in total)
• 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
• conventional surgery
Surgery undertaken after 3 cycles of pre-operative chemotherapy. Followed by 3 cycles of chemotherapy.
• 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.

Locations

Country	Name	City	State
United Kingdom	Aberdeen Royal Infirmary	Aberdeen	Scotland
United Kingdom	Basingstoke and North Hampshire Hospital	Basingstoke
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	Royal Bournemouth Hospital	Bournemouth	England
United Kingdom	Bradford Royal Infirmary	Bradford	England
United Kingdom	Bristol Haematology and Oncology Centre	Bristol	England
United Kingdom	Addenbrooke's Hospital	Cambridge	England
United Kingdom	Velindre Cancer Center at Velindre Hospital	Cardiff	Wales
United Kingdom	Cumberland Infirmary	Carlisle	England
United Kingdom	Castle Hill Hospital	Cottingham
United Kingdom	University Hospitals Coventry and Warwickshire	Coventry
United Kingdom	Doncaster Royal Infirmary	Doncaster	England
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	St. Luke's Cancer Centre at Royal Surrey County Hospital	Guildford	England
United Kingdom	Huddersfield Royal Infirmary	Huddersfield, West Yorks	England
United Kingdom	Leeds Cancer Centre at St. James's University Hospital	Leeds	England
United Kingdom	St James Hospital	Leeds
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Lincoln County Hospital	Lincoln	England
United Kingdom	Aintree University Hospital	Liverpool	England
United Kingdom	Saint Bartholomew's Hospital	London	England
United Kingdom	St. George's Hospital	London	England
United Kingdom	St. Mary's Hospital	London	England
United Kingdom	Mid Kent Oncology Centre at Maidstone Hospital	Maidstone	England
United Kingdom	Christie Hospital	Manchester	England
United Kingdom	Clatterbridge Centre for Oncology	Merseyside	England
United Kingdom	Northern Centre for Cancer Treatment at Newcastle General Hospital	Newcastle-Upon-Tyne	England
United Kingdom	Norfolk and Norwich University Hospital	Norwich
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Derriford Hospital	Plymouth	England
United Kingdom	Dorset Cancer Centre	Poole Dorset	England
United Kingdom	Berkshire Cancer Centre at Royal Berkshire Hospital	Reading	England
United Kingdom	Rochdale Infirmary	Rochdale	England
United Kingdom	Queens Hospital	Romford
United Kingdom	Salisbury District Hospital	Salisbury	England
United Kingdom	Weston Park	Sheffield
United Kingdom	Wexham Park Hospital	Slough, Berkshire	England
United Kingdom	Southampton General Hospital	Southampton	England
United Kingdom	Royal Marsden - Surrey	Sutton	England
United Kingdom	Great Western Hospital	Swindon
United Kingdom	Musgrove Park Hospital	Taunton

Sponsors (4)

Lead Sponsor	Collaborator
Professor David Cunningham	Cancer Research UK, GlaxoSmithKline, Roche Pharma AG

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

Okines AF, Langley RE, Thompson LC, Stenning SP, Stevenson L, Falk S, Seymour M, Coxon F, Middleton GW, Smith D, Evans L, Slater S, Waters J, Ford D, Hall M, Iveson TJ, Petty RD, Plummer C, Allum WH, Blazeby JM, Griffin M, Cunningham D. Bevacizumab with p — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety		at the end of phase II and phase III	Yes
Primary	Efficacy		end of trial	No
Primary	Overall survival		end of trial	No
Secondary	Feasibility		end of trial	No
Secondary	Treatment-related morbidity		end of trial	No
Secondary	Response rates to pre-operative treatment		at phase II review and at end of trial	No
Secondary	Surgical resection rates		end of trial	No
Secondary	Disease-free survival		end of trial	No
Secondary	Quality of life		end of trial	No
Secondary	Cost-effectiveness		end of trial	No
Secondary	HER-2 Positivity Rate		End of trial	No
Secondary	Feasibility of centralised HER-2 testing		After 60 patients tested and then after 110 patients tested and then at end of trial	No