Clinical trial NCT00450203: Chemotherapy With or Without Bevacizumab or Lapatinib to Treat Operable Oesophagogastric Cancer
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Oesophagogastric Cancer
Keywords: adenocarcinoma of the stomach
adenocarcinoma of the gastro oesophageal junction
adenocarcinoma of the lower oesophagus
Lead sponsor: Medical Research Council
Sponsor class: OTHER_GOV
Collaborators: name: Cancer Research UK
name: Roche Pharma AG
name: GlaxoSmithKline
First posted: 2007-03-22
Enrollment: 1103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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

Primary outcomes:
measure: Safety
timeFrame: at the end of phase II and phase III
measure: Efficacy
timeFrame: end of trial
measure: Overall survival
timeFrame: end of trial
Secondary outcomes:
measure: Feasibility
timeFrame: end of trial
measure: Treatment-related morbidity
timeFrame: end of trial
measure: Response rates to pre-operative treatment
timeFrame: at phase II review and at end of trial
measure: Surgical resection rates
timeFrame: end of trial
measure: Disease-free survival
timeFrame: end of trial
measure: Quality of life
timeFrame: end of trial
measure: Cost-effectiveness
timeFrame: end of trial
measure: HER-2 Positivity Rate
timeFrame: End of trial
measure: Feasibility of centralised HER-2 testing
timeFrame: After 60 patients tested and then after 110 patients tested and then at end of trial
Other outcomes:
Locations:
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: England
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
state: England
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Carlisle
country: United Kingdom
facility: Cumberland Infirmary
state: England
city: Doncaster
country: United Kingdom
facility: Doncaster Royal Infirmary
state: England
city: Guildford
country: United Kingdom
facility: St. Luke's Cancer Centre at Royal Surrey County Hospital
state: England
city: Huddersfield, West Yorks
country: United Kingdom
facility: Huddersfield Royal Infirmary
state: England
city: Leeds
country: United Kingdom
facility: Leeds Cancer Centre at St. James's University Hospital
state: England
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: London
country: United Kingdom
facility: St. George's Hospital
state: England
city: London
country: United Kingdom
facility: St. Mary's Hospital
state: England
city: Maidstone
country: United Kingdom
facility: Mid Kent Oncology Centre at Maidstone Hospital
state: England
city: Manchester
country: United Kingdom
facility: Christie Hospital
state: England
city: Merseyside
country: United Kingdom
facility: Clatterbridge Centre for Oncology
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Northern Centre for Cancer Treatment at Newcastle General Hospital
state: England
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: England
city: Poole Dorset
country: United Kingdom
facility: Dorset Cancer Centre
state: England
city: Reading
country: United Kingdom
facility: Berkshire Cancer Centre at Royal Berkshire Hospital
state: England
city: Rochdale
country: United Kingdom
facility: Rochdale Infirmary
state: England
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
state: England
city: Slough, Berkshire
country: United Kingdom
facility: Wexham Park Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Center at Velindre Hospital
state: Wales
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Cottingham
country: United Kingdom
facility: Castle Hill Hospital
city: Coventry
country: United Kingdom
facility: University Hospitals Coventry and Warwickshire
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Leeds
country: United Kingdom
facility: St James Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Romford
country: United Kingdom
facility: Queens Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park
city: Swindon
country: United Kingdom
facility: Great Western Hospital
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
Study officials:
affiliation: Royal Marsden NHS Foundation Trust
name: David Cunningham, MD
role: STUDY_CHAIR
References:
citation: 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 peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report. Ann Oncol. 2013 Mar;24(3):702-9. doi: 10.1093/annonc/mds533. Epub 2012 Oct 28.
citation: Allum WH, Smyth EC, Blazeby JM, Grabsch HI, Griffin SM, Rowley S, Cafferty FH, Langley RE, Cunningham D. Quality assurance of surgery in the randomized ST03 trial of perioperative chemotherapy in carcinoma of the stomach and gastro-oesophageal junction. Br J Surg. 2019 Aug;106(9):1204-1215. doi: 10.1002/bjs.11184. Epub 2019 Jul 3.
citation: Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, Stevenson L, Grabsch HI, Alderson D, Crosby T, Griffin SM, Mansoor W, Coxon FY, Falk SJ, Darby S, Sumpter KA, Blazeby JM, Langley RE. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol. 2017 Mar;18(3):357-370. doi: 10.1016/S1470-2045(17)30043-8. Epub 2017 Feb 3.