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

Sponsor

Professor David Cunningham (Other)

Overall Status

Unknown status

CT.gov ID

NCT00450203

Collaborator

Cancer Research UK (Other), Roche Pharma AG (Industry), GlaxoSmithKline (Industry)

1,103

Enrollment

Locations

Arms

122

Duration (Months)

26.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	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

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

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1103 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (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

Study Start Date :

Oct 1, 2007

Anticipated Primary Completion Date :

Dec 1, 2017

Anticipated Study Completion Date :

Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Tyverb

Arm

Intervention/Treatment

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 Names:

Tyverb

Outcome Measures

Primary Outcome Measures

Safety [at the end of phase II and phase III]
Efficacy [end of trial]
Overall survival [end of trial]

Secondary Outcome Measures

Feasibility [end of trial]
Treatment-related morbidity [end of trial]
Response rates to pre-operative treatment [at phase II review and at end of trial]
Surgical resection rates [end of trial]
Disease-free survival [end of trial]
Quality of life [end of trial]
Cost-effectiveness [end of trial]
HER-2 Positivity Rate [End of trial]
Feasibility of centralised HER-2 testing [After 60 patients tested and then after 110 patients tested and then at end of trial]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Royal Bournemouth Hospital	Bournemouth	England	United Kingdom	BH7 7DW
2	Bradford Royal Infirmary	Bradford	England	United Kingdom	BD9 6RJ
3	Bristol Haematology and Oncology Centre	Bristol	England	United Kingdom	BS2 8ED
4	Addenbrooke's Hospital	Cambridge	England	United Kingdom	CB2 2QQ
5	Cumberland Infirmary	Carlisle	England	United Kingdom	CA2 7HY
6	Doncaster Royal Infirmary	Doncaster	England	United Kingdom	DN2 5LT
7	St. Luke's Cancer Centre at Royal Surrey County Hospital	Guildford	England	United Kingdom	GU2 7XX
8	Huddersfield Royal Infirmary	Huddersfield, West Yorks	England	United Kingdom	HD3 3EA
9	Leeds Cancer Centre at St. James's University Hospital	Leeds	England	United Kingdom	LS9 7TF
10	Lincoln County Hospital	Lincoln	England	United Kingdom	LN2 5QY
11	Aintree University Hospital	Liverpool	England	United Kingdom	L9 7AL
12	Saint Bartholomew's Hospital	London	England	United Kingdom	EC1A 7BE
13	St. George's Hospital	London	England	United Kingdom	SW17 0QT
14	St. Mary's Hospital	London	England	United Kingdom	W2 1NY
15	Mid Kent Oncology Centre at Maidstone Hospital	Maidstone	England	United Kingdom	ME16 9QQ
16	Christie Hospital	Manchester	England	United Kingdom	M20 4BX
17	Clatterbridge Centre for Oncology	Merseyside	England	United Kingdom	CH63 4JY
18	Northern Centre for Cancer Treatment at Newcastle General Hospital	Newcastle-Upon-Tyne	England	United Kingdom	NE4 6BE
19	Derriford Hospital	Plymouth	England	United Kingdom	PL6 8DH
20	Dorset Cancer Centre	Poole Dorset	England	United Kingdom	BH15 2JB
21	Berkshire Cancer Centre at Royal Berkshire Hospital	Reading	England	United Kingdom	RG1 5AN
22	Rochdale Infirmary	Rochdale	England	United Kingdom	0L12 0NB
23	Salisbury District Hospital	Salisbury	England	United Kingdom	SP2 8BJ
24	Wexham Park Hospital	Slough, Berkshire	England	United Kingdom	SL2 4HL
25	Southampton General Hospital	Southampton	England	United Kingdom	SO16 6YD
26	Royal Marsden - Surrey	Sutton	England	United Kingdom	SM2 5PT
27	Aberdeen Royal Infirmary	Aberdeen	Scotland	United Kingdom	AB25 2ZN
28	Velindre Cancer Center at Velindre Hospital	Cardiff	Wales	United Kingdom	CF14 2TL
29	Basingstoke and North Hampshire Hospital	Basingstoke		United Kingdom
30	Birmingham Heartlands Hospital	Birmingham		United Kingdom
31	Castle Hill Hospital	Cottingham		United Kingdom
32	University Hospitals Coventry and Warwickshire	Coventry		United Kingdom
33	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom
34	St James Hospital	Leeds		United Kingdom
35	Leicester Royal Infirmary	Leicester		United Kingdom
36	Norfolk and Norwich University Hospital	Norwich		United Kingdom
37	Churchill Hospital	Oxford		United Kingdom
38	Queens Hospital	Romford		United Kingdom
39	Weston Park	Sheffield		United Kingdom
40	Great Western Hospital	Swindon		United Kingdom
41	Musgrove Park Hospital	Taunton		United Kingdom