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Trial registered on ANZCTR


Registration number
ACTRN12609000035224
Ethics application status
Approved
Date submitted
8/01/2009
Date registered
19/01/2009
Date last updated
20/02/2019
Date data sharing statement initially provided
20/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
TOP GEAR: Trial of Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma
A randomised phase II/III trial of preoperative chemoradiotherapy versus preoperative chemotherapy for resectable gastric cancer
Scientific title
TOP GEAR: Trial of Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma

A randomised II/III trial of preoperative chemoradiotherapy versus preoperative chemotherapy for resectable gastric cancer
Secondary ID [1] 253112 0
AGITG protocol number: AG0407GR
Secondary ID [2] 282364 0
TROG number: 08.08
Secondary ID [3] 282365 0
EORTC protocol number: 22114-40111
Secondary ID [4] 282366 0
NCIC CTG protocol number: GA.1
Secondary ID [5] 283042 0
ClinicalTrials.gov: NCT01924819
Universal Trial Number (UTN)
U1111-1146-0762
Trial acronym
TOPGEAR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Resectable Gastric Cancer 4175 0
Condition category
Condition code
Cancer 4384 4384 0 0
Stomach

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group 2:
Chemotherapy:
ECF - Epirubicin (E) 50 mg/m2 IV day 1, Cisplatin (C) 60 mg/m2 IV day 1, 5-Fluorouracil (F)200 mg/m2/d IV 21 day continuous infusion
or
ECX - Epirubicin 50 mg/m2 IV day 1, Cisplatin 60 mg/m2 IV day 1, Capecitabine (X = Xeloda) 625mg/m2, bid days 1-21
or
EOX - Epirubicin 50mg/m2 IV day 1, Oxaliplatin (O) 130mg/m2 IV day 1, Capecitabine 625mg/m2, bid days 1-21
or
FLOT - 5-Fluorouracil 2600 mg/m² IV 24 h infusion day 1, Leucovorin (L) 200 mg/m² IV day 1, Oxaliplatin 85 mg/m² IV day 1, Docetaxel (T) 50 mg/m² IV day 1

Pre-operative chemoradiotherapy (CRT):
Continuous infusional 5-FU- 200 mg/m2/day, 7 days per week, throughout the entire period of radiotherapy via CADD pump (or other infuser device depending on usual practice) through a PICC line.
or
Capecitabine 825mg/m2, bid, days 1 to 5 each week of RT (without weekends)

Radiotherapy: 45 Gy of radiation in 25 fractions, five days per week for five weeks.

Surgery: The acceptable resections are a total gastrectomy, a subtotal gastrectomy, and an esophago-gastrectomy (Ivor-Lewis esophago-gastrectomy for gastroesophageal junction [GEJ] cancers [Siewert Type II and Siewert Type III] invading up to but no more than 2cm of the lower esophagus). It is considered that the minimum extent of the operation should be a D1+ lymph node dissection but it is recommended that a D2 dissection should be performed or a D1+ for GEJ cancers requiring an esophago-gastrectomy.

Treatment schedule: Patients randomised to Group 2 will receive 2 cycles of ECF or EOX at three-weekly intervals pre-operatively or 3 cycles of FLOT at two-weekly intervals, then 2-4 week break between last cycle of chemotherapy and chemoradiotherapy. Following chemoradiotherapy patients should have up to 6 weeks break between chemoradiotherapy and surgery and then 3 cycles of ECF or EOX or 4 cycles of FLOT should be commenced post-operatively between 4-10 weeks after surgery.
Intervention code [1] 3894 0
Treatment: Drugs
Intervention code [2] 257634 0
Treatment: Other
Comparator / control treatment
Group 1:
Chemotherapy
ECF - Epirubicin (E) 50 mg/m2 IV day 1, Cisplatin (C) 60 mg/m2 IV day 1, 5-Fluorouracil (F)200 mg/m2/d IV 21 day continuous infusion
or
ECX - Epirubicin 50 mg/m2 IV day 1, Cisplatin 60 mg/m2 IV day 1, Capecitabine (X = Xeloda) 625mg/m2, bid days 1-21
or
EOX - Epirubicin 50mg/m2 IV day 1, Oxaliplatin (O) 130mg/m2 IV day 1, Capecitabine 625mg/m2, bid days 1-21
or
FLOT - 5-Fluorouracil 2600 mg/m² IV 24 h infusion day 1, Leucovorin (L) 200 mg/m² IV day 1, Oxaliplatin 85 mg/m² IV day 1, Docetaxel (T) 50 mg/m² IV day 1

Surgery: The acceptable resections are a total gastrectomy, a subtotal gastrectomy, and an esophago-gastrectomy (Ivor-Lewis esophago-gastrectomy for gastroesophageal junction [GEJ] cancers [Siewert Type II and Siewert Type III] invading up to but no more than 2cm of the lower esophagus). It is considered that the minimum extent of the operation should be a D1+ lymph node dissection but it is recommended that a D2 dissection should be performed or a D1+ for GEJ cancers requiring an esophago-gastrectomy.

Treatment schedule: Patients randomised to Group 1 will receive 3 cycles of ECF or ECX or EOX at three-weekly intervals or 4 cycles of FLOT at two-weekly intervals pre-operatively . Surgery should be performed within 6 weeks of the end of the last ECF cycle. Following surgery, 3 cycles of ECF or ECX or EOX or 4 cycles of FLOT should be commenced between 4-10 weeks after surgery.
Control group
Active

Outcomes
Primary outcome [1] 5264 0
Overall survival
Timepoint [1] 5264 0
Overall survival will be measured from date of patient entry onto the study to date of death from any cause. Following completion of study every 6 months from year 2 assessment until 5 years (date to be calculated from last day of last post-op ECF (or ECX) cycle)
Secondary outcome [1] 8874 0
Disease Free Survival. Disease free survival (DFS), defined as the time from commencement of protocol treatment to disease progression or death without disease progression. Patients without an event prior to the study close-out date will be censored at the study close-out date or at the date of last contact if the patient is lost to follow-up. If a patient receives a subsequent anti-cancer therapy without prior documentation of disease progression, the patient will be censored at the date the patient was last seen for tumour assessment before starting the new chemotherapy. Notional significance will be 0.05 for comparisons of disease free survival.
Timepoint [1] 8874 0
Following completion of study every 6 months from year 2 assessment until 5 years (date to be calculated from last day of last post-op ECF (or ECX) cycle)
Secondary outcome [2] 8875 0
Toxicity as measured by adverse events. Examples include febrile neutropaenia, nausea, vomiting and oesophagitis, which will be measured by clinician assessment and graded according to the National Cancer Institute Common Terminology Criteria Grading Scale v3.0 (NCI CTCAEv3.0).
Timepoint [2] 8875 0
Following completion of study every 6 months from year 2 assessment until 5 years (date to be calculated from last day of last post-op ECF (or ECX) cycle)
Secondary outcome [3] 8876 0
Pathological Response Rate. The definition of Patholigic response rate is the proportion of patients achieving a complete or partial pathologic response in each treatment group will be compared with the conditional binomial exact test. The 95% confidence intervals for the treatment extimates and for the differences between arms will be presented. With multiple logistic regressions modelling, the potential influence of patient baseline characteristics on these rates will be studied.
Timepoint [3] 8876 0
Surgery should be performed within 6 weeks of the final radiation dose for Group 2 and within 6 weeks of the end of the last ECF (or ECX) cycle for Group 1.
Secondary outcome [4] 8877 0
Surgical R0 resection rate. This is complete macroscopic resection of gross tumour with negative surgical margins. The margins assessed include proximal (esophageal, gastric), distal (gastric for proximal resection or duodenum) and lateral margins (posterior cardia, GEJ, esophageal and nodal tissue on the lesser curve) of the specimen. The margin will be deemed involved (R1 resection) if there is carcinoma seen at or within 1mm of the margin. It will be deemed uncertain if there are malignant cells within 10mm of the margin and clear otherwise. The presence of carcinoma at a true serosal surface will be noted but not considered an involved surgical margin.
Timepoint [4] 8877 0
Surgery should be performed within 6 weeks of the final radiation dose for Group 2 and within 6 weeks of the end of the last ECF (or ECX) cycle for Group 1.

Eligibility
Key inclusion criteria
1. Histologically proven adenocarcinoma of the stomach or gastroesophageal junction that is:
a. Stage IB (T1N1 only, T2N0 not eligible) – IIIC, i.e. T3 – T4 and/or N +ve, according to AJCC 7th edition.
b. Considered operable following initial staging investigations (surgeon believes that an R0 resection can be achieved).
(Gastroesophageal tumours are defined as tumours that arise in the cardia or at the GEJ that do not involve more than 2cm of the lower esophagus, i.e. Siewert Type II and Siewert Type III)
2. Age >= 18 years
3. ECOG performance status 0-1
4. Adequate organ function defined as follows:
Bone marrow: Haemoglobin >= 90 g/L
Absolute neutrophil count (ANC) >= 1.5 x 109 /L
White blood cell count >= 3 x 109 /L
Platelet count >= 100 x 109 /L
Hepatic: Serum bilirubin <= 1.5 x ULN
AST and/or ALT <= 3.0 x ULN
Renal: Serum creatinine <= 0.150 mmol/L, and calculated creatinine clearance >= 50mL/min.
5. Disease which can be radically treated with radiotherapy to 45 Gy with standard fractionation
6. Any patient with a history of ischaemic heart disease and abnormal ECG, or who is over 60 years of age should have a pre-treatment evaluation of cardiac function with a MUGA scan or echocardiogram. Patients will only be included if the left ventricular ejection fraction is >= 50%.
7. Written informed consent obtained before randomization.
8. Negative pregnancy test for women of childbearing potential within 7 days of commencing study treatment. Males and females of reproductive potential must agree to practice adequate contraceptive measures
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
None of the following must apply:
1. Evidence of metastatic disease
2. Prior chemotherapy or radiotherapy
3. Patients with a past history of cancer in the 5 years before randomization except for the following. Patients with squamous or basal cell carcinoma of the skin that has been effectively treated, and patients with carcinoma in situ of the cervix that has been treated by operation only are eligible, even if they were diagnosed and treated within the 5 years before randomization.
4. Patients with other significant underlying medical conditions that may be aggravated by the study treatment or are not controlled.
5. Pregnant or lactating females or female patients of childbearing potential who have not been surgically sterilized or are without adequate contraceptive measures.
6. Cardiac failure and other contraindications to epirubicin.
7. Patients with impaired gastrointestinal absorption for whatever reason.
8. Patients medically unfit for cisplatin chemotherapy due to one or more of the following reasons:
a. Clinically significant sensori-neural hearing impairment (audiometric abnormalities without corresponding clinical deafness will not be regarded as a contraindication to cisplatin)
b. Severe tinnitus
c. Renal impairment (GFR<= 50ml/min)
d. Peripheral neuropathy => grade 2
e. Inability to tolerate intravenous hydration e.g due to cardiac disease
f. Co-morbidities (based on clinical judgement by the investigator) that in the view of the investigator would preclude the safe administration of cisplatin.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be carried out by site staff via an internet based central randomisation system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The method of randomisation will be using minimisation where patients will be stratified on: age (< 50yrs vs 50yrs-70yrs vs = >70yrs), primary tumour site: gastroesophageal junction (esophago-gastrectomy [Ivor Lewis]) vs gastroesophageal junction (total gastrectomy) vs upper third vs middle third vs lower third vs tumour extends into 2 or more of the adjacent sites, clinical tumour stage (T1 and T2 vs T3 and T4), nodal status (N+ve vs N-ve), gender, treating institution, and baseline staging investigations.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC,QLD,SA,WA,TAS
Recruitment hospital [1] 904 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 905 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 906 0
Westmead Hospital - Westmead
Recruitment hospital [4] 907 0
Prince of Wales Hospital - Randwick
Recruitment hospital [5] 908 0
Liverpool Hospital - Liverpool
Recruitment hospital [6] 909 0
St George Hospital - Kogarah
Recruitment hospital [7] 910 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [8] 911 0
Nepean Hospital - Kingswood
Recruitment hospital [9] 912 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [10] 913 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [11] 914 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [12] 915 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [13] 916 0
Monash Medical Centre - Moorabbin campus - East Bentleigh
Recruitment hospital [14] 917 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [15] 918 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [16] 919 0
Royal Perth Hospital - Perth
Recruitment hospital [17] 920 0
Royal Hobart Hospital - Hobart
Recruitment hospital [18] 921 0
Launceston General Hospital - Launceston
Recruitment hospital [19] 1447 0
Wollongong Hospital - Wollongong
Recruitment hospital [20] 4961 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [21] 4962 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [22] 4963 0
Sunshine Hospital - St Albans
Recruitment outside Australia
Country [1] 1521 0
New Zealand
State/province [1] 1521 0
Country [2] 5025 0
Canada
State/province [2] 5025 0
Country [3] 5026 0
Belgium
State/province [3] 5026 0
Country [4] 5027 0
France
State/province [4] 5027 0
Country [5] 5028 0
Germany
State/province [5] 5028 0
Country [6] 5029 0
Israel
State/province [6] 5029 0
Country [7] 5030 0
Italy
State/province [7] 5030 0
Country [8] 5031 0
Poland
State/province [8] 5031 0
Country [9] 5032 0
Slovenia
State/province [9] 5032 0
Country [10] 5033 0
Spain
State/province [10] 5033 0
Country [11] 5034 0
Switzerland
State/province [11] 5034 0
Country [12] 5035 0
Turkey
State/province [12] 5035 0
Country [13] 5036 0
Czech Republic
State/province [13] 5036 0

Funding & Sponsors
Funding source category [1] 4356 0
Government body
Name [1] 4356 0
Cancer Australia through The Priority-driven Collaborative Cancer Research Scheme
Address [1] 4356 0
Cancer Australia
PO Box 1201
Dickson ACT 2602
Country [1] 4356 0
Australia
Funding source category [2] 4357 0
Government body
Name [2] 4357 0
Cancer Council Australia
Address [2] 4357 0
GPO Box 4708
Sydney, NSW 2001
Country [2] 4357 0
Australia
Funding source category [3] 287132 0
Government body
Name [3] 287132 0
National Health and Medical Research Council
Address [3] 287132 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [3] 287132 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastro-Intestinal Trials Group (AGITG)
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 3921 0
None
Name [1] 3921 0
Address [1] 3921 0
Country [1] 3921 0
Other collaborator category [1] 277366 0
Other Collaborative groups
Name [1] 277366 0
European Organisation for Research and Treatment of Cancer (EORTC)
Address [1] 277366 0
Avenue Emmanuel Mounier 83/11 1200
Brussels
Country [1] 277366 0
Belgium
Other collaborator category [2] 277367 0
Other Collaborative groups
Name [2] 277367 0
NCIC Clinical Trials Group (NCIC CTG)
Address [2] 277367 0
Cancer Research Institute
Queen's University
10 Stuart Street
Kingston, ON K7L 3N6
Country [2] 277367 0
Canada

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6409 0
Cancer Institue NSW Ethics Committee
Ethics committee address [1] 6409 0
PO Box 41
ALEXANDRIA NSW 1435
Ethics committee country [1] 6409 0
Australia
Date submitted for ethics approval [1] 6409 0
Approval date [1] 6409 0
15/10/2008
Ethics approval number [1] 6409 0
2008C/03/045
Ethics committee name [2] 294045 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [2] 294045 0
Research Ethics and Governance Office
Royal Prince Alfred Hospital
Camperdown NSW 2050
Ethics committee country [2] 294045 0
Australia
Date submitted for ethics approval [2] 294045 0
Approval date [2] 294045 0
18/10/2013
Ethics approval number [2] 294045 0
X13-0174

Summary
Brief summary
This study aims to evaluate whether the addition of pre-operative chemoradiotherapy to chemotherapy is superior to chemotherapy alone in patients undergoing surgery for resectable gastric cancer.

You may be eligible to join this study if you are aged 18 years or over and have a diagnosis of stomach cancer that is suitable for removal with surgery.
If you join the study, you will be expected to attend the following visits over a period of approximately 28 weeks:
• 1 set of screening visits over a period of 3 weeks
• Up to 20 chemotherapy visits (once a week during chemotherapy)
• 25 radiotherapy visits if being treated with chemoradiation (daily, Monday to Friday, for 5 weeks)
• 1 set of pre-surgery visits over a period of 3 weeks
• 1 surgery

Following treatment, you will be expected to attend approximately 14 follow-up visits over a period of 5 years (one visit every 3-6 months).
You will be asked to fill in Quality of Life questionnaires before you start treatment, twice during preoperative treatment, before surgery, around 1, 4, 6, 9 and 12 months after surgery and at each subsequent follow-up appointment until 5 years. This is so we can find out how you are feeling in yourself and the effect treatment has upon you and your daily activities.

The study aims to further medical knowledge and may improve future treatment of stomach cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 35076 0
Prof Trevor Leong
Address 35076 0
Division of Radiation Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne Victoria 8006
Country 35076 0
Australia
Phone 35076 0
+61 3 9656 1111
Fax 35076 0
+61 3 9656 1424
Email 35076 0
trevor.leong@petermac.org
Contact person for public queries
Name 12423 0
Ms Christine Aiken
Address 12423 0
National Health and Medical Research Council (NHMRC) Clinical Trials Centre Locked Bag 77 Camperdown NSW 1450
Country 12423 0
Australia
Phone 12423 0
+61 2 9562 5000
Fax 12423 0
+61 2 9562 5094
Email 12423 0
topgear@ctc.usyd.edu.au
Contact person for scientific queries
Name 3351 0
Prof Trevor Leong
Address 3351 0
Division of Radiation Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne Victoria 8006
Country 3351 0
Australia
Phone 3351 0
+61 3 9656 1111
Fax 3351 0
+61 3 9656 1424
Email 3351 0
trevor.leong@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable