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Trial registered on ANZCTR


Registration number
ACTRN12616000420448
Ethics application status
Approved
Date submitted
30/03/2016
Date registered
1/04/2016
Date last updated
14/06/2019
Date data sharing statement initially provided
14/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised Phase III Double-Blind Placebo-Controlled Study of regorafenib in
Refractory Advanced Gastro-Oesophageal Cancer (AGOC)
Scientific title
A Randomised Phase III Double-Blind Placebo-Controlled Study to determine if regorafenib improves overall survival in refractory Advanced Gastro-Oesophageal Cancer (AGOC)
Secondary ID [1] 288724 0
AG0315OG
Secondary ID [2] 296251 0
CTC0140
Universal Trial Number (UTN)
Trial acronym
Integrate II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced (metastatic or locally recurrent) Gastro-Oesophageal Cancer (AGOC) 297961 0
Condition category
Condition code
Cancer 298120 298120 0 0
Stomach
Cancer 298121 298121 0 0
Oesophageal (gullet)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group 1: Regorafenib will be self-administered by participants at 160mg (4 x 40mg tablets) orally once daily on days 1-21 of each 28 day cycle plus best supportive care until progression or prohibitive toxicity as defined by the protocol. The pharmacy at Participating Institutions will maintain a record of drugs dispensed for each participant and tablets returned.
Intervention code [1] 294160 0
Treatment: Drugs
Comparator / control treatment
Group 2: Placebo (matching in appearance to regorafenib) made of microcrystalline cellulose, will be self-administered by participants (4 x 40mg tablets) orally once daily on days 1-21 of each 28 day cycle plus best supportive care until progression or prohibitive toxicity as defined by the protocol.
Control group
Placebo

Outcomes
Primary outcome [1] 297627 0
Overall survival (death from any cause)
Timepoint [1] 297627 0
Patient status updates will be sought every 2-4 weeks at clinic visit whilst on treatment and then every 8 weeks until death.
Secondary outcome [1] 321614 0
To evaluate progression free survival (disease progression or death)
Timepoint [1] 321614 0
Tumour response will be assessed according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) guidelines via CT scan within 21 days prior to randomisation and then every 8 weeks until disease progression.
Secondary outcome [2] 321615 0
Objective tumour response rate (partial or complete response)
Timepoint [2] 321615 0
Tumour response will be assessed according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) guidelines via CT scan within 21 days prior to randomisation and then every 8 weeks until disease progression.
Secondary outcome [3] 321616 0
Patient-rated quality of life (EORTC QLQ-C30, STO22, EQ5D-5L, and Patient D.A.T.A form)
Timepoint [3] 321616 0
Patient rated quality of life will be assessed via self-report questionnaires at baseline and every 4 weeks thereafter until disease progression.
Secondary outcome [4] 321617 0
Safety- The NCI Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE) will be used to classify and grade the intensity of adverse events after each treatment cycle.
AEs include the following;
- All suspected adverse drug or device reactions
- All reactions from drug or device – overdose, abuse, withdrawal, sensitivity, toxicity or
failure of expected pharmacological action (if appropriate)
- Apparently unrelated illnesses, including the worsening (severity, frequency) of pre-existing illnesses
- Injury or accidents.
- Abnormalities in physiological testing or physical examination that require clinical intervention or further investigation (beyond ordering a repeat examination)
- Laboratory abnormalities that require clinical intervention or further investigation (beyond
ordering a laboratory test).
- Any untoward event that occurs after the protocol-specified reporting period, which the Investigator believes may be related to the study drug or device.
Timepoint [4] 321617 0
Adverse events will be reported at baseline and assessed 4 weekly whilst on study treatment, and at the 30 Day safety visit.

Eligibility
Key inclusion criteria
1. Adults (18 years or over) with metastatic or locally recurrent gastro-oesophageal cancer which:
a. has arisen in any primary gastro-oesophageal site (oesophago-gastric junction (GOJ) or stomach); and
b. is of adenocarcinoma or undifferentiated carcinoma histology , and
c. is evaluable according to Response Evaluation Criteria in Solid Tumours (RECIST Version 1.1) by computed tomography (CT) scan performed within 21 days prior to randomisation. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrolment; and
d. has failed or been intolerant to a minimum of 2 lines of prior anti-cancer therapy for recurrent/metastatic disease which must have included at least one platinum agent and one fluoropyrimidine analogue, Note: Neoadjuvant or adjuvant chemotherapy or chemoradiotherapy will be considered as first line treatment where people have relapsed or progressed within 6 months of completing treatment; Radiosensitising chemotherapy given solely for this purpose concurrent with palliative radiation will not be considered as a line of treatment. Ramucirumab monotherapy, or immunotherapy with a checkpoint inhibitor, will be considered a line of treatment.
e. HRE2- positive participants mush have received trastuzumab.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
3. Ability to swallow oral medication.
4. Adequate bone marrow function (Platelets greater than or equal to 100x109/L; Absolute Neutrophil Count (ANC) greater than or equal to 1.5x109/L and Haemoglobin greater than or equal to 9.0g/dL).
5. Adequate renal function (Creatinine clearance greater than 50 ml/min) based on either the Cockcroft-Gault formula (Appendix 2), 24-hour urine or Glomerular Filtration Rate (GFR) scan; and serum creatinine less than or equal to 1.5 x Upper Limit of Normal (ULN).
6. Adequate liver function (Serum total bilirubin less than or equal to 1.5 x ULN, and INR less than or equal to 1.5 x ULN, and Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) less than or equal to 2.5 x ULN (less than or equal to 5 x ULN for participants with liver metastases)).
Participants being treated with an anti-coagulant, such as warfarin or heparin, will be allowed to participate provided that no prior evidence of an underlying abnormality in these parameters exists.
7. Adequate cardiac function (Left Ventricular Ejection Fraction (LVEF) greater than or equal to 50% or above the lower limit of normal (LLN) for the Institution (whichever is lower).
Cardiac function should be assessed within 3 months prior to randomisation, but after completion of any anthracycline containing chemotherapy.
8. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments and follow-up.
9. Study treatment both planned and able to start within 7 days after randomisation (note: subjects randomised on a Friday should commence treatment no earlier than the following Monday)
10. Signed, written informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known allergy to the investigational product drug class or excipients in the regorafenib
2. Poorly controlled hypertension (systolic blood pressure greater than 140mmHg or diastolic pressure greater than 90mmHg despite optimal medical management).
3. Participants with known uncontrolled malabsorption syndromes
4. Any prior anti-VEGF targeted therapy using small molecule VEGF TKIs (e.g. apatinib). Prior anti-VEGF targeted monoclonal antibody therapies (e.g. bevacizumab and ramucirumab) are permitted.
5. Treatment with any previous drug therapy within 2 weeks prior to first dose of study treatment. This includes any investigational therapy.
6. Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
7. Concurrent treatment with strong CYP3A4 inhibitors or inducers.
8. Palliative radiotherapy, unless more than 14 days have elapsed between completion of radiation and the date of registration, and adverse events resulting from radiation have resolved to less than Grade 2 according to CTCAE V4.03
9. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
10. Arterial thrombotic or ischaemic events, such as cerebrovascular accident within 6 months prior to randomization.
11. Venous thrombotic events and pulmonary embolism within 3 months prior to randomization
12. Any haemorrhage or bleeding event greater than or equal to Grade 3 according to CTCAE v4.03 within 4 weeks prior to randomization.
13. Non-healing wound, ulcer, or bone fracture.
14. Interstitial lung disease with ongoing signs and symptoms
15. Clinical hyperthyroidism or hypothyroidism. Note: non-clinically significant abnormal TFTs (abnormal TSH and abnormal T3 and/or abnormal T4) considered to be due to sick euthyroid syndrome is allowed.
16. Persistent proteinuria of greater than or equal to Grade 3 according to CTCAE v4.03
(Equivalent to greater than or equal to 3.5g of protein over 24 hours, measured on either a random specimen of 24 hour collection).
17. Uncontrolled metastatic disease to the central nervous system.
To be eligible, CNS metastases should have been treated with surgery and/or radiotherapy and the patient should have been receiving a stable dose of steroids for at least 2 weeks prior to randomization, with no deterioration in neurological symptoms during this time.
18. History of another malignancy within 2 years prior to randomization. Participants with the following are eligible for this study:
a) curatively treated cervical carcinoma in situ,
b) non-melanomatous carcinoma of the skin,
c) superficial bladder tumours (T1a [Non-invasive tumour], and Tis[Carcinoma in situ]),
d) treated thyroid papillary cancer
19. Any significant active infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated. Participants with known Hepatitis B/C infection will be allowed to participate providing evidence of viral suppression has been documented and the patient remains on appropriate anti-viral therapy.
20. Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol.
21. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to randomization. Men must have been surgically sterilized or use a barrier method of contraception.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 6849 0
The Townsville Hospital - Douglas
Recruitment hospital [2] 7339 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 7340 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [4] 7341 0
Gosford Hospital - Gosford
Recruitment hospital [5] 7342 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [6] 7343 0
Monash Medical Centre - Moorabbin campus - East Bentleigh
Recruitment hospital [7] 7345 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [8] 7346 0
Royal Hobart Hospital - Hobart
Recruitment hospital [9] 7347 0
Newcastle Private Hospital - New Lambton Heights
Recruitment hospital [10] 12088 0
The Canberra Hospital - Garran
Recruitment hospital [11] 12089 0
Westmead Hospital - Westmead
Recruitment hospital [12] 12090 0
Prince of Wales Hospital - Randwick
Recruitment hospital [13] 12091 0
Concord Repatriation Hospital - Concord
Recruitment hospital [14] 12092 0
St George Hospital - Kogarah
Recruitment hospital [15] 12093 0
Coffs Harbour Base Hospital - Coffs Harbour
Recruitment hospital [16] 12094 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [17] 12095 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [18] 12096 0
Border Medical Oncology - Albury
Recruitment hospital [19] 12097 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [20] 12098 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [21] 12099 0
Ashford Cancer Centre: Adelaide Cancer Centre - Kurralta Park
Recruitment hospital [22] 12100 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [23] 12101 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [24] 12102 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [25] 12103 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [26] 12104 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 14514 0
4814 - Douglas
Recruitment postcode(s) [2] 15126 0
2065 - St Leonards
Recruitment postcode(s) [3] 15127 0
2010 - Darlinghurst
Recruitment postcode(s) [4] 15128 0
2250 - Gosford
Recruitment postcode(s) [5] 15129 0
2485 - Tweed Heads
Recruitment postcode(s) [6] 15130 0
3165 - East Bentleigh
Recruitment postcode(s) [7] 15131 0
3355 - Wendouree
Recruitment postcode(s) [8] 15133 0
6008 - Subiaco
Recruitment postcode(s) [9] 15134 0
7000 - Hobart
Recruitment postcode(s) [10] 15135 0
2305 - New Lambton Heights
Recruitment postcode(s) [11] 24250 0
2605 - Garran
Recruitment postcode(s) [12] 24251 0
2145 - Westmead
Recruitment postcode(s) [13] 24252 0
2031 - Randwick
Recruitment postcode(s) [14] 24253 0
2139 - Concord
Recruitment postcode(s) [15] 24254 0
2217 - Kogarah
Recruitment postcode(s) [16] 24255 0
2450 - Coffs Harbour
Recruitment postcode(s) [17] 24256 0
2444 - Port Macquarie
Recruitment postcode(s) [18] 24257 0
3084 - Heidelberg
Recruitment postcode(s) [19] 24258 0
3690 - Wodonga
Recruitment postcode(s) [20] 24259 0
4029 - Herston
Recruitment postcode(s) [21] 24260 0
5042 - Bedford Park
Recruitment postcode(s) [22] 24261 0
5037 - Kurralta Park
Recruitment postcode(s) [23] 24262 0
5011 - Woodville
Recruitment postcode(s) [24] 24263 0
6009 - Nedlands
Recruitment postcode(s) [25] 24264 0
0810 - Tiwi
Recruitment postcode(s) [26] 24265 0
4575 - Birtinya
Recruitment postcode(s) [27] 24266 0
3168 - Clayton
Recruitment outside Australia
Country [1] 7657 0
New Zealand
State/province [1] 7657 0
Country [2] 7658 0
Canada
State/province [2] 7658 0
Country [3] 7659 0
Taiwan, Province Of China
State/province [3] 7659 0
Country [4] 7660 0
Korea, Republic Of
State/province [4] 7660 0
Country [5] 7661 0
Japan
State/province [5] 7661 0
Country [6] 7663 0
United States of America
State/province [6] 7663 0

Funding & Sponsors
Funding source category [1] 293076 0
Commercial sector/Industry
Name [1] 293076 0
Bayer HealthCare Pharmaceuticals Inc.
Address [1] 293076 0
Bayer HealthCare Pharmaceuticals Inc.
100 Bayer Boulevard
Whippany, NJ 07981
Country [1] 293076 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
The Australasian Gastro-Intestinal Trials Group (AGITG)
Address
Australasian Gastro-Intestinal Trials Group (AGITG)
Level 6, 119-143 Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 291857 0
None
Name [1] 291857 0
Address [1] 291857 0
Country [1] 291857 0
Other collaborator category [1] 278866 0
University
Name [1] 278866 0
NHMRC Clinical Trials Centre, The University of Sydney
Address [1] 278866 0
NHMRC Clinical Trials Centre
Level 6, 92-94 Parramatta Road
Camperdown NSW 2050
Country [1] 278866 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294584 0
Northern Sydney Local Distrct HREC
Ethics committee address [1] 294584 0
Level 13, Kolling Building
Royal North Shore Hospital
St. Leonard’s, NSW, 2065
Ethics committee country [1] 294584 0
Australia
Date submitted for ethics approval [1] 294584 0
30/11/2015
Approval date [1] 294584 0
31/03/2016
Ethics approval number [1] 294584 0
HREC/15/HAWKE/491
Ethics committee name [2] 301616 0
ACT Health Human Research Ethics Committee
Ethics committee address [2] 301616 0
ACT Health
GPO Box 825
Canberra City ACT 2601.
Ethics committee country [2] 301616 0
Australia
Date submitted for ethics approval [2] 301616 0
Approval date [2] 301616 0
30/11/2016
Ethics approval number [2] 301616 0
Ethics committee name [3] 301617 0
Bellberry Human Research Ethics Committee A
Ethics committee address [3] 301617 0
129 Glen Osmond Road
Eastwood Adelaide
South Australia 5063
Ethics committee country [3] 301617 0
Australia
Date submitted for ethics approval [3] 301617 0
Approval date [3] 301617 0
23/12/2016
Ethics approval number [3] 301617 0
Ethics committee name [4] 301618 0
Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee
Ethics committee address [4] 301618 0
Hospital Avenue, Nedlands,
Perth 6009, Western Australia
Ethics committee country [4] 301618 0
Australia
Date submitted for ethics approval [4] 301618 0
Approval date [4] 301618 0
20/01/2017
Ethics approval number [4] 301618 0
Ethics committee name [5] 301619 0
St John of God Health Care Human Research Ethics Committee
Ethics committee address [5] 301619 0
St John of God Health Care Human Research Ethics Committee
C/o St John of God Subiaco Hospital
12 Salvado Road
Subiaco Western Australia 6008
Ethics committee country [5] 301619 0
Australia
Date submitted for ethics approval [5] 301619 0
Approval date [5] 301619 0
10/11/2016
Ethics approval number [5] 301619 0
Ethics committee name [6] 301620 0
Tasmania Health and Medical Human Research Ethics Committee
Ethics committee address [6] 301620 0
Office of Research Services, University of Tasmania, Private Bag 1, Hobart, TAS, 7001
Ethics committee country [6] 301620 0
Australia
Date submitted for ethics approval [6] 301620 0
Approval date [6] 301620 0
18/11/2016
Ethics approval number [6] 301620 0
Ethics committee name [7] 301621 0
The Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research
Ethics committee address [7] 301621 0
Ethics administration officer
Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research
PO Box 41096
Casuarina NT 0811
Ethics committee country [7] 301621 0
Australia
Date submitted for ethics approval [7] 301621 0
Approval date [7] 301621 0
14/10/2016
Ethics approval number [7] 301621 0
Ethics committee name [8] 301622 0
Southern Health and Disability Ethic Committee
Ethics committee address [8] 301622 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [8] 301622 0
New Zealand
Date submitted for ethics approval [8] 301622 0
Approval date [8] 301622 0
02/12/2016
Ethics approval number [8] 301622 0

Summary
Brief summary
The purpose of this Phase III study is to determine whether regorafenib is effective in prolonging survival in patients with Advanced Gastro-oesophageal Carcinoma

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with advanced (metastatic or locally recurrent) Gastro-oesophageal Carcinoma
which has not responded to a minimum of 2 lines of prior anti-cancer therapy.

Trial Details:
Participants in this trial will be randomly (by chance) allocated to one of two groups. Participants will either take regorafenib (Group 1) or a placebo (Group 2) tablet oncer per day on days 1-21 of each 28 day cycle. Treatment will continue until disease progression or prohibitive adverse events. Participants will not know whether they are taking regorafenib or the placebo until after the trial is completed. Participants will be followed up every 2-4 weeks in order to evaluate how they are responding to treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64266 0
A/Prof Nick Pavlakis
Address 64266 0
Royal North Shore Hospital
Reserve Road
St Leonards NSW 2065
Country 64266 0
Australia
Phone 64266 0
+61 (0)2 9926 5020
Fax 64266 0
+61 (0)2 9438 2604
Email 64266 0
nick.pavlakis@sydney.edu.au
Contact person for public queries
Name 64267 0
Mr Eric Tsobanis (Project Manager)
Address 64267 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 64267 0
Australia
Phone 64267 0
+61 2 9562 5000
Fax 64267 0
+61 2 9562 5094
Email 64267 0
INTEGRATEII@ctc.usyd.edu.au
Contact person for scientific queries
Name 64268 0
Mr Eric Tsobanis (Project Manager)
Address 64268 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 64268 0
Australia
Phone 64268 0
+61 2 9562 5000
Fax 64268 0
+61 2 9562 5094
Email 64268 0
INTEGRATEII@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Please contact the CTC for the publication and data sharing SOP
What supporting documents are/will be available?
No other documents available
Summary results
No Results