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Trial registered on ANZCTR


Registration number
ACTRN12612000239864
Ethics application status
Approved
Date submitted
8/02/2012
Date registered
24/02/2012
Date last updated
16/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised Phase II Double-Blind Study of Regorafenib or Placebo in Refractory Advanced Oesophago-Gastric Cancer (AOGC)
Scientific title
A randomised phase II double-blind study to evaluate the effect of Regorafenib or placebo on progression-free survival and objective response rate in refractory advanced oesophago-gastric cancer (AOGC)
Secondary ID [1] 279900 0
AG0212OG
Universal Trial Number (UTN)
Trial acronym
INTEGRATE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced (metastatic or locally recurrent) oesophago-gastric cancer. 285804 0
Condition category
Condition code
Cancer 285980 285980 0 0
Oesophageal (gullet)
Cancer 285981 285981 0 0
Stomach

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 until progression or prohibitive toxicity as defined by the protocol.
Intervention code [1] 284223 0
Treatment: Drugs
Comparator / control treatment
Group 2: Placebo will be self-administered by participants (4 x 40mg tablets) orally once daily on days 1-21 of each 28 day cycle until progression or prohibitive toxicity as defined by the protocol.
Control group
Placebo

Outcomes
Primary outcome [1] 286475 0
To evaluate progression free survival (disease progression or death)
Timepoint [1] 286475 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 4 weeks for the first 12 weeks and then every 6 weeks for a further 12 weeks and then every 8 weeks thereafter until disease progression.
Secondary outcome [1] 295957 0
Objective response rate (partial or complete response)
Timepoint [1] 295957 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 4 weeks for the first 12 weeks and then every 6 weeks for a further 12 weeks and then every 8 weeks thereafter until disease progression.
Secondary outcome [2] 296080 0
Clinical benefit (complete response (CR) or partial response (PR), or stable disease (SD)).
Timepoint [2] 296080 0
Clinical benefit will be assessed according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) guidelines via CT scan at 8 weeks.
Secondary outcome [3] 296081 0
Progression free survival by Vascular Endothelial Growth Factor-A (VEGFA) circulating levels (plasma) with disease progression or death for plasma VEGF high and low subgroups.
Timepoint [3] 296081 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 4 weeks for the first 12 weeks and then every 6 weeks for a further 12 weeks and then every 8 weeks thereafter until disease progression. 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 [4] 296082 0
Safety (Adverse events graded according to NCI CTC AE Version 4.0)
Timepoint [4] 296082 0
Adverse events will be reported at baseline and assessed 4 weekly whilst on study treatment, and at the end of treatment study visit.
Secondary outcome [5] 296083 0
Patient-rated quality of life (EORTC QLQ-C30, STO22, EQ5D, and Patient D.A.T.A form)
Timepoint [5] 296083 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 [6] 296816 0
Overall survival (death from any cause)
Timepoint [6] 296816 0
Patient status updates will be sought every 2-4 weeks at clinic visit whilst on treatment and then every 8 weeks until death.

Eligibility
Key inclusion criteria
1. Adults (18 years or over) with metastatic or locally recurrent oesophago-gastric cancer which:
i) has arisen in any primary oesophago-gastric site (oesophago-gastric junction (OGJ) or stomach); and
ii) is of adenocarcinoma or undifferentiated carcinoma histology, and
iii) is measurable according to Response Evaluation Criteria in Solid Tumours (RECIST Version 1.1) criteria 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
iv) has been treated with a maximum of 2 lines of chemotherapy for recurrent/metastatic disease; to be eligibile all participants should have received or been intolerant of one or more platinum agents and one or more fluoropyrimidine analogues.

Note: Neoadjuvant or adjuvant chemotherapy or chemoradiotherapy will be considered as first line treatment where people have relapsed or progessed 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.

2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

3. Ability to swallow oral medication.

4. Adequate bone marrow function (Platelets >=100x109/L; Absolute Neurophil Count (ANC) >=1.5x109/L and Haemoglobin >= 9.0g/dL).

5. Adequate renal function (Creatinine clearance >50 ml/min based on the Cockcroft-Gault formula, 24-hour urine or Glomerular Filtration Rate (GFR) scan; and serum creatinine <=1.5 x Upper Limit of Normal (ULN).

6. Adequate liver function (Serum total bilirubin <=1.5 x ULN, and INR <= 1.5, and Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) <=2.5 x ULN (= 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) >= 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 of randomisation.

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 formulation.

2. Poorly controlled hypertension (systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).

3. Participants with known malabsorption syndromes.

4. Any prior anti-VEGF targeted therapy (e.g. bevacizumab) or treatment with small molecule VEGF TKIs.

5. Treatment with any investigational agent within 4 weeks prior to randomisation. For the purposes of this study trastuzumab is not considered an investigational agent.

6. 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 < Grade 2 according to CTCAE V4.0.

7. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before prior to randomisation.

8. Arterial thrombotic or ischaemic events, such as cerebrovascular accident or pulmonary embolism within 6 months prior to randomisation.

9. Venous thrombotic events within 3 months prior to randomisation.

10. Any hemorrhage or bleeding event CTCAE V4.0 >= Grade 3 within 4 weeks prior to the date of randomisation.

11. Non-healing wound, ulcer, or bone fracture.

12. Interstitial lung disease with ongoing signs and symptoms.

13. Life expectancy of less than 12 weeks.

14. Abnormal thyroid function (TSH outside normal range).

15. Persistent proteinuria of CTCAE V4.0 >= Grade 3 (>3.5g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).

16. 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, with no deterioration in neurological symptoms during this time.

17. History of another malignancy within 5 years prior to randomisation. Participants with curatively treated cervical carcinoma in situ, non-melanomatous carcinoma of the skin, or superficial bladder tumours (T1a [Non-invasive tumor], and Tis [Carcinoma in situ]), or participants who have been free of other malignancies for >= 5 years prior to randomisation are eligible for this study.

18. 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.

19. Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol.
20. 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 randomisation. Men must have been surgically sterilised 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)
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)
Patients will be randomised to receive one of the two arms using the method of permuted blocks, stratified by Eastern Cooperative Oncology Group (ECOG) Performance Status (0, 1 versus 2), number of lines of previous chemotherapy for advanced disease (1 versus 2), and country of recruitment.
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 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
People with AOGC are anticipated to have a median PFS of 2 months after prior chemotherapy (i.e. a PFS rate at 2 months of 50%). An increase in median PFS to 3.33 months for the participant group given regorafenib is considered of clinical interest. Assuming that time to progression follows an exponential distribution, a median PFS time of 3.33 months corresponds to a progression free rate at 2 months of 66%. Based on Simon’s optimal two stage design, a sample size of 92 participants in the regorafenib group will have 90% power at the 5% level of significance to reject the null hypothesis of a PFS rate at 2 months of =50% compared to the alternative hypothesis of a PFS rate at 2 months of =66%. This design allows for a futility analysis after 33 regorafenib participants have had PFS evaluated at 2 months. If 16 or more out of 33 (evaluable) regorafenib participants have progressed by 2 months then the study regimen/design will be reassessed or the study stopped.

The target sample size for the regorafenib arm will be 100 to allow for drop-outs/ ineligibility. A sample of 50 placebo participants will allow estimation of the endpoints to inform the reference values used in any future sample size calculations for a phase III trial. Accrual will take place over 18 months with the final analysis planned to be undertaken after the last participant has either progressed or been followed for a minimum of 3 months (from date of randomisation), whichever comes first.

Recruitment
Recruitment status
Completed
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,SA,WA,TAS,NSW,VIC,QLD
Recruitment hospital [1] 360 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [2] 361 0
The Alfred - Prahran
Recruitment hospital [3] 362 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [4] 363 0
Prince of Wales Hospital - Randwick
Recruitment hospital [5] 364 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [6] 365 0
St George Hospital - Kogarah
Recruitment hospital [7] 366 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [8] 367 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [9] 368 0
Western Hospital - Footscray
Recruitment hospital [10] 369 0
Royal Hobart Hospital - Hobart
Recruitment hospital [11] 370 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [12] 371 0
The Townsville Hospital - Douglas
Recruitment hospital [13] 372 0
Nambour General Hospital - Nambour
Recruitment hospital [14] 373 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [15] 374 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 4944 0
2605, 2031, 2065, 2145, 2340, 2010, 2217, 2298, 2444, 3144, 3181, 3220, 3011, 3199, 3081, 3168, 3350, 4006, 4560, 4810, 5000, 5042, 5011, 6008, 7000
Recruitment outside Australia
Country [1] 4117 0
New Zealand
State/province [1] 4117 0
North Island
Country [2] 4118 0
New Zealand
State/province [2] 4118 0
South Island
Country [3] 4119 0
Canada
State/province [3] 4119 0
Ontario, Nova Scotia, British Columbia, Quebec, Alberta
Country [4] 4120 0
Korea, Republic Of
State/province [4] 4120 0
Seoul, Gyeonggi-do
Country [5] 4776 0
Korea, Republic Of
State/province [5] 4776 0

Funding & Sponsors
Funding source category [1] 284668 0
Commercial sector/Industry
Name [1] 284668 0
Bayer AG
Address [1] 284668 0
Bayer AG
51368 Leverkusen
Germany
Country [1] 284668 0
Germany
Primary sponsor type
Other Collaborative groups
Name
The Australasian Gastro-Intestinal Trials Group (AGITG)
Address
GI CANCER Institute
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 283575 0
None
Name [1] 283575 0
Address [1] 283575 0
Country [1] 283575 0
Other collaborator category [1] 260525 0
University
Name [1] 260525 0
NHMRC Clinical Trials Centre, The University of Sydney
Address [1] 260525 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country [1] 260525 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286672 0
Cancer Institute Clinical Human Research Ethics Committee
Ethics committee address [1] 286672 0
Australian Technology Park
Level 9, 8 Central Avenue
EVELEIGH NSW 2015
AUSTRALIA
Ethics committee country [1] 286672 0
Australia
Date submitted for ethics approval [1] 286672 0
27/03/2011
Approval date [1] 286672 0
16/07/2012
Ethics approval number [1] 286672 0
AU RED Reference: HREC/12/CIC/6
CI NSW HREC Reference: 2012C/03/184
Ethics committee name [2] 288059 0
The Human Research Ethics Committee (TQEH/LMH/MH)
Ethics committee address [2] 288059 0
28 Woodville Road,
Woodville South, SA 5011
Ethics committee country [2] 288059 0
Australia
Date submitted for ethics approval [2] 288059 0
22/08/2012
Approval date [2] 288059 0
21/11/2012
Ethics approval number [2] 288059 0
HREC/12/TQEHLMH/105
Ethics committee name [3] 288060 0
Bellberry Human Research Ethics Committee
Ethics committee address [3] 288060 0
81 Flinders Street
DULWICH SA 5065
Ethics committee country [3] 288060 0
Australia
Date submitted for ethics approval [3] 288060 0
01/08/2012
Approval date [3] 288060 0
16/10/2012
Ethics approval number [3] 288060 0
2012-08-976-A-1
Ethics committee name [4] 288131 0
Alfred Health Human Ethics Committee
Ethics committee address [4] 288131 0
Ground Floor, Linay Pavilion
The Alfred Hospital
55 Commercial Road
Melbourne VIC 3004
Ethics committee country [4] 288131 0
Australia
Date submitted for ethics approval [4] 288131 0
Approval date [4] 288131 0
13/11/2012
Ethics approval number [4] 288131 0
Unknown
Ethics committee name [5] 288132 0
St John of God Health Care Ethics Committee
Ethics committee address [5] 288132 0
Level 3, St John of God House
177-179 Cambridge Street
Wembley WA 6014
Ethics committee country [5] 288132 0
Australia
Date submitted for ethics approval [5] 288132 0
03/09/2012
Approval date [5] 288132 0
Ethics approval number [5] 288132 0
H0012759
Ethics committee name [6] 288306 0
Human Research Ethics Committee (Tasmania) Network
Ethics committee address [6] 288306 0
Office of Research Services, University of Tasmania
Private Bag 1, HOBART Tasmania 7001
Ethics committee country [6] 288306 0
Australia
Date submitted for ethics approval [6] 288306 0
Approval date [6] 288306 0
05/10/2012
Ethics approval number [6] 288306 0
H0012759

Summary
Brief summary
This study will evaluate the effect of a drug called regorafenib for treatment of advanced oesophago-gastric cancer.
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) oesophago-gastric cancer which has not responded to treatment.
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 (sham) (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
http://www.gicancer.org.au/
http://www.ctc.usyd.edu.au/
Trial related presentations / publications
Pavlakis, N., Sjoquist, K.M., Tsobanis, E., Martin, A.J., Kang, Y.K., et al. INTEGRATE: A randomized, phase II, double-blind, placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC): A study by the Australasian Gastrointestinal Trials Group (AGITG)—Final overall and subgroup results. 2015. J Clin Oncol 33 (suppl; abstr 4003)
Public notes

Contacts
Principal investigator
Name 33749 0
A/Prof Nick Pavlakis
Address 33749 0
Royal North Shore Hospital
Reserve Road
St Leonards NSW 2065
Country 33749 0
Australia
Phone 33749 0
+61 (0)2 9926 5020
Fax 33749 0
+61 (0)2 9438 2604
Email 33749 0
nick.pavlakis@sydney.edu.au
Contact person for public queries
Name 16996 0
Mr INTEGRATE Project Manager
Address 16996 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 16996 0
Australia
Phone 16996 0
+61 2 9562 5000
Fax 16996 0
+61 2 9562 5094
Email 16996 0
INTEGRATE@ctc.usyd.edu.au
Contact person for scientific queries
Name 7924 0
Mr INTGRATE Project Manager
Address 7924 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 7924 0
Australia
Phone 7924 0
+61 2 9562 5000
Fax 7924 0
+61 2 9562 5094
Email 7924 0
INTEGRATE@ctc.usyd.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary