Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02773524




Registration number
NCT02773524
Ethics application status
Date submitted
4/05/2016
Date registered
16/05/2016
Date last updated
13/01/2022

Titles & IDs
Public title
A Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer
Scientific title
A Randomised Phase III Double-Blind Placebo-Controlled Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)
Secondary ID [1] 0 0
AG0315OG
Universal Trial Number (UTN)
Trial acronym
INTEGRATEIIa
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gastro-Oesophageal Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Oesophageal (gullet)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Regorafenib
Other interventions - Placebo

Experimental: Regorafenib - Regorafenib 160mg (4 x 40 mg tablets) orally, once daily on days 1-21 of each 28 day cycle + best supportive care until progression

Placebo Comparator: Placebo - Placebo 160mg (4 x 40 mg tablets) orally, once daily on days 1-21 of each 28 day cycle + best supportive care until progression


Treatment: Drugs: Regorafenib
Regorafenib is the experimental intervention in this study. 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.

Other interventions: Placebo
Placebo (matching in appearance to regorafenib) made of microcrystalline cellulose, 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.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Survival
Timepoint [1] 0 0
From time of patient randomisation until date last known alive (up to 12 months following end of treatment).
Secondary outcome [1] 0 0
Progression Free Survival
Timepoint [1] 0 0
From time of patient randomisation until first evidence of disease progression or death (up to 12 months following randomisation).
Secondary outcome [2] 0 0
Objective Tumour Response Rate
Timepoint [2] 0 0
From time of patient randomisation until evidence of complete or partial response (up to 12 months following randomisation).
Secondary outcome [3] 0 0
Evaluation of health states experienced by participants
Timepoint [3] 0 0
From time of commencement of treatment until first evidence of disease progression (up to 12 months following commencement of treatment).
Secondary outcome [4] 0 0
Rates of Adverse Events
Timepoint [4] 0 0
From time dose of study treatment until 30 days after last dose of study treatment

Eligibility
Key inclusion criteria
Inclusion Criteria

1. Adults (18 years or over) with metastatic or locally recurrent gastro-oesophageal
cancer which:

1. has arisen in any primary gastro-oesophageal site (oesophago-gastric junction
(GOJ) or stomach); and

2. is of adenocarcinoma or undifferentiated carcinoma histology , and

3. 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

4. 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.

5. HER2-positive participants must 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 =100x109/L; Absolute Neutrophil Count (ANC)
=1.5x109/L and Haemoglobin = 9.0g/dL).

5. Adequate renal function (Creatinine clearance >50 ml/min) based on either the
Cockcroft-Gault formula (Appendix 2), 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 x ULN, 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 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
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

1. Known allergy to the investigational product drug class or excipients in the
regorafenib.

2. Poorly-controlled hypertension (systolic blood pressure >140mmHg or diastolic
pressure> 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< 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 = 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 = Grade 3 according to CTCAE v4.03 (equivalent to > 3.5g of
protein over 24 hours, measured on either a random specimen or 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:

1. curatively treated cervical carcinoma in situ,

2. non-melanomatous carcinoma of the skin,

3. superficial bladder tumours (T1a [Non-invasive tumour], and Tis[Carcinoma in
situ]),

4. 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 analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Unknown status
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/11/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2022
Actual
Sample size
Target
Accrual to date
Final
250
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,VIC,WA
Recruitment hospital [1] 0 0
Canberra Hospital - Canberra
Recruitment hospital [2] 0 0
Border Medical Oncology - Albury
Recruitment hospital [3] 0 0
Monash Medical Centre - Clayton
Recruitment hospital [4] 0 0
Coffs Harbour Health Campus - Coffs Harbour
Recruitment hospital [5] 0 0
Concord Repatriation General Hospital - Concord
Recruitment hospital [6] 0 0
St Vincent's Public Hospital - Darlinghurst
Recruitment hospital [7] 0 0
Gosford Hospital - Gosford
Recruitment hospital [8] 0 0
St George Hospital - Kogarah
Recruitment hospital [9] 0 0
Newcastle Private Hospital - New Lambton Heights
Recruitment hospital [10] 0 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [11] 0 0
Prince of Wales Hospital - Randwick
Recruitment hospital [12] 0 0
Royal North Shore Hospital - Saint Leonards
Recruitment hospital [13] 0 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [14] 0 0
Ballarat Oncology and Haematology Services - Wendouree
Recruitment hospital [15] 0 0
Westmead Hospital - Westmead
Recruitment hospital [16] 0 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [17] 0 0
The Townsville Hospital - Douglas
Recruitment hospital [18] 0 0
Royal Brisbane and Womens Hospital - Herston
Recruitment hospital [19] 0 0
Sunshine Coast University Hospital - Sunshine Coast
Recruitment hospital [20] 0 0
Ashford Cancer Centre Research - Ashford
Recruitment hospital [21] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [22] 0 0
The Queen Elizabeth Hospital - Woodville South
Recruitment hospital [23] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [24] 0 0
Austin Hospital - Heidelberg
Recruitment hospital [25] 0 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [26] 0 0
St John of God Hospital Subiaco - Subiaco
Recruitment postcode(s) [1] 0 0
- Canberra
Recruitment postcode(s) [2] 0 0
2640 - Albury
Recruitment postcode(s) [3] 0 0
3168 - Clayton
Recruitment postcode(s) [4] 0 0
2450 - Coffs Harbour
Recruitment postcode(s) [5] 0 0
2139 - Concord
Recruitment postcode(s) [6] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [7] 0 0
2250 - Gosford
Recruitment postcode(s) [8] 0 0
2217 - Kogarah
Recruitment postcode(s) [9] 0 0
2035 - New Lambton Heights
Recruitment postcode(s) [10] 0 0
2444 - Port Macquarie
Recruitment postcode(s) [11] 0 0
2031 - Randwick
Recruitment postcode(s) [12] 0 0
- Saint Leonards
Recruitment postcode(s) [13] 0 0
2485 - Tweed Heads
Recruitment postcode(s) [14] 0 0
3355 - Wendouree
Recruitment postcode(s) [15] 0 0
2145 - Westmead
Recruitment postcode(s) [16] 0 0
0810 - Tiwi
Recruitment postcode(s) [17] 0 0
4814 - Douglas
Recruitment postcode(s) [18] 0 0
4029 - Herston
Recruitment postcode(s) [19] 0 0
4560 - Sunshine Coast
Recruitment postcode(s) [20] 0 0
5035 - Ashford
Recruitment postcode(s) [21] 0 0
5042 - Bedford Park
Recruitment postcode(s) [22] 0 0
5011 - Woodville South
Recruitment postcode(s) [23] 0 0
700 - Hobart
Recruitment postcode(s) [24] 0 0
3084 - Heidelberg
Recruitment postcode(s) [25] 0 0
6009 - Nedlands
Recruitment postcode(s) [26] 0 0
6008 - Subiaco
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Virginia
Country [5] 0 0
Canada
State/province [5] 0 0
Charlottetown
Country [6] 0 0
Canada
State/province [6] 0 0
Nova Scotia
Country [7] 0 0
Canada
State/province [7] 0 0
Ottawa
Country [8] 0 0
Canada
State/province [8] 0 0
Québec
Country [9] 0 0
Canada
State/province [9] 0 0
Regina
Country [10] 0 0
Canada
State/province [10] 0 0
Saskatoon
Country [11] 0 0
Canada
State/province [11] 0 0
Toronto
Country [12] 0 0
Japan
State/province [12] 0 0
Kashiwa
Country [13] 0 0
Japan
State/province [13] 0 0
Kita
Country [14] 0 0
Korea, Republic of
State/province [14] 0 0
Anyang
Country [15] 0 0
Korea, Republic of
State/province [15] 0 0
Busan
Country [16] 0 0
Korea, Republic of
State/province [16] 0 0
Jeonju
Country [17] 0 0
Korea, Republic of
State/province [17] 0 0
Jinju
Country [18] 0 0
Korea, Republic of
State/province [18] 0 0
Seoul
Country [19] 0 0
New Zealand
State/province [19] 0 0
Auckland
Country [20] 0 0
Taiwan
State/province [20] 0 0
Kaohsiung
Country [21] 0 0
Taiwan
State/province [21] 0 0
Taichung
Country [22] 0 0
Taiwan
State/province [22] 0 0
Taipei

Funding & Sponsors
Primary sponsor type
Other
Name
Australasian Gastro-Intestinal Trials Group
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Canadian Cancer Trials Group
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Academic and Community Cancer Research United
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
National Health and Medical Research Council, Australia
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
A randomised phase III, double-blind, placebo-controlled trial with 2:1 (regorafenib :
placebo)
Trial website
https://clinicaltrials.gov/ct2/show/NCT02773524
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Nick Pavlakis, Prof
Address 0 0
AGITG
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT02773524