A Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer

Gastro-Oesophageal Cancer Clinical Trial

— INTEGRATEIIa  

Official title:

A Randomised Phase III Double-Blind Placebo-Controlled Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02773524
• Other study ID #: AG0315OG
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 2016
• Est. completion date: December 2022

Study information

• Verified date: January 2022
• Source: Australasian Gastro-Intestinal Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A randomised phase III, double-blind, placebo-controlled trial with 2:1 (regorafenib : placebo)

Description:

Purpose: The purpose of this Phase III study is to determine if regorafenib improves overall 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 will be randomly (by chance) allocated to one of two groups: regorafenib or placebo in 2:1 ratio respectively and will not be aware of their group allocation. Regorafenib or matching placebo will be self-administered by participants orally once daily on days 1-21 of each 28 days cycle. Treatment will continue until disease progression or prohibitive toxicity. Participants will be followed up every 2-4 weeks in order to evaluate their progress on the study.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 250
• Est. completion date: December 2022
• Est. primary completion date: January 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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. 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.

Related Conditions & MeSH terms

• Esophageal Neoplasms
• Gastro-Oesophageal Cancer

Intervention

Drug:
• 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:
• 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.

Locations

Country	Name	City	State
Australia	Border Medical Oncology	Albury	New South Wales
Australia	Ashford Cancer Centre Research	Ashford	South Australia
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Canberra Hospital	Canberra	Australian Capital Territory
Australia	Monash Medical Centre	Clayton	New South Wales
Australia	Coffs Harbour Health Campus	Coffs Harbour	New South Wales
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	St Vincent's Public Hospital	Darlinghurst	New South Wales
Australia	The Townsville Hospital	Douglas	Queensland
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Royal Brisbane and Womens Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	St George Hospital	Kogarah	New South Wales
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Newcastle Private Hospital	New Lambton Heights	New South Wales
Australia	Port Macquarie Base Hospital	Port Macquarie	New South Wales
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Royal North Shore Hospital	Saint Leonards	New South Wales
Australia	St John of God Hospital Subiaco	Subiaco	Western Australia
Australia	Sunshine Coast University Hospital	Sunshine Coast	Queensland
Australia	Royal Darwin Hospital	Tiwi	Northern Territory
Australia	The Tweed Hospital	Tweed Heads	New South Wales
Australia	Ballarat Oncology and Haematology Services	Wendouree	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Australia	The Queen Elizabeth Hospital	Woodville South	South Australia
Canada	PEI Cancer Treatment Centre, Queen Elizabeth Hospital	Charlottetown
Canada	Queen Elizabeth II Health Sciences Centre	Nova Scotia
Canada	Ottawa Hospital Research Institute	Ottawa
Canada	The Research Institute of the McGill University Health Centre	Québec
Canada	Allan Blair Cancer Centre	Regina
Canada	Saskatoon Cancer Centre	Saskatoon
Canada	University Health Network Princess Margaret Cancer Centre	Toronto
Japan	National Cancer Centre Hospital East	Chiba	Kashiwa
Japan	Hokkaido University Hospital	Sapporo	Kita
Korea, Republic of	Hallym University Sacred Heart Hospital	Anyang
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Chonbuk National University Hospital	Jeonju
Korea, Republic of	Gyeongsang National University Hospital	Jinju
Korea, Republic of	Chung-Ang University Hospital	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Bundang Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	SMG-SNU Boramae Medical Center	Seoul
Korea, Republic of	The Catholic University of Korea - Seoul St. Mary's Hospital	Seoul
Korea, Republic of	The Catholic University of Korea - Yeouido St. Mary's Hospital	Seoul
Korea, Republic of	Yonsei University Health System - Gangnam Severance Hospital	Seoul
Korea, Republic of	Yonsei University Health System - Severance Hospital	Seoul
New Zealand	Auckland Hospital	Auckland
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Taipei
Taiwan	National Taiwan University Hospital (NTUH)	Taipei
Taiwan	Taipei Veterans General Hospital (TPVGH)	Taipei
United States	USC Norris	Los Angeles	California
United States	Bon Secours Cancer Institute	Midlothian	Virginia
United States	Mayo Clinic Arizona	Scottsdale	Arizona
United States	Carle Cancer Center NCI Community Oncology Research Program	Urbana	Illinois

Sponsors (4)

Lead Sponsor	Collaborator
Australasian Gastro-Intestinal Trials Group	Academic and Community Cancer Research United, Canadian Cancer Trials Group, National Health and Medical Research Council, Australia

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Japan,  Korea, Republic of,  New Zealand,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Identification of tumour markers to that predict treatment outcomes for AGOC	Biomarker assessment, CTC DNA assessment to predict whether treatment for AGOC is efficacious	Up to 24 months following close of recruitment.
Other	Evaluation of regorafenib Maximum Plasma Concentration [Cmax] between Asia and Rest of World cohorts.	Evaluation of regorafenib Maximum Plasma Concentration [Cmax] in patients from either Asia or ROW to assess whether genetic factors aide/hinder metabolic rate of consumption of regorafenib	Up to 24 months following close of recruitment.
Primary	Overall Survival	The interval from the date of randomisation to date of death from any cause, or the date last known alive.	From time of patient randomisation until date last known alive (up to 12 months following end of treatment).
Secondary	Progression Free Survival	The interval from the date of randomisation to the date of first evidence of disease progression or death, whichever occurs first.	From time of patient randomisation until first evidence of disease progression or death (up to 12 months following randomisation).
Secondary	Objective Tumour Response Rate	The OTRR will be calculated by summing the number of participants in a given arm that are assessed as having a complete or partial response (as per RECIST criteria), and dividing this by the total number of participants in the corresponding arm of the analysis set.	From time of patient randomisation until evidence of complete or partial response (up to 12 months following randomisation).
Secondary	Evaluation of health states experienced by participants	Questionnaire used to assess quality of life	From time of commencement of treatment until first evidence of disease progression (up to 12 months following commencement of treatment).
Secondary	Rates of Adverse Events	A descriptive analysis of the adverse events (AE) data will be prepared for participants in the safety population. The number and percentage of participants who experience AEs will be tabulated according to CTCAE term/category, grade, and seriousness.	From time dose of study treatment until 30 days after last dose of study treatment