Clinical trial NCT02773524: A Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer
Official title: A Randomised Phase III Double-Blind Placebo-Controlled Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Gastro-Oesophageal Cancer
Keywords: Metastatic
Locally recurrent
Oesophago-gastric junction
Stomach
Adenocarcinoma
Undifferentiated Carcinoma
Lead sponsor: Australasian Gastro-Intestinal Trials Group
Sponsor class: NETWORK
Collaborators: name: Canadian Cancer Trials Group
name: Academic and Community Cancer Research United
name: National Health and Medical Research Council, Australia
First posted: 2016-05-16
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed 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.

Eligibility 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.

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.

Primary outcomes:
measure: Overall Survival
timeFrame: From time of patient randomisation until date last known alive (up to 12 months following end of treatment).
Secondary outcomes:
measure: Progression Free Survival
timeFrame: From time of patient randomisation until first evidence of disease progression or death (up to 12 months following randomisation).
measure: Objective Tumour Response Rate
timeFrame: From time of patient randomisation until evidence of complete or partial response (up to 12 months following randomisation).
measure: Evaluation of health states experienced by participants
timeFrame: From time of commencement of treatment until first evidence of disease progression (up to 12 months following commencement of treatment).
measure: Rates of Adverse Events
timeFrame: From time dose of study treatment until 30 days after last dose of study treatment
Other outcomes:
measure: Identification of tumour markers to that predict treatment outcomes for AGOC
timeFrame: Up to 24 months following close of recruitment.
measure: Evaluation of regorafenib Maximum Plasma Concentration [Cmax] between Asia and Rest of World cohorts.
timeFrame: Up to 24 months following close of recruitment.
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Los Angeles
country: United States
facility: USC Norris
state: California
city: Urbana
country: United States
facility: Carle Cancer Center NCI Community Oncology Research Program
state: Illinois
city: Midlothian
country: United States
facility: Bon Secours Cancer Institute
state: Virginia
city: Canberra
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Albury
country: Australia
facility: Border Medical Oncology
state: New South Wales
city: Clayton
country: Australia
facility: Monash Medical Centre
state: New South Wales
city: Coffs Harbour
country: Australia
facility: Coffs Harbour Health Campus
state: New South Wales
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Public Hospital
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: Newcastle Private Hospital
state: New South Wales
city: Port Macquarie
country: Australia
facility: Port Macquarie Base Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Tweed Heads
country: Australia
facility: The Tweed Hospital
state: New South Wales
city: Wendouree
country: Australia
facility: Ballarat Oncology and Haematology Services
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Tiwi
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Douglas
country: Australia
facility: The Townsville Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Womens Hospital
state: Queensland
city: Sunshine Coast
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Ashford
country: Australia
facility: Ashford Cancer Centre Research
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Woodville South
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Subiaco
country: Australia
facility: St John of God Hospital Subiaco
state: Western Australia
city: Charlottetown
country: Canada
facility: PEI Cancer Treatment Centre, Queen Elizabeth Hospital
city: Nova Scotia
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
city: Québec
country: Canada
facility: The Research Institute of the McGill University Health Centre
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
city: Toronto
country: Canada
facility: University Health Network Princess Margaret Cancer Centre
city: Chiba
country: Japan
facility: National Cancer Centre Hospital East
state: Kashiwa
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Kita
city: Anyang
country: Korea, Republic of
facility: Hallym University Sacred Heart Hospital
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Jeonju
country: Korea, Republic of
facility: Chonbuk National University Hospital
city: Jinju
country: Korea, Republic of
facility: Gyeongsang National University Hospital
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: SMG-SNU Boramae Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea - Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea - Yeouido St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System - Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System - Severance Hospital
city: Auckland
country: New Zealand
facility: Auckland Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taipei
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital (NTUH)
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital (TPVGH)
Study officials:
affiliation: AGITG
name: Nick Pavlakis, Prof
role: STUDY_CHAIR
References: