RegoNivo vs Standard of Care Chemotherapy in AGOC
- Conditions
- Gastro-Oesophageal Cancer
- Interventions
- Biological: NivolumabDrug: Trifluridine/Tipracil
- Registration Number
- NCT04879368
- Lead Sponsor
- Australasian Gastro-Intestinal Trials Group
- Brief Summary
To determine if the regorafenib and nivolumab combination (RegoNivo) improves overall survival compared with current standard chemotherapy options in refractory AGOC.
- Detailed Description
The purpose of this international study is to determine if the combination of regorafenib and nivolumab is more effective than standard chemotherapy in prolonging overall survival in a broad group of participants with AGOC, who have progressed after treatment with standard anti-cancer therapy.
In the INTEGRATE study, regorafenib alone was shown to be effective in prolonging the progression-free period in people with AGOC following standard anti-cancer therapy (i.e. it delayed tumour growth), and demonstrated a potential benefit on long term survival. Recent research has shown the early results from this combination of regorafenib \& nivolumab may improve outcomes for cancer patients. INTEGRATE IIb will investigate this effect further in a larger group of participants with AGOC.
The study aims to determine:
i. Whether the combination of regorafenib/nivolumab is likely to help patients with AGOC live longer; ii. The effects of this treatment on progression-free survival; iii. The numbers of participants responding to the treatment iv. The effects of this treatment on quality of life v. The side effects and tolerability of this treatment vi. Molecular differences (e.g. variations in genes or proteins) that may account for the effects of this treatment vii. Differences in the costs of care for people on this treatment.
The Investigators plan to enrol 460 participants in the study from, but not limited to; Australia, South Korea, Japan, Taiwan, USA, Germany, Austria, Spain, and Italy.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 450
-
Adults (18 years or over) with metastatic or locally recurrent gastro-oesophageal cancer which:
- has arisen in any primary gastro-oesophageal site (oesophago-gastric junction (GOJ) or stomach); and
- is of adenocarcinoma or undifferentiated carcinoma histology; and
- 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
- 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.
- HER2-positive participants must have received trastuzumab
-
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 1).
-
Ability to swallow oral medication.
-
Adequate bone marrow function (Platelets ≥100x109/L; Absolute Neutrophil Count (ANC) ≥1.5x109/L and Haemoglobin ≥ 9.0g/dL).
-
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).
-
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.
-
Willing and able to comply with all study requirements, including treatment, timing, and/or nature of required assessments and follow-up.
-
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)
-
Signed, written informed consent
-
Known allergy to the investigational product drug class or excipients in the regorafenib and/or nivolumab
-
Poorly-controlled hypertension (systolic blood pressure >140mmHg or diastolic pressure> 90mmHg despite optimal medical management).
-
Participants with known, uncontrolled malabsorption syndromes
-
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.
-
Any prior use of more than one immune checkpoint inhibitor
-
Treatment with any previous drug therapy within 2 weeks prior to first dose of study treatment. This includes any investigational therapy.
-
Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
-
Concurrent treatment with strong CYP3A4 inhibitors or inducers.
-
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 V5.0
-
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
-
Arterial thrombotic or ischaemic events, such as cerebrovascular accident, within 6 months prior to randomization.
-
Venous thrombotic events and pulmonary embolism within 3 months prior to randomization
-
Any haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v5.0 within 4 weeks prior to randomization.
-
Non-healing wound, ulcer, or bone fracture.
-
Interstitial lung disease with ongoing signs and symptoms
-
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.
-
Persistent proteinuria of ≥ Grade 3 according to CTCAE v5.0 (equivalent to > 3.5g of protein over 24 hour measured on either a random specimen or 24 hour collection.
-
Uncontrolled metastatic disease to the central nervous system. To be eligible, known 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.
-
History of another malignancy within 2 years prior to randomization. Participants with the following are eligible for this study:
- curatively treated cervical carcinoma in situ,
- non-melanomatous carcinoma of the skin,
- superficial bladder tumours (T1a [Non-invasive tumour], and Tis [Carcinoma in situ]),
- treated thyroid papillary cancer
-
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.
-
Patients with acute coronary syndrome (including myocardial infarction and unstable angina), and with a history of coronary angioplasty or stent placement performed within 6 months before enrolment
-
Patients with a ≥ grade 3 active infection according to CTCAE version 5.0
-
Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease
-
Patients who require systemic corticosteroids (excluding temporary usage for tests, prophylactic administration for allergic reactions, or to alleviate swelling associated with radiotherapy; if used as replacement therapy e.g. ≤ 10 mg prednisolone or dexamethasone ≤ 2 mg per day) or immunosuppressants, or who have received such a therapy < 14 days prior to randomisation
-
Patients with a seizure disorder who require pharmacotherapy
-
Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol.
-
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
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description RegoNivo Regorafenib Participants in the RegoNivo arm will; 1. self-administer 90mg (3x30mg) of regorafenib days 1-21 of each 28-day treatment cycle and; 2. receive intravenous nivolumab 240 mg day 1 of each 14 day cycle until disease progression or prohibitive adverse events as per protocol, given in hospital by infusion. After 2 months, patients whose disease is controlled may have nivolumab administered 480 mg every 28 days. RegoNivo Nivolumab Participants in the RegoNivo arm will; 1. self-administer 90mg (3x30mg) of regorafenib days 1-21 of each 28-day treatment cycle and; 2. receive intravenous nivolumab 240 mg day 1 of each 14 day cycle until disease progression or prohibitive adverse events as per protocol, given in hospital by infusion. After 2 months, patients whose disease is controlled may have nivolumab administered 480 mg every 28 days. Standard of Care Paclitaxel Participants in the control arm will receive investigator choice chemotherapy with any of the following agents * taxane (paclitaxel or docetaxel) * irinotecan or * oral trifluridine/tipiracil (TAS102) All treatment groups will receive Best Supportive Care (BSC). Standard of Care Trifluridine/Tipracil Participants in the control arm will receive investigator choice chemotherapy with any of the following agents * taxane (paclitaxel or docetaxel) * irinotecan or * oral trifluridine/tipiracil (TAS102) All treatment groups will receive Best Supportive Care (BSC). Standard of Care Docetaxel Participants in the control arm will receive investigator choice chemotherapy with any of the following agents * taxane (paclitaxel or docetaxel) * irinotecan or * oral trifluridine/tipiracil (TAS102) All treatment groups will receive Best Supportive Care (BSC). Standard of Care Irinotecan Participants in the control arm will receive investigator choice chemotherapy with any of the following agents * taxane (paclitaxel or docetaxel) * irinotecan or * oral trifluridine/tipiracil (TAS102) All treatment groups will receive Best Supportive Care (BSC).
- Primary Outcome Measures
Name Time Method O/S 5 years To determine the effect of RegoNivo on overall survival (OS) (death from any cause) in the overall study population and in the Asian sub-population.
- Secondary Outcome Measures
Name Time Method Determine the effect of RegoNivo on; OTRR 5 years Objective tumour response rate (OTRR)((partial or complete response (PR or CR)) according to Response Evaluation Criteria in Solid Tumours (RECIST) version. 1.1, and iRECIST on study population
Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire 5 years Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study EORTC QLQ-C30: Q29 \& Q30 Min 1 Max 7, Higher = Better
Determine the effect of RegoNivo on; Safety 5 years Safety (rates of adverse events) of participants on study
Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (self assessment of pain on health aspect) 5 years Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study Patient D.A.T.A Form: Q1 - Q17 Min 0 Max 10, Higher Score = Worse
Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (self rating on health aspects) 5 years Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study Patient D.A.T.A Form: Q18 - Q24 Min 0 Max 10, Higher Score = Better
Determine the effect of RegoNivo on; QoL - Health Questionnaire 5 years Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study EQ-5D-5L Health questionnaire Min 0 Max 100, Higher Score = Better
Determine the effect of RegoNivo on; PFS 5 years Progression free survival (PFS)(disease progression or death) in the study population
Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire -Stomach Cancer 5 years Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study EORTC QLQ STO22 Min 1 Max 4, Higher Score = Worse
Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (health aspect impact self assessment) 5 years Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study Patient D.A.T.A Form: Q25 - Q47 Min 0 Max 10, Higher Score = Worse
Trial Locations
- Locations (94)
Austin Health
🇦🇺Melbourne, Victoria, Australia
Medizinische Universitaet Wien
🇦🇹Vienna, Austria
Landesklinikum Wiener Neustadt
🇦🇹Wiener Neustadt, Austria
The Queen Elizabeth Hospital
🇦🇺Adelaide, South Australia, Australia
Philipps-Universitat Marburg
🇩🇪Marburg, Germany
Hallym University Sacred Heart Hospital
🇰🇷Anyang, Korea, Republic of
Korea University Anam Hospital
🇰🇷Seoul, Korea, Republic of
Flinders Medical Centre
🇦🇺Bedford Park, South Australia, Australia
Royal North Shore Private Hospital
🇦🇺Sydney, New South Wales, Australia
Kliniken der Stadt Köln
🇩🇪Koeln, Germany
San Camillo Forlanini Hospitals
🇮🇹Roma, Italy
KEM/Evang. Kliniken Essen Mitte gGmbH
🇩🇪Essen, Germany
Universitätsklinikum Leipzig
🇩🇪Leipzig, Germany
Landeskrankenanstalten-Betriebsgesellschaft-KABEG
🇦🇹Klagenfurt, Austria
Ordensklinikum Linz GmbH Barmherzige schwestern
🇦🇹Linz, Austria
Royal Hobart Hospital
🇦🇺Hobart, Tasmania, Australia
The Tweed Hospital
🇦🇺Tweed Heads, New South Wales, Australia
The Townsville Hospital
🇦🇺Douglas, Queensland, Australia
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Haeundae Paik Hospital
🇰🇷Busan, Korea, Republic of
Helios Bad Saarow
🇩🇪Bad Saarow, Germany
Universitätsklinikum Jena
🇩🇪Jena, Germany
Vall d'Hebron University Hospital
🇪🇸Barcelona, Spain
Universita Cattolica del Sacro Cuore, University Hospital Gemelli
🇮🇹Roma, Italy
Asan Medical Centre
🇰🇷Seoul, Korea, Republic of
Klinikum Bayreuth
🇩🇪Bayreuth, Germany
Ballarat Oncology and Haematology Services
🇦🇺Wendouree, New South Wales, Australia
Monash Health
🇦🇺Clayton, Victoria, Australia
Charité Universitätsmedizin Berlin
🇩🇪Berlin, Germany
Royal Brisbane and Womens Hospital
🇦🇺Herston, Queensland, Australia
Seoul National University Bundang Hospital
🇰🇷Seoul, Korea, Republic of
Klinikum Ludwigburg
🇩🇪Ludwigsburg, Germany
Universitae degli studi della Campania "Luigi Vanvitelli"
🇮🇹Napoli, Italy
Sunshine Coast University Hospital
🇦🇺Sunshine Coast, Queensland, Australia
Norddeutsches Studienzentrum für Innovative Onkologie (NIO)
🇩🇪Hamburg, Germany
Gyeongsang National University Hospital
🇰🇷Jinju, Korea, Republic of
Hospital Universitario de Navarra
🇪🇸Pamplona, Spain
Yonsei University Health System - Severance Hospital
🇰🇷Seoul, Korea, Republic of
Universitätsklinikum Mainz
🇩🇪Mainz, Germany
National Cheng Kung University Hospital
🇨🇳Taipei, Taiwan
National Taiwan University Hospital (NTUH)
🇨🇳Taipei, Taiwan
Kyushu Cancer Center
🇯🇵Fukuoka, Japan
Klinikum Leverkusen gGmbH
🇩🇪Leverkusen, Germany
National Cancer Centre Hospital East
🇯🇵Chiba, Kashiwa, Japan
Korea University Guro Hospital
🇰🇷Seoul, Korea, Republic of
Istituto Nazionale Tumori di Napoli-IRCCS Fondazione G. Pascale
🇮🇹Napoli, Italy
Azienda USL-IRCCS Di Reggio Emilia
🇮🇹Reggio Emilia, Italy
Saitama Cancer Center
🇯🇵Saitama, Japan
Jeonbuk National University Hospital
🇰🇷Jeonju, Korea, Republic of
Universitätsklinikum Greifswald
🇩🇪Greifswald, Germany
China Medical University Hospital (CMUH)
🇨🇳Taichung, Taiwan
IRCCS Fondazione Casa Sollievo della Sofferenza
🇮🇹San Giovanni Rotondo, Italy
Shikoku Cancer Center
🇯🇵Matsuyama, Japan
Chungbuk National University Hospital
🇰🇷Cheongju, Korea, Republic of
Chung-Ang University Hospital
🇰🇷Seoul, Korea, Republic of
Hospital Clinico Universitario De Valencia
🇪🇸Valencia, Spain
Taipei Veterans General Hospital (TPVGH)
🇨🇳Taipei, Taiwan
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Western Australia, Australia
St John of God Hospital Subiaco
🇦🇺Subiaco, Western Australia, Australia
Shizuoka Cancer Center
🇯🇵Shizuoka, Japan
Universitätsklinikum Heidelberg
🇩🇪Heidelberg, Germany
Klinikum Magdeburg gGmbH
🇩🇪Magdeburg, Germany
Klinikum rechts der Isar der TU München
🇩🇪München, Germany
Studienzentrum Onkologie Ravensburg
🇩🇪Ravensburg, Germany
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
SMG-SNU Boramae Medical Center
🇰🇷Seoul, Korea, Republic of
Yonsei University Health System - Gangnam Severance Hospital
🇰🇷Seoul, Korea, Republic of
Mayo Clinic Arizona
🇺🇸Scottsdale, Arizona, United States
Siouxland Regional Cancer Center
🇺🇸Sioux City, Iowa, United States
Monument Health Rapid City Hospital
🇺🇸Rapid City, South Dakota, United States
USC Norris
🇺🇸Los Angeles, California, United States
Fred Hutchinson Cancer Research Centre - South Lake Union Clinic
🇺🇸Seattle, Washington, United States
Coffs Harbour Health Campus
🇦🇺Coffs Harbour, New South Wales, Australia
St Vincent's Public Hospital
🇦🇺Darlinghurst, New South Wales, Australia
Concord Repatriation General Hospital
🇦🇺Concord, New South Wales, Australia
Border Medical Oncology Research Unit
🇦🇺East Albury, New South Wales, Australia
St George Hospital
🇦🇺Kogarah, New South Wales, Australia
Gosford Hospital
🇦🇺Gosford, New South Wales, 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
Universitätsklinikum Bonn
🇩🇪Bonn, Germany
Evang. Klinikum Bethel Bielefeld
🇩🇪Gütersloh, Nordrhein-Westfalen, Germany
Institut für Klinisch Onkol Forschung am Krankenhaus Nordwest
🇩🇪Frankfurt, Germany
Universitätsklinikum Ulm
🇩🇪Ulm, Germany
Caritas Klinikum Saarbrücken St. Theresia
🇩🇪Saarbrücken, Germany
Dong-A University Hospital
🇰🇷Busan, Korea, Republic of
Kangbuk Samsung Hospital
🇰🇷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
Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳Kaohsiung, Taiwan
Hokkaido University Hospital
🇯🇵Sapporo, Kita, Japan
St Elizabeth Healthcare
🇺🇸Edgewood, Kentucky, United States
Royal Darwin Hospital
🇦🇺Tiwi, Northern Territory, Australia