Study Results
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Basic Information
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ACTIVE_NOT_RECRUITING
PHASE3
450 participants
INTERVENTIONAL
2021-06-01
2026-06-01
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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RegoNivo
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.
Regorafenib
Oral multi-targeted tyrosine kinase inhibitor (TKI) which targets angiogenic (VEGF, TIE-2), stromal (PDGF-β), and oncogenic (RAF, RET and KIT) receptor tyrosine kinases
Nivolumab
human IgG4 monoclonal antibody inhibitor of PD-1
Standard of Care
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).
Docetaxel
Docetaxel is taxane-derivative chemotherapy drug, used in the treatment of early, locally advanced and metastatic breast cancer. It is an anti-microtubule agent. Other uses are in the treatment of non-small cell lung cancer, advanced stomach cancer, head and neck cancers, soft tissue sarcoma, ovarian cancer, metastatic prostate cancer, etc.
microtubules, and simultaneously promotes assembly and inhibits disassembly of them
Paclitaxel
Paclitaxel is one of several cytoskeletal drugs that target tubulin. Paclitaxel-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. Unlike other tubulin-targeting drugs, such as colchicine, that inhibit microtubule assembly, paclitaxel stabilizes the microtubule polymer and protects it from disassembly. Chromosomes are thus unable to achieve a metaphase spindle configuration. This blocks the progression of mitosis and prolonged activation of the mitotic checkpoint triggers apoptosis or reversion to the G0-phase of the cell cycle without cell division
Irinotecan
Camptothecin, one of the four major structural classifications of plant-derived anti-cancerous compounds, is a cytotoxic alkaloid which consists of a pentacyclic ring structure containing a pyrrole (3, 4 β) quinoline moiety, an S-configured lactone form, and a carboxylate form. Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.
Trifluridine/Tipracil
The drug consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil. Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Trifluridine (TFT) is incorporated into DNA by phosphorylation by thymidylate kinase (TK) to TF-TMP; TF-TMP then covalently binds to tyrosine 146 of the active site of thymidylate synthase (TS) inhibiting the enzyme's activity. TS is vital to the synthesis of DNA because it is an enzyme involved in the synthesis of the deoxynucleotide, thymidine triphosphate (dTTP). Inhibition of TS depletes the cell of dTTP and causes accumulation of deoxyuridine monophosphate (dUMP), which increases the likelihood that uracil gets misincorporated into the DNA.
Interventions
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Regorafenib
Oral multi-targeted tyrosine kinase inhibitor (TKI) which targets angiogenic (VEGF, TIE-2), stromal (PDGF-β), and oncogenic (RAF, RET and KIT) receptor tyrosine kinases
Nivolumab
human IgG4 monoclonal antibody inhibitor of PD-1
Docetaxel
Docetaxel is taxane-derivative chemotherapy drug, used in the treatment of early, locally advanced and metastatic breast cancer. It is an anti-microtubule agent. Other uses are in the treatment of non-small cell lung cancer, advanced stomach cancer, head and neck cancers, soft tissue sarcoma, ovarian cancer, metastatic prostate cancer, etc.
microtubules, and simultaneously promotes assembly and inhibits disassembly of them
Paclitaxel
Paclitaxel is one of several cytoskeletal drugs that target tubulin. Paclitaxel-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. Unlike other tubulin-targeting drugs, such as colchicine, that inhibit microtubule assembly, paclitaxel stabilizes the microtubule polymer and protects it from disassembly. Chromosomes are thus unable to achieve a metaphase spindle configuration. This blocks the progression of mitosis and prolonged activation of the mitotic checkpoint triggers apoptosis or reversion to the G0-phase of the cell cycle without cell division
Irinotecan
Camptothecin, one of the four major structural classifications of plant-derived anti-cancerous compounds, is a cytotoxic alkaloid which consists of a pentacyclic ring structure containing a pyrrole (3, 4 β) quinoline moiety, an S-configured lactone form, and a carboxylate form. Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.
Trifluridine/Tipracil
The drug consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil. Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Trifluridine (TFT) is incorporated into DNA by phosphorylation by thymidylate kinase (TK) to TF-TMP; TF-TMP then covalently binds to tyrosine 146 of the active site of thymidylate synthase (TS) inhibiting the enzyme's activity. TS is vital to the synthesis of DNA because it is an enzyme involved in the synthesis of the deoxynucleotide, thymidine triphosphate (dTTP). Inhibition of TS depletes the cell of dTTP and causes accumulation of deoxyuridine monophosphate (dUMP), which increases the likelihood that uracil gets misincorporated into the DNA.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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 (Appendix 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. Willing and able to comply with all study requirements, including treatment, timing, and/or nature of required assessments and follow-up.
8. 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)
9. Signed, written informed consent
Exclusion Criteria
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. Any prior use of more than one immune checkpoint inhibitor
6. Treatment with any previous drug therapy within 2 weeks prior to first dose of study treatment. This includes any investigational therapy.
7. Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
8. Concurrent treatment with strong CYP3A4 inhibitors or inducers.
9. 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
10. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
11. Arterial thrombotic or ischaemic events, such as cerebrovascular accident, within 6 months prior to randomization.
12. Venous thrombotic events and pulmonary embolism within 3 months prior to randomization
13. Any haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v5.0 within 4 weeks prior to randomization.
14. Non-healing wound, ulcer, or bone fracture.
15. Interstitial lung disease with ongoing signs and symptoms
16. 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.
17. 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.
18. 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.
19. 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
20. 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.
21. 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
22. Patients with a ≥ grade 3 active infection according to CTCAE version 5.0
23. Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease
24. 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
25. Patients with a seizure disorder who require pharmacotherapy
26. Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol.
27. 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.
18 Years
ALL
No
Sponsors
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Bayer
INDUSTRY
Bristol-Myers Squibb
INDUSTRY
University of Sydney
OTHER
Academic and Community Cancer Research United
OTHER
Taiwanese Cooperative Oncology Group
UNKNOWN
Frankfurter Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
UNKNOWN
National Cancer Center Hospital East
OTHER
Syneos Health
OTHER
Australasian Gastro-Intestinal Trials Group
NETWORK
Responsible Party
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Principal Investigators
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Nick Pavlakis, Prof
Role: STUDY_CHAIR
AGITG
Locations
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Mayo Clinic Arizona
Scottsdale, Arizona, United States
USC Norris
Los Angeles, California, United States
Siouxland Regional Cancer Center
Sioux City, Iowa, United States
St Elizabeth Healthcare
Edgewood, Kentucky, United States
Monument Health Rapid City Hospital
Rapid City, South Dakota, 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
Concord Repatriation General Hospital
Concord, New South Wales, Australia
St Vincent's Public Hospital
Darlinghurst, New South Wales, Australia
Border Medical Oncology Research Unit
East Albury, New South Wales, Australia
Gosford Hospital
Gosford, New South Wales, Australia
St George Hospital
Kogarah, 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
Royal North Shore Private Hospital
Sydney, New South Wales, 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
Royal Darwin Hospital
Tiwi, Northern Territory, Australia
The Townsville Hospital
Douglas, Queensland, Australia
Royal Brisbane and Womens Hospital
Herston, Queensland, Australia
Sunshine Coast University Hospital
Sunshine Coast, Queensland, Australia
The Queen Elizabeth Hospital
Adelaide, South Australia, Australia
Flinders Medical Centre
Bedford Park, South Australia, Australia
Royal Hobart Hospital
Hobart, Tasmania, Australia
Monash Health
Clayton, Victoria, Australia
Austin Health
Melbourne, Victoria, Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia
St John of God Hospital Subiaco
Subiaco, Western Australia, Australia
Landeskrankenanstalten-Betriebsgesellschaft-KABEG
Klagenfurt, , Austria
Ordensklinikum Linz GmbH Barmherzige schwestern
Linz, , Austria
Medizinische Universitaet Wien
Vienna, , Austria
Landesklinikum Wiener Neustadt
Wiener Neustadt, , Austria
Evang. Klinikum Bethel Bielefeld
Gütersloh, North Rhine-Westphalia, Germany
Helios Bad Saarow
Bad Saarow, , Germany
Klinikum Bayreuth
Bayreuth, , Germany
Charité Universitätsmedizin Berlin
Berlin, , Germany
Universitätsklinikum Bonn
Bonn, , Germany
Kliniken der Stadt Köln
Cologne, , Germany
KEM/Evang. Kliniken Essen Mitte gGmbH
Essen, , Germany
Institut für Klinisch Onkol Forschung am Krankenhaus Nordwest
Frankfurt, , Germany
Universitätsklinikum Greifswald
Greifswald, , Germany
Norddeutsches Studienzentrum für Innovative Onkologie (NIO)
Hamburg, , Germany
Universitätsklinikum Heidelberg
Heidelberg, , Germany
Universitätsklinikum Jena
Jena, , Germany
Universitätsklinikum Leipzig
Leipzig, , Germany
Klinikum Leverkusen gGmbH
Leverkusen, , Germany
Klinikum Ludwigburg
Ludwigsburg, , Germany
Klinikum Magdeburg gGmbH
Magdeburg, , Germany
Universitätsklinikum Mainz
Mainz, , Germany
Philipps-Universitat Marburg
Marburg, , Germany
Klinikum rechts der Isar der TU München
München, , Germany
Studienzentrum Onkologie Ravensburg
Ravensburg, , Germany
Caritas Klinikum Saarbrücken St. Theresia
Saarbrücken, , Germany
Universitätsklinikum Ulm
Ulm, , Germany
Istituto Nazionale Tumori di Napoli-IRCCS Fondazione G. Pascale
Napoli, , Italy
Universitae degli studi della Campania "Luigi Vanvitelli"
Napoli, , Italy
Azienda USL-IRCCS Di Reggio Emilia
Reggio Emilia, , Italy
San Camillo Forlanini Hospitals
Roma, , Italy
Universita Cattolica del Sacro Cuore, University Hospital Gemelli
Roma, , Italy
IRCCS Fondazione Casa Sollievo della Sofferenza
San Giovanni Rotondo, , Italy
National Cancer Centre Hospital East
Chiba, Kashiwa, Japan
Hokkaido University Hospital
Sapporo, Kita, Japan
Kyushu Cancer Center
Fukuoka, , Japan
Shikoku Cancer Center
Matsuyama, , Japan
Saitama Cancer Center
Saitama, , Japan
Shizuoka Cancer Center
Shizuoka, , Japan
Hallym University Sacred Heart Hospital
Anyang, , South Korea
Dong-A University Hospital
Busan, , South Korea
Haeundae Paik Hospital
Busan, , South Korea
Chungbuk National University Hospital
Cheongju-si, , South Korea
Jeonbuk National University Hospital
Jeonju, , South Korea
Gyeongsang National University Hospital
Jinju, , South Korea
Asan Medical Centre
Seoul, , South Korea
Chung-Ang University Hospital
Seoul, , South Korea
Kangbuk Samsung Hospital
Seoul, , South Korea
Korea University Anam Hospital
Seoul, , South Korea
Korea University Guro Hospital
Seoul, , South Korea
Seoul National University Bundang Hospital
Seoul, , South Korea
Seoul National University Hospital
Seoul, , South Korea
SMG-SNU Boramae Medical Center
Seoul, , South Korea
The Catholic University of Korea - Seoul St. Mary's Hospital
Seoul, , South Korea
The Catholic University of Korea - Yeouido St. Mary's Hospital
Seoul, , South Korea
Yonsei University Health System - Gangnam Severance Hospital
Seoul, , South Korea
Yonsei University Health System - Severance Hospital
Seoul, , South Korea
Vall d'Hebron University Hospital
Barcelona, , Spain
Hospital Universitario de Navarra
Pamplona, , Spain
Hospital Clinico Universitario De Valencia
Valencia, , Spain
Kaohsiung Medical University Chung-Ho Memorial Hospital
Kaohsiung City, , Taiwan
China Medical University Hospital (CMUH)
Taichung, , Taiwan
National Cheng Kung University Hospital
Taipei, , Taiwan
National Taiwan University Hospital (NTUH)
Taipei, , Taiwan
Taipei Veterans General Hospital (TPVGH)
Taipei, , Taiwan
Countries
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References
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Lam LL, Pavlakis N, Shitara K, Sjoquist KM, Martin AJ, Yip S, Kang YK, Bang YJ, Chen LT, Moehler M, Bekaii-Saab T, Alcindor T, O'Callaghan CJ, Tebbutt NC, Hague W, Chan H, Rha SY, Lee KW, Gebski V, Jaworski A, Zalcberg J, Price T, Simes J, Goldstein D. INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG). BMC Cancer. 2023 Feb 22;23(1):180. doi: 10.1186/s12885-023-10642-7.
Other Identifiers
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2020-004617-12
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
AG0315OG/CTC0140
Identifier Type: -
Identifier Source: org_study_id
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