RegoNivo vs Standard of Care Chemotherapy in AGOC

NCT04879368 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: AG0315OG/CTC01402020-004617-12
• Study Type: interventional
• Target: 450
• Locations: 8 countries
• Sites: 90

Brief Summary

To determine if the regorafenib and nivolumab combination (RegoNivo) improves overall survival compared with current standard chemotherapy options in refractory AGOC.

Conditions

Gastro-Oesophageal Cancer

Keywords

Metastatic; Locally recurrent; Oesophago-gastric junction; Stomach; Adenocarcinoma; Undifferentiated carcinoma; RegoNivo

Outcome Measures

Primary Outcomes (1)

• O/S

  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.

  5 years

Secondary Outcomes (10)

• Determine the effect of RegoNivo on; PFS

  5 years

• Determine the effect of RegoNivo on; OTRR

  5 years

• Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire

  5 years

• Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire

  5 years

• Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire -Stomach Cancer

  5 years

Other Outcomes (3)

• Prognostic biomarker identification for AGOC

  Up to 24 months following close of study.

• Regorafenib max plasma concentration level assessment (Cmax) across geographical regions

  Up to 24 months following close of study.

• Regorafenib levels and correlation to treatment

  Up to 24 months following close of study.

Study Arms (2)

RegoNivo

EXPERIMENTAL

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.

Drug: Regorafenib; Biological: Nivolumab

Standard of Care

ACTIVE COMPARATOR

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).

Drug: Docetaxel; Drug: Paclitaxel; Drug: Irinotecan; Drug: Trifluridine/Tipracil

Interventions

Regorafenib DRUG

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

Also known as: Stivarga

RegoNivo

Nivolumab BIOLOGICAL

human IgG4 monoclonal antibody inhibitor of PD-1

Also known as: Opdivo

RegoNivo

Docetaxel DRUG

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

Also known as: Taxotere

Standard of Care

Paclitaxel DRUG

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

Also known as: Abraxane

Standard of Care

Irinotecan DRUG

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.

Also known as: Camptosar

Standard of Care

Trifluridine/Tipracil DRUG

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.

Also known as: Lonsurf

Standard of Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Australasian Gastro-Intestinal Trials Group: lead
• Bayer: collaborator
• Bristol-Myers Squibb: collaborator
• University of Sydney: collaborator
• Academic and Community Cancer Research United: collaborator
• Taiwanese Cooperative Oncology Group: collaborator
• Frankfurter Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest: collaborator
• National Cancer Center Hospital East: collaborator
• Syneos Health: collaborator

Study Sites (94)

Mayo Clinic Arizona

Scottsdale, Arizona, 85054, United States

Location

USC Norris

Los Angeles, California, 90001, United States

Location

Siouxland Regional Cancer Center

Sioux City, Iowa, 51101, United States

Location

St Elizabeth Healthcare

Edgewood, Kentucky, 41017, United States

Location

Monument Health Rapid City Hospital

Rapid City, South Dakota, 57701, United States

Location

Fred Hutchinson Cancer Research Centre - South Lake Union Clinic

Seattle, Washington, 98109, United States

Location

Coffs Harbour Health Campus

Coffs Harbour, New South Wales, 2450, Australia

Location

Concord Repatriation General Hospital

Concord, New South Wales, 2139, Australia

Location

St Vincent's Public Hospital

Darlinghurst, New South Wales, 2010, Australia

Location

Border Medical Oncology Research Unit

East Albury, New South Wales, 2640, Australia

Location

Gosford Hospital

Gosford, New South Wales, 2250, Australia

Location

St George Hospital

Kogarah, New South Wales, 2217, Australia

Location

Newcastle Private Hospital

New Lambton Heights, New South Wales, 2035, Australia

Location

Port Macquarie Base Hospital

Port Macquarie, New South Wales, 2444, Australia

Location

Prince of Wales Hospital

Randwick, New South Wales, 2031, Australia

Location

Royal North Shore Private Hospital

Sydney, New South Wales, 2065, Australia

Location

The Tweed Hospital

Tweed Heads, New South Wales, 2485, Australia

Location

Ballarat Oncology and Haematology Services

Wendouree, New South Wales, 3355, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Royal Darwin Hospital

Tiwi, Northern Territory, 0810, Australia

Location

The Townsville Hospital

Douglas, Queensland, 4814, Australia

Location

Royal Brisbane and Womens Hospital

Herston, Queensland, 4029, Australia

Location

Sunshine Coast University Hospital

Sunshine Coast, Queensland, 4560, Australia

Location

The Queen Elizabeth Hospital

Adelaide, South Australia, 5011, Australia

Location

Flinders Medical Centre

Bedford Park, South Australia, 5042, Australia

Location

Royal Hobart Hospital

Hobart, Tasmania, 700, Australia

Location

Monash Health

Clayton, Victoria, 3168, Australia

Location

Austin Health

Melbourne, Victoria, 3084, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

Location

St John of God Hospital Subiaco

Subiaco, Western Australia, 6008, Australia

Location

Landeskrankenanstalten-Betriebsgesellschaft-KABEG

Klagenfurt, Austria

Location

Ordensklinikum Linz GmbH Barmherzige schwestern

Linz, Austria

Location

Medizinische Universitaet Wien

Vienna, Austria

Location

Landesklinikum Wiener Neustadt

Wiener Neustadt, Austria

Location

Evang. Klinikum Bethel Bielefeld

Gütersloh, North Rhine-Westphalia, Germany

Location

Helios Bad Saarow

Bad Saarow, Germany

Location

Klinikum Bayreuth

Bayreuth, Germany

Location

Charité Universitätsmedizin Berlin

Berlin, Germany

Location

Universitätsklinikum Bonn

Bonn, Germany

Location

Kliniken der Stadt Köln

Cologne, Germany

Location

KEM/Evang. Kliniken Essen Mitte gGmbH

Essen, Germany

Location

Institut für Klinisch Onkol Forschung am Krankenhaus Nordwest

Frankfurt, Germany

Location

Universitätsklinikum Greifswald

Greifswald, Germany

Location

Norddeutsches Studienzentrum für Innovative Onkologie (NIO)

Hamburg, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, Germany

Location

Universitätsklinikum Jena

Jena, Germany

Location

Universitätsklinikum Leipzig

Leipzig, Germany

Location

Klinikum Leverkusen gGmbH

Leverkusen, Germany

Location

Klinikum Ludwigburg

Ludwigsburg, Germany

Location

Klinikum Magdeburg gGmbH

Magdeburg, Germany

Location

Universitätsklinikum Mainz

Mainz, Germany

Location

Philipps-Universitat Marburg

Marburg, Germany

Location

Klinikum rechts der Isar der TU München

München, Germany

Location

Studienzentrum Onkologie Ravensburg

Ravensburg, Germany

Location

Caritas Klinikum Saarbrücken St. Theresia

Saarbrücken, Germany

Location

Universitätsklinikum Ulm

Ulm, Germany

Location

Istituto Nazionale Tumori di Napoli-IRCCS Fondazione G. Pascale

Napoli, Italy

Location

Universitae degli studi della Campania "Luigi Vanvitelli"

Napoli, Italy

Location

Azienda USL-IRCCS Di Reggio Emilia

Reggio Emilia, Italy

Location

San Camillo Forlanini Hospitals

Roma, Italy

Location

Universita Cattolica del Sacro Cuore, University Hospital Gemelli

Roma, Italy

Location

IRCCS Fondazione Casa Sollievo della Sofferenza

San Giovanni Rotondo, Italy

Location

National Cancer Centre Hospital East

Chiba, Kashiwa, Japan

Location

Hokkaido University Hospital

Sapporo, Kita, Japan

Location

Kyushu Cancer Center

Fukuoka, Japan

Location

Shikoku Cancer Center

Matsuyama, Japan

Location

Saitama Cancer Center

Saitama, Japan

Location

Shizuoka Cancer Center

Shizuoka, Japan

Location

Hallym University Sacred Heart Hospital

Anyang, South Korea

Location

Dong-A University Hospital

Busan, South Korea

Location

Haeundae Paik Hospital

Busan, South Korea

Location

Chungbuk National University Hospital

Cheongju-si, South Korea

Location

Jeonbuk National University Hospital

Jeonju, South Korea

Location

Gyeongsang National University Hospital

Jinju, South Korea

Location

Asan Medical Centre

Seoul, South Korea

Location

Chung-Ang University Hospital

Seoul, South Korea

Location

Kangbuk Samsung Hospital

Seoul, South Korea

Location

Korea University Anam Hospital

Seoul, South Korea

Location

Korea University Guro Hospital

Seoul, South Korea

Location

Seoul National University Bundang Hospital

Seoul, South Korea

Location

Seoul National University Hospital

Seoul, South Korea

Location

SMG-SNU Boramae Medical Center

Seoul, South Korea

Location

The Catholic University of Korea - Seoul St. Mary's Hospital

Seoul, South Korea

Location

The Catholic University of Korea - Yeouido St. Mary's Hospital

Seoul, South Korea

Location

Yonsei University Health System - Gangnam Severance Hospital

Seoul, South Korea

Location

Yonsei University Health System - Severance Hospital

Seoul, South Korea

Location

Vall d'Hebron University Hospital

Barcelona, Spain

Location

Hospital Universitario de Navarra

Pamplona, Spain

Location

Hospital Clinico Universitario De Valencia

Valencia, Spain

Location

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, Taiwan

Location

China Medical University Hospital (CMUH)

Taichung, Taiwan

Location

National Cheng Kung University Hospital

Taipei, Taiwan

Location

National Taiwan University Hospital (NTUH)

Taipei, Taiwan

Location

Taipei Veterans General Hospital (TPVGH)

Taipei, Taiwan

Location

Related Publications (1)

• 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.

  PMID: 36814222 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis; Adenocarcinoma; Carcinoma

Interventions

regorafenib; Nivolumab; Docetaxel; Paclitaxel; Albumin-Bound Paclitaxel; Irinotecan; Trifluridine; trifluridine tipiracil drug combination

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Camptothecin; Alkaloids; Heterocyclic Compounds; Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Nick Pavlakis, Prof

  AGITG

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Parallel assignment

Study Record Dates

• First Submitted: February 24, 2021
• First Posted: May 10, 2021
• Study Start: June 1, 2021
• Primary Completion: July 9, 2025
• Study Completion (Estimated): June 1, 2026
• Last Updated: July 17, 2025

Record last verified: 2025-07

Locations

AU (24); DE (22); KR (18); US (6); IT (6); JP (6); ES (3); TW (5)