Clinical trial NCT04879368: RegoNivo vs Standard of Care Chemotherapy in AGOC
Official title: A Randomised Phase III Open Label Study of Regorafenib + Nivolumab vs Standard Chemotherapy in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Gastro-Oesophageal Cancer
Keywords: Metastatic
Locally recurrent
Oesophago-gastric junction
Stomach
Adenocarcinoma
Undifferentiated carcinoma
RegoNivo
Lead sponsor: Australasian Gastro-Intestinal Trials Group
Sponsor class: NETWORK
Collaborators: name: Bayer
name: Bristol-Myers Squibb
name: University of Sydney
name: Academic and Community Cancer Research United
name: Taiwanese Cooperative Oncology Group
name: Frankfurter Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
name: National Cancer Center Hospital East
name: Syneos Health
First posted: 2021-05-10
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel assignment
Primary purpose: TREATMENT

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.

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 (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:

1. Known allergy to the investigational product drug class or excipients in the regorafenib and/or nivolumab
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.

Primary outcomes:
measure: O/S
timeFrame: 5 years
Secondary outcomes:
measure: Determine the effect of RegoNivo on; PFS
timeFrame: 5 years
measure: Determine the effect of RegoNivo on; OTRR
timeFrame: 5 years
measure: Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire
timeFrame: 5 years
measure: Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire
timeFrame: 5 years
measure: Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire -Stomach Cancer
timeFrame: 5 years
measure: Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (self assessment of pain on health aspect)
timeFrame: 5 years
measure: Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (self rating on health aspects)
timeFrame: 5 years
measure: Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (health aspect impact self assessment)
timeFrame: 5 years
measure: Determine the effect of RegoNivo on; QoL - Health Questionnaire
timeFrame: 5 years
measure: Determine the effect of RegoNivo on; Safety
timeFrame: 5 years
Other outcomes:
measure: Prognostic biomarker identification for AGOC
timeFrame: Up to 24 months following close of study.
measure: Regorafenib max plasma concentration level assessment (Cmax) across geographical regions
timeFrame: Up to 24 months following close of study.
measure: Regorafenib levels and correlation to treatment
timeFrame: Up to 24 months following close of study.
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Los Angeles
country: United States
facility: USC Norris
state: California
city: Sioux City
country: United States
facility: Siouxland Regional Cancer Center
state: Iowa
city: Edgewood
country: United States
facility: St Elizabeth Healthcare
state: Kentucky
city: Rapid City
country: United States
facility: Monument Health Rapid City Hospital
state: South Dakota
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Centre - South Lake Union Clinic
state: Washington
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: East Albury
country: Australia
facility: Border Medical Oncology Research Unit
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: Sydney
country: Australia
facility: Royal North Shore Private 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: Adelaide
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Melbourne
country: Australia
facility: Austin Health
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: Klagenfurt
country: Austria
facility: Landeskrankenanstalten-Betriebsgesellschaft-KABEG
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH Barmherzige schwestern
city: Vienna
country: Austria
facility: Medizinische Universitaet Wien
city: Wiener Neustadt
country: Austria
facility: Landesklinikum Wiener Neustadt
city: Gütersloh
country: Germany
facility: Evang. Klinikum Bethel Bielefeld
state: Nordrhein-Westfalen
city: Bad Saarow
country: Germany
facility: Helios Bad Saarow
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Essen
country: Germany
facility: KEM/Evang. Kliniken Essen Mitte gGmbH
city: Frankfurt
country: Germany
facility: Institut für Klinisch Onkol Forschung am Krankenhaus Nordwest
city: Greifswald
country: Germany
facility: Universitätsklinikum Greifswald
city: Hamburg
country: Germany
facility: Norddeutsches Studienzentrum für Innovative Onkologie (NIO)
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Koeln
country: Germany
facility: Kliniken der Stadt Köln
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Leverkusen
country: Germany
facility: Klinikum Leverkusen gGmbH
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigburg
city: Magdeburg
country: Germany
facility: Klinikum Magdeburg gGmbH
city: Mainz
country: Germany
facility: Universitätsklinikum Mainz
city: Marburg
country: Germany
facility: Philipps-Universitat Marburg
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Ravensburg
country: Germany
facility: Studienzentrum Onkologie Ravensburg
city: Saarbrücken
country: Germany
facility: Caritas Klinikum Saarbrücken St. Theresia
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori di Napoli-IRCCS Fondazione G. Pascale
city: Napoli
country: Italy
facility: Universitae degli studi della Campania "Luigi Vanvitelli"
city: Reggio Emilia
country: Italy
facility: Azienda USL-IRCCS Di Reggio Emilia
city: Roma
country: Italy
facility: San Camillo Forlanini Hospitals
city: Roma
country: Italy
facility: Universita Cattolica del Sacro Cuore, University Hospital Gemelli
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Fondazione Casa Sollievo della Sofferenza
city: Chiba
country: Japan
facility: National Cancer Centre Hospital East
state: Kashiwa
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Kita
city: Fukuoka
country: Japan
facility: Kyushu Cancer Center
city: Matsuyama
country: Japan
facility: Shikoku Cancer Center
city: Saitama
country: Japan
facility: Saitama Cancer Center
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Anyang
country: Korea, Republic of
facility: Hallym University Sacred Heart Hospital
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Busan
country: Korea, Republic of
facility: Haeundae Paik Hospital
city: Cheongju
country: Korea, Republic of
facility: Chungbuk National University Hospital
city: Jeonju
country: Korea, Republic of
facility: Jeonbuk National University Hospital
city: Jinju
country: Korea, Republic of
facility: Gyeongsang National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Centre
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University Hospital
city: Seoul
country: Korea, Republic of
facility: Kangbuk Samsung 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: 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: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Pamplona
country: Spain
facility: Hospital Universitario de Navarra
city: Valencia
country: Spain
facility: Hospital Clinico Universitario De Valencia
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital (CMUH)
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: