RegoNivo vs Standard of Care Chemotherapy in AGOC

Gastro-Oesophageal Cancer Clinical Trial

— INTEGRATEIIb  

Official title:

A Randomised Phase III Open Label Study of Regorafenib + Nivolumab vs Standard Chemotherapy in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04879368
• Other study ID #: AG0315OG/CTC0140
• Secondary ID: 2020-004617-12
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 1, 2021
• Est. completion date: June 1, 2026

Study information

• Verified date: May 2024
• Source: Australasian Gastro-Intestinal Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 450
• Est. completion date: June 1, 2026
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Gastro-Oesophageal Cancer

Intervention

Drug:
• Regorafenib
Oral multi-targeted tyrosine kinase inhibitor (TKI) which targets angiogenic (VEGF, TIE-2), stromal (PDGF-ß), and oncogenic (RAF, RET and KIT) receptor tyrosine kinases

Biological:
• Nivolumab
human IgG4 monoclonal antibody inhibitor of PD-1

Drug:
• 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 ß) 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.

Locations

Country	Name	City	State
Australia	The Queen Elizabeth Hospital	Adelaide	South Australia
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Monash Health	Clayton	Victoria
Australia	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	The Townsville Hospital	Douglas	Queensland
Australia	Border Medical Oncology Research Unit	East Albury	New South Wales
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Royal Brisbane and Womens Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	St George Hospital	Kogarah	New South Wales
Australia	Austin Health	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
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	St John of God Hospital Subiaco	Subiaco	Western Australia
Australia	Sunshine Coast University Hospital	Sunshine Coast	Queensland
Australia	Royal North Shore Private Hospital	Sydney	New South Wales
Australia	Royal Darwin Hospital	Tiwi	Northern Territory
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
Austria	Landeskrankenanstalten-Betriebsgesellschaft-KABEG	Klagenfurt
Austria	Ordensklinikum Linz GmbH Barmherzige schwestern	Linz
Austria	Medizinische Universitaet Wien	Vienna
Austria	Landesklinikum Wiener Neustadt	Wiener Neustadt
Germany	Helios Bad Saarow	Bad Saarow
Germany	Klinikum Bayreuth	Bayreuth
Germany	Charité Universitätsmedizin Berlin	Berlin
Germany	Universitätsklinikum Bonn	Bonn
Germany	KEM/Evang. Kliniken Essen Mitte gGmbH	Essen
Germany	Institut für Klinisch Onkol Forschung am Krankenhaus Nordwest	Frankfurt
Germany	Universitätsklinikum Greifswald	Greifswald
Germany	Evang. Klinikum Bethel Bielefeld	Gütersloh	Nordrhein-Westfalen
Germany	Norddeutsches Studienzentrum für Innovative Onkologie (NIO)	Hamburg
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Jena	Jena
Germany	Kliniken der Stadt Köln	Koeln
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
Italy	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
Japan	National Cancer Centre Hospital East	Chiba	Kashiwa
Japan	Kyushu Cancer Center	Fukuoka
Japan	Shikoku Cancer Center	Matsuyama
Japan	Saitama Cancer Center	Saitama
Japan	Hokkaido University Hospital	Sapporo	Kita
Japan	Shizuoka Cancer Center	Shizuoka
Korea, Republic of	Hallym University Sacred Heart Hospital	Anyang
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Haeundae Paik Hospital	Busan
Korea, Republic of	Chungbuk National University Hospital	Cheongju
Korea, Republic of	Jeonbuk National University Hospital	Jeonju
Korea, Republic of	Gyeongsang National University Hospital	Jinju
Korea, Republic of	Asan Medical Centre	Seoul
Korea, Republic of	Chung-Ang University Hospital	Seoul
Korea, Republic of	Kangbuk Samsung Hospital	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Seoul National University Bundang Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	SMG-SNU Boramae Medical Center	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	Yonsei University Health System - Gangnam Severance Hospital	Seoul
Korea, Republic of	Yonsei University Health System - Severance Hospital	Seoul
Spain	Vall d'Hebron University Hospital	Barcelona
Spain	Hospital Universitario de Navarra	Pamplona
Spain	Hospital Clinico Universitario De Valencia	Valencia
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
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
United States	St Elizabeth Healthcare	Edgewood	Kentucky
United States	USC Norris	Los Angeles	California
United States	Monument Health Rapid City Hospital	Rapid City	South Dakota
United States	Mayo Clinic Arizona	Scottsdale	Arizona
United States	Fred Hutchinson Cancer Research Centre - South Lake Union Clinic	Seattle	Washington
United States	Siouxland Regional Cancer Center	Sioux City	Iowa

Sponsors (9)

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

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Germany,  Italy,  Japan,  Korea, Republic of,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Prognostic biomarker identification for AGOC	To identify prognostic and predictive biomarkers (tissue and circulating) for study endpoints (relating to survival, response and safety).	Up to 24 months following close of study.
Other	Regorafenib max plasma concentration level assessment (Cmax) across geographical regions	To evaluate regorafenib Cmax in patient populations from different geographical regions (regorafenib levels).	Up to 24 months following close of study.
Other	Regorafenib levels and correlation to treatment	To evaluate regorafenib levels and their correlation to outcomes in treatment	Up to 24 months following close of study.
Primary	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	Determine the effect of RegoNivo on; PFS	Progression free survival (PFS)(disease progression or death) in the study population	5 years
Secondary	Determine the effect of RegoNivo on; OTRR	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	5 years
Secondary	Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire	Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study EORTC QLQ-C30: Q1 - Q28, Min 1 Max 4, Higher Score = Worse	5 years
Secondary	Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire	Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study EORTC QLQ-C30: Q29 & Q30 Min 1 Max 7, Higher = Better	5 years
Secondary	Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire -Stomach Cancer	Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study EORTC QLQ STO22 Min 1 Max 4, Higher Score = Worse	5 years
Secondary	Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (self assessment of pain on health aspect)	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	5 years
Secondary	Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (self rating on health aspects)	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	5 years
Secondary	Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (health aspect impact self assessment)	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	5 years
Secondary	Determine the effect of RegoNivo on; QoL - Health Questionnaire	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	5 years
Secondary	Determine the effect of RegoNivo on; Safety	Safety (rates of adverse events) of participants on study	5 years