INTEGRATEIIb: RegoNivo vs Standard of Care Chemotherapy in AGOC

• Sponsor: Australasian Gastro-Intestinal Trials Group (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04879368
• Collaborator: Bayer (Industry), Bristol-Myers Squibb (Industry), University of Sydney (Other), Academic and Community Cancer Research United (Other), Taiwanese Cooperative Oncology Group (Other), Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest (Other), National Cancer Center Hospital East (Other)
• Enrollment: 450
• Locations: 75
• Arms: 2
• Anticipated Duration (Months): 60
• Patients Per Site: 6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Gastro-Oesophageal Cancer	Drug: Regorafenib; Biological: Nivolumab; Drug: Docetaxel; Drug: Paclitaxel; Drug: Irinotecan; Drug: Trifluridine/Tipracil	Phase 3

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:

1. 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
2. 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 450 participants in the study from, but not limited to; Australia, New Zealand, South Korea, Japan, Taiwan, Canada, USA, Germany, Belgium, Spain, France, Switzerland, Netherlands and Italy.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 450 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Parallel assignmentParallel assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomised Phase III Open Label Study of Regorafenib + Nivolumab vs Standard Chemotherapy in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)
• Actual Study Start Date: Jun 1, 2021
• Anticipated Primary Completion Date: Jun 1, 2025
• Anticipated Study Completion Date: Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RegoNivo Participants in the RegoNivo arm will; self-administer 90mg (3x30mg) of regorafenib days 1-21 of each 28-day treatment cycle and; 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; 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; Other Names: Stivarga ; Biological: Nivolumab; human IgG4 monoclonal antibody inhibitor of PD-1; Other Names: Opdivo
Active Comparator: 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).	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; Other Names: Taxotere ; Drug: 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; Other Names: Abraxane ; Drug: 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.; Other Names: Camptosar ; Drug: 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 Names: Lonsurf

Outcome Measures

Primary Outcome Measures

1. 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

1. Determine the effect of RegoNivo on; PFS [5 years]

   Progression free survival (PFS)(disease progression or death) in the study population

2. 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

3. 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: Q1 - Q28, Min 1 Max 4, Higher Score = Worse

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. Determine the effect of RegoNivo on; Safety [5 years]

    Safety (rates of adverse events) of participants on study

Other Outcome Measures

1. Prognostic biomarker identification for AGOC [Up to 24 months following close of study.]

   To identify prognostic and predictive biomarkers (tissue and circulating) for study endpoints (relating to survival, response and safety).

2. Regorafenib max plasma concentration level assessment (Cmax) across geographical regions [Up to 24 months following close of study.]

   To evaluate regorafenib Cmax in patient populations from different geographical regions (regorafenib levels).

3. Regorafenib levels and correlation to treatment [Up to 24 months following close of study.]

   To evaluate regorafenib levels and their correlation to outcomes in treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Adults (18 years or over) with metastatic or locally recurrent gastro-oesophageal cancer which:

2. has arisen in any primary gastro-oesophageal site (oesophago-gastric junction (GOJ) or stomach); and

3. is of adenocarcinoma or undifferentiated carcinoma histology; and

4. 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

5. 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.

6. HER2-positive participants must have received trastuzumab

7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 1).

8. Ability to swallow oral medication.

9. Adequate bone marrow function (Platelets ≥100x109/L; Absolute Neutrophil Count (ANC) ≥1.5x109/L and Haemoglobin ≥ 9.0g/dL).

10. 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).

11. 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.

1. Willing and able to comply with all study requirements, including treatment, timing, and/or nature of required assessments and follow-up.

2. 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)

3. 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:

20. curatively treated cervical carcinoma in situ,

21. non-melanomatous carcinoma of the skin,

22. superficial bladder tumours (T1a [Non-invasive tumour], and Tis [Carcinoma in situ]),

23. treated thyroid papillary cancer

24. 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.

25. 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

26. Patients with a ≥ grade 3 active infection according to CTCAE version 5.0

27. Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease

28. 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

29. Patients with a seizure disorder who require pharmacotherapy

30. Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol.

31. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Arizona	Scottsdale	Arizona	United States	85054
2	USC Norris	Los Angeles	California	United States	90001
3	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
4	Toledo Clinic Cancer Centres	Toledo	Ohio	United States	45009
5	Canberra Hospital	Canberra	Australian Capital Territory	Australia
6	Border Cancer Hospital	Albury	New South Wales	Australia	2640
7	Monash Medical Centre	Clayton	New South Wales	Australia	3168
8	Coffs Harbour Health Campus	Coffs Harbour	New South Wales	Australia	2450
9	Concord Repatriation General Hospital	Concord	New South Wales	Australia	2139
10	St Vincent's Public Hospital	Darlinghurst	New South Wales	Australia	2010
11	Gosford Hospital	Gosford	New South Wales	Australia	2250
12	St George Hospital	Kogarah	New South Wales	Australia	2217
13	Newcastle Private Hospital	New Lambton Heights	New South Wales	Australia	2035
14	Calvary Mater Newcastle	Newcastle	New South Wales	Australia
15	Port Macquarie Base Hospital	Port Macquarie	New South Wales	Australia	2444
16	Prince of Wales Hospital	Randwick	New South Wales	Australia	2031
17	Royal North Shore Hospital	St Leonards	New South Wales	Australia	2065
18	Campbelltown Hospital	Sydney	New South Wales	Australia
19	Liverpool Hospital	Sydney	New South Wales	Australia
20	Nepean Hospital	Sydney	New South Wales	Australia
21	North Shore Private Hospital	Sydney	New South Wales	Australia
22	Tamworth Base Hospital	Tamworth	New South Wales	Australia
23	The Tweed Hospital	Tweed Heads	New South Wales	Australia	2485
24	Ballarat Oncology and Haematology Services	Wendouree	New South Wales	Australia	3355
25	Westmead Hospital	Westmead	New South Wales	Australia	2145
26	Royal Darwin Hospital	Tiwi	Northern Territory	Australia	0810
27	The Townsville Hospital	Douglas	Queensland	Australia	4814
28	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
29	Royal Brisbane and Womens Hospital	Herston	Queensland	Australia	4029
30	Royal Brisbane Hospital	Herston	Queensland	Australia	4029
31	Sunshine Coast University Hospital	Sunshine Coast	Queensland	Australia	4560
32	Queen Elizabeth Hospital / Lyell McEwin Centre	Adelaide	South Australia	Australia
33	Royal Adelaide Hospital	Adelaide	South Australia	Australia
34	Ashford Cancer Centre Research	Ashford	South Australia	Australia	5035
35	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
36	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
37	The Queen Elizabeth Hospital	Woodville South	South Australia	Australia	5011
38	Royal Hobart Hospital	Hobart	Tasmania	Australia	700
39	Ballarat Health Service	Ballarat	Victoria	Australia
40	Eastern Health	Box Hill	Victoria	Australia
41	Monash Health	Clayton	Victoria	Australia	3168
42	Austin Hospital	Heidelberg	Victoria	Australia	3084
43	Olivia Newton-John Cancer Wellness and Research Centre	Heidelberg	Victoria	Australia	3084
44	Austin Health	Melbourne	Victoria	Australia
45	Box Hill Hospital	Melbourne	Victoria	Australia
46	Frankston Hospital	Melbourne	Victoria	Australia
47	Peter MacCallum Cancer Institute	Melbourne	Victoria	Australia
48	Peninsula Health/Frankston Hospital	Mornington	Victoria	Australia	3931
49	Sir Charles Gairdner Hospital	Nedlands	Western Australia	Australia	6009
50	Fremantle Hospital	Perth	Western Australia	Australia
51	St John of God Hospital Subiaco	Subiaco	Western Australia	Australia	6008
52	Ottawa Hospital Research Institute	Ottawa		Canada
53	The Research Institute of the McGill University Health Centre	Québec		Canada
54	National Cancer Centre Hospital East	Chiba	Kashiwa	Japan
55	Hokkaido University Hospital	Sapporo	Kita	Japan
56	Hallym University Sacred Heart Hospital	Anyang		Korea, Republic of
57	Dong-A University Hospital	Busan		Korea, Republic of
58	Gyeongsang National University Hospital	Jinju		Korea, Republic of
59	Chung-Ang University Hospital	Seoul		Korea, Republic of
60	Korea University Anam Hospital	Seoul		Korea, Republic of
61	Korea University Guro Hospital	Seoul		Korea, Republic of
62	Samsung Medical Center	Seoul		Korea, Republic of
63	Seoul National University Bundang Hospital	Seoul		Korea, Republic of
64	Seoul National University Hospital	Seoul		Korea, Republic of
65	SMG-SNU Boramae Medical Center	Seoul		Korea, Republic of
66	The Catholic University of Korea - Seoul St. Mary's Hospital	Seoul		Korea, Republic of
67	The Catholic University of Korea - Yeouido St. Mary's Hospital	Seoul		Korea, Republic of
68	Yonsei University Health System - Gangnam Severance Hospital	Seoul		Korea, Republic of
69	Yonsei University Health System - Severance Hospital	Seoul		Korea, Republic of
70	Auckland Hospital	Auckland		New Zealand	1023
71	Christchurch Hospital	Christchurch		New Zealand
72	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan
73	National Cheng Kung University Hospital	Taipei		Taiwan
74	National Taiwan University Hospital (NTUH)	Taipei		Taiwan
75	Taipei Veterans General Hospital (TPVGH)	Taipei		Taiwan

Sponsors and Collaborators

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

Investigators

• Study Chair: Nick Pavlakis, Prof, AGITG

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Australasian Gastro-Intestinal Trials Group
• ClinicalTrials.gov Identifier: NCT04879368
• Other Study ID Numbers: AG0315OG/CTC0140; 2020-004617-12
• First Posted: May 10, 2021
• Last Update Posted: Jan 26, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Australasian Gastro-Intestinal Trials Group: Metastatic; Locally recurrent; Oesophago-gastric junction; Stomach; Adenocarcinoma; Undifferentiated carcinoma; RegoNivo
• Additional relevant MeSH terms: Trifluridine; Paclitaxel; Docetaxel; Nivolumab; Irinotecan

Study Results

No Results Posted as of Jan 26, 2022