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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04879368




Registration number
NCT04879368
Ethics application status
Date submitted
24/02/2021
Date registered
10/05/2021
Date last updated
16/05/2024

Titles & IDs
Public title
RegoNivo vs Standard of Care Chemotherapy in AGOC
Scientific title
A Randomised Phase III Open Label Study of Regorafenib + Nivolumab vs Standard Chemotherapy in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)
Secondary ID [1] 0 0
2020-004617-12
Secondary ID [2] 0 0
AG0315OG/CTC0140
Universal Trial Number (UTN)
Trial acronym
INTEGRATEIIb
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gastro-Oesophageal Cancer 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Regorafenib
Treatment: Other - Nivolumab
Treatment: Drugs - Docetaxel
Treatment: Drugs - Paclitaxel
Treatment: Drugs - Irinotecan
Treatment: Drugs - Trifluridine/Tipracil

Experimental: 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.

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).


Treatment: Drugs: 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

Treatment: Other: Nivolumab
human IgG4 monoclonal antibody inhibitor of PD-1

Treatment: Drugs: 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

Treatment: Drugs: 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

Treatment: Drugs: 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.

Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
O/S
Timepoint [1] 0 0
5 years
Secondary outcome [1] 0 0
Determine the effect of RegoNivo on; PFS
Timepoint [1] 0 0
5 years
Secondary outcome [2] 0 0
Determine the effect of RegoNivo on; OTRR
Timepoint [2] 0 0
5 years
Secondary outcome [3] 0 0
Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire
Timepoint [3] 0 0
5 years
Secondary outcome [4] 0 0
Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire
Timepoint [4] 0 0
5 years
Secondary outcome [5] 0 0
Determine the effect of RegoNivo on; QoL - EORTC Quality of Life Questionnaire -Stomach Cancer
Timepoint [5] 0 0
5 years
Secondary outcome [6] 0 0
Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (self assessment of pain on health aspect)
Timepoint [6] 0 0
5 years
Secondary outcome [7] 0 0
Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (self rating on health aspects)
Timepoint [7] 0 0
5 years
Secondary outcome [8] 0 0
Determine the effect of RegoNivo on; QoL - Patient D.A.T.A form (health aspect impact self assessment)
Timepoint [8] 0 0
5 years
Secondary outcome [9] 0 0
Determine the effect of RegoNivo on; QoL - Health Questionnaire
Timepoint [9] 0 0
5 years
Secondary outcome [10] 0 0
Determine the effect of RegoNivo on; Safety
Timepoint [10] 0 0
5 years

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/06/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2026
Actual
Sample size
Target
450
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,TAS,VIC,WA
Recruitment hospital [1] 0 0
Coffs Harbour Health Campus - Coffs Harbour
Recruitment hospital [2] 0 0
Concord Repatriation General Hospital - Concord
Recruitment hospital [3] 0 0
St Vincent's Public Hospital - Darlinghurst
Recruitment hospital [4] 0 0
Border Medical Oncology Research Unit - East Albury
Recruitment hospital [5] 0 0
Gosford Hospital - Gosford
Recruitment hospital [6] 0 0
St George Hospital - Kogarah
Recruitment hospital [7] 0 0
Newcastle Private Hospital - New Lambton Heights
Recruitment hospital [8] 0 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [9] 0 0
Prince of Wales Hospital - Randwick
Recruitment hospital [10] 0 0
Royal North Shore Private Hospital - Sydney
Recruitment hospital [11] 0 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [12] 0 0
Ballarat Oncology and Haematology Services - Wendouree
Recruitment hospital [13] 0 0
Westmead Hospital - Westmead
Recruitment hospital [14] 0 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [15] 0 0
The Townsville Hospital - Douglas
Recruitment hospital [16] 0 0
Royal Brisbane and Womens Hospital - Herston
Recruitment hospital [17] 0 0
Sunshine Coast University Hospital - Sunshine Coast
Recruitment hospital [18] 0 0
The Queen Elizabeth Hospital - Adelaide
Recruitment hospital [19] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [20] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [21] 0 0
Monash Health - Clayton
Recruitment hospital [22] 0 0
Austin Health - Melbourne
Recruitment hospital [23] 0 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [24] 0 0
St John of God Hospital Subiaco - Subiaco
Recruitment postcode(s) [1] 0 0
2450 - Coffs Harbour
Recruitment postcode(s) [2] 0 0
2139 - Concord
Recruitment postcode(s) [3] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [4] 0 0
2640 - East Albury
Recruitment postcode(s) [5] 0 0
2250 - Gosford
Recruitment postcode(s) [6] 0 0
2217 - Kogarah
Recruitment postcode(s) [7] 0 0
2035 - New Lambton Heights
Recruitment postcode(s) [8] 0 0
2444 - Port Macquarie
Recruitment postcode(s) [9] 0 0
2031 - Randwick
Recruitment postcode(s) [10] 0 0
2065 - Sydney
Recruitment postcode(s) [11] 0 0
2485 - Tweed Heads
Recruitment postcode(s) [12] 0 0
3355 - Wendouree
Recruitment postcode(s) [13] 0 0
2145 - Westmead
Recruitment postcode(s) [14] 0 0
0810 - Tiwi
Recruitment postcode(s) [15] 0 0
4814 - Douglas
Recruitment postcode(s) [16] 0 0
4029 - Herston
Recruitment postcode(s) [17] 0 0
4560 - Sunshine Coast
Recruitment postcode(s) [18] 0 0
5011 - Adelaide
Recruitment postcode(s) [19] 0 0
5042 - Bedford Park
Recruitment postcode(s) [20] 0 0
700 - Hobart
Recruitment postcode(s) [21] 0 0
3168 - Clayton
Recruitment postcode(s) [22] 0 0
3084 - Melbourne
Recruitment postcode(s) [23] 0 0
6009 - Nedlands
Recruitment postcode(s) [24] 0 0
6008 - Subiaco
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Iowa
Country [4] 0 0
United States of America
State/province [4] 0 0
Kentucky
Country [5] 0 0
United States of America
State/province [5] 0 0
South Dakota
Country [6] 0 0
United States of America
State/province [6] 0 0
Washington
Country [7] 0 0
Austria
State/province [7] 0 0
Klagenfurt
Country [8] 0 0
Austria
State/province [8] 0 0
Linz
Country [9] 0 0
Austria
State/province [9] 0 0
Vienna
Country [10] 0 0
Austria
State/province [10] 0 0
Wiener Neustadt
Country [11] 0 0
Germany
State/province [11] 0 0
Nordrhein-Westfalen
Country [12] 0 0
Germany
State/province [12] 0 0
Bad Saarow
Country [13] 0 0
Germany
State/province [13] 0 0
Bayreuth
Country [14] 0 0
Germany
State/province [14] 0 0
Berlin
Country [15] 0 0
Germany
State/province [15] 0 0
Bonn
Country [16] 0 0
Germany
State/province [16] 0 0
Essen
Country [17] 0 0
Germany
State/province [17] 0 0
Frankfurt
Country [18] 0 0
Germany
State/province [18] 0 0
Greifswald
Country [19] 0 0
Germany
State/province [19] 0 0
Hamburg
Country [20] 0 0
Germany
State/province [20] 0 0
Heidelberg
Country [21] 0 0
Germany
State/province [21] 0 0
Jena
Country [22] 0 0
Germany
State/province [22] 0 0
Koeln
Country [23] 0 0
Germany
State/province [23] 0 0
Leipzig
Country [24] 0 0
Germany
State/province [24] 0 0
Leverkusen
Country [25] 0 0
Germany
State/province [25] 0 0
Ludwigsburg
Country [26] 0 0
Germany
State/province [26] 0 0
Magdeburg
Country [27] 0 0
Germany
State/province [27] 0 0
Mainz
Country [28] 0 0
Germany
State/province [28] 0 0
Marburg
Country [29] 0 0
Germany
State/province [29] 0 0
München
Country [30] 0 0
Germany
State/province [30] 0 0
Ravensburg
Country [31] 0 0
Germany
State/province [31] 0 0
Saarbrücken
Country [32] 0 0
Germany
State/province [32] 0 0
Ulm
Country [33] 0 0
Italy
State/province [33] 0 0
Napoli
Country [34] 0 0
Italy
State/province [34] 0 0
Reggio Emilia
Country [35] 0 0
Italy
State/province [35] 0 0
Roma
Country [36] 0 0
Italy
State/province [36] 0 0
San Giovanni Rotondo
Country [37] 0 0
Japan
State/province [37] 0 0
Kashiwa
Country [38] 0 0
Japan
State/province [38] 0 0
Kita
Country [39] 0 0
Japan
State/province [39] 0 0
Fukuoka
Country [40] 0 0
Japan
State/province [40] 0 0
Matsuyama
Country [41] 0 0
Japan
State/province [41] 0 0
Saitama
Country [42] 0 0
Japan
State/province [42] 0 0
Shizuoka
Country [43] 0 0
Korea, Republic of
State/province [43] 0 0
Anyang
Country [44] 0 0
Korea, Republic of
State/province [44] 0 0
Busan
Country [45] 0 0
Korea, Republic of
State/province [45] 0 0
Cheongju
Country [46] 0 0
Korea, Republic of
State/province [46] 0 0
Jeonju
Country [47] 0 0
Korea, Republic of
State/province [47] 0 0
Jinju
Country [48] 0 0
Korea, Republic of
State/province [48] 0 0
Seoul
Country [49] 0 0
Spain
State/province [49] 0 0
Barcelona
Country [50] 0 0
Spain
State/province [50] 0 0
Pamplona
Country [51] 0 0
Spain
State/province [51] 0 0
Valencia
Country [52] 0 0
Taiwan
State/province [52] 0 0
Kaohsiung
Country [53] 0 0
Taiwan
State/province [53] 0 0
Taichung
Country [54] 0 0
Taiwan
State/province [54] 0 0
Taipei

Funding & Sponsors
Primary sponsor type
Other
Name
Australasian Gastro-Intestinal Trials Group
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Bayer
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/industry
Name [2] 0 0
Bristol-Myers Squibb
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
University of Sydney
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Academic and Community Cancer Research United
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
Taiwanese Cooperative Oncology Group
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Other
Name [6] 0 0
Frankfurter Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Address [6] 0 0
Country [6] 0 0
Other collaborator category [7] 0 0
Other
Name [7] 0 0
National Cancer Center Hospital East
Address [7] 0 0
Country [7] 0 0
Other collaborator category [8] 0 0
Other
Name [8] 0 0
Syneos Health
Address [8] 0 0
Country [8] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
To determine if the regorafenib and nivolumab combination (RegoNivo) improves overall survival compared with current standard chemotherapy options in refractory AGOC.
Trial website
https://clinicaltrials.gov/study/NCT04879368
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Nick Pavlakis, Prof
Address 0 0
AGITG
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04879368