RegoNivo vs Standard of Care Chemotherapy in AGOC

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

Detailed Description
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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 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.

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

Conditions
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Gastro-Oesophageal Cancer

Intervention / Treatment
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* Drug: Regorafenib
* Biological: Nivolumab
* Drug: Docetaxel
* Drug: Paclitaxel
* Drug: Irinotecan
* Drug: Trifluridine/Tipracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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 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. 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. 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. History of another malignancy within 2 years prior to randomization. Participants with the following are eligible for this study: curatively treated cervical carcinoma in situ, non-melanomatous carcinoma of the skin, superficial bladder tumours (T1a [Non-invasive tumour], and Tis [Carcinoma in situ]), treated thyroid papillary cancer 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. 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 Patients with a ≥ grade 3 active infection according to CTCAE version 5.0 Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease 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 Patients with a seizure disorder who require pharmacotherapy Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RegoNivo<br>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<br>* 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<br>* Other names: Stivarga;Biological: Nivolumab<br>* human IgG4 monoclonal antibody inhibitor of PD-1<br>* Other names: Opdivo;|
| Active Comparator: Standard of Care<br>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<br>* 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<br>* Other names: Taxotere;Drug: Paclitaxel<br>* 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<br>* Other names: Abraxane;Drug: Irinotecan<br>* 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.<br>* Other names: Camptosar;Drug: Trifluridine/Tipracil<br>* 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.<br>* Other names: Lonsurf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the effect of RegoNivo on; PFS | Progression free survival (PFS)(disease progression or death) in the study population | 5 years | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Determine the effect of RegoNivo on; Safety | Safety (rates of adverse events) of participants on study | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic, Locally recurrent, Oesophago-gastric junction, Stomach, Adenocarcinoma, Undifferentiated carcinoma, RegoNivo