Gastro-Oesophageal Cancer
Conditions
Keywords
Metastatic, Locally recurrent, Oesophago-gastric junction, Stomach, Adenocarcinoma, Undifferentiated carcinoma, RegoNivo
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.
Interventions
DRUGRegorafenib
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
BIOLOGICALNivolumab
human IgG4 monoclonal antibody inhibitor of PD-1
DRUGDocetaxel
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
DRUGPaclitaxel
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
DRUGIrinotecan
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.
DRUGTrifluridine/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.
Sponsors
Australasian Gastro-Intestinal Trials Group
Bayer
Bristol-Myers Squibb
University of Sydney
Academic and Community Cancer Research United
Taiwanese Cooperative Oncology Group
Frankfurter Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
National Cancer Center Hospital East
Syneos Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Parallel assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| O/S | From the date of randomisation to date of death from any cause or the date last known alive, assessed up to approximately 44 months. | 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. Overall survival is defined as the interval from the date of randomisation to date of death from any cause, or the date last known alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Effect of RegoNivo on; PFS | From the date of randomisation to the date of first evidence of disease progression or death, whichever occurs first, assessed up to approximately 44 months. | A PFS (Progressive free survival) event is defined as the first occasion that either RECIST criteria and iRECIST for disease progression are met, a patient is judged to have progressed by the responsible investigator (in the event that no RECIST assessment is available) or death occurs. Progression is defined using RECIST v1.1 and iRECIST, as a 20% increase in the sum of the longest diameter of target lesions taking as reference the smallest sum of diameters recorded in the study (including baseline) and an absolute increase of at least 5mm. The appearance of one or more new lesions is also considered progression. In exceptional circumstances, unequivocal progression of non-target disease was accepted as evidence of disease progression, where the overall tumour burden has increased sufficiently to merit discontinuation of treatment or where the tumour burden appears to have increased by at least 73% in volume. |
| Determine the Effect of RegoNivo on; OTRR | From randomisation until disease progression, with tumour assessments performed every 8 weeks (±7 days), assessed up to approximately 44 months. | Number of participants achieving a Partial Response (PR) or Complete Response (CR) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and iRECIST. Complete Response (CR): Disappearance of all target and non-target lesions and normalisation of any specified tumour markers Partial Response (PR): \>=30% decrease in the sum of diameters of target lesions (longest diameter for tumour lesions and short axis measure for target lymph nodes), taking as reference the baseline sum of diameters. |
| Deterioration-Free Survival (DFS) Based on Physical Function (EORTC QLQ-C30) | 6 months and 12 months after randomisation. | Quality of life (scores from participant-completed questionnaires) of participants on study EORTC QoL Questionnaire: QLQ-C30: Q1 - Q28, Min 1 Max 4, Higher Score = Worse QLQ-C30: Q29 \& Q30 Min 1 Max 7, Higher = Better Deterioration-Free Survival (DFS) rate based on Physical Function is defined as the percentage of participants who have not experienced deterioration, disease progression, death, or treatment discontinuation at the specified time point. Deterioration is defined as a ≥10-point decrease from baseline in the Physical Function scale of the EORTC QLQ-C30, without a subsequent ≥10-point improvement compared with baseline. Physical function is assessed using the EORTC QLQ-C30 Physical Function Scale to identify the percentage of participants who were deterioration-free at 6 months and 12 months. |
| Deterioration-Free Survival Rate Based on Global Health Status (EORTC QLQ-C30) | 6 months and 12 months after randomisation | Quality of life (QoL)(scores from participant-completed questionnaires) of participants on study EORTC Quality of Life Questionnaire: EORTC QLQ-C30: Q1 - Q28, Min 1 Max 4, Higher Score = Worse EORTC QLQ-C30: Q29 \& Q30 Min 1 Max 7, Higher = Better Deterioration-Free Survival (DFS) rate based on Global Health Status is defined as the percentage of participants who have not experienced any of the following events by the specified time point; A ≥10-point deterioration from baseline in the Global Health Status/QoL scale of the EORTC QLQ-C30, without a subsequent ≥10-point improvement, disease progression, death from any cause or treatment discontinuation. Global Health Status is assessed using the EORTC QLQ-C30 Global Health Status to identify the percentage of participants who were deterioration free at 6 months and 12 months. |
| Determine the Effect of RegoNivo on; Safety | From the first dose of study treatment until 30 days following the last dose of study treatment, up to approximately 44 months. | Safety (rates of adverse events) of participants on study |
Countries
Australia, Austria, Germany, Italy, Japan, South Korea, Spain, Taiwan, United States
Contacts
STUDY_CHAIRNick Pavlakis, Prof
AGITG
Participant flow
Recruitment details
Participants were recruited from 73 clinical sites across Austria, Australia, Germany, Italy, Japan, Spain, South Korea, Taiwan and United States of America. Eligibility was confirmed through screening visits, and informed consent was obtained prior to any study procedures. Randomisation occurred between 05/05/2021 and 30/04/2024.
Pre-assignment details
Before randomisation, participants underwent screening assessments to confirm eligibility, including laboratory tests, imaging, medical history and physical assessment. Participants who met all inclusion and exclusion criteria were randomised into the treatment arms.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized <=64 | 173 Participants |
| Age, Customized >64 | 71 Participants |
| Prior immunotherapy | 50 Participants |
| Prior use of VEGF inhibitors | 190 Participants |
| Race/Ethnicity, Customized Asia | 220 Participants |
| Race/Ethnicity, Customized Rest of the world | 80 Participants |
| Sex: Female, Male Female | 83 Participants |
| Sex: Female, Male Male | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 262 / 309 | 128 / 153 |
| other Total, other adverse events | 293 / 300 | 127 / 138 |
| serious Total, serious adverse events | 122 / 300 | 34 / 138 |
Outcome results
None listed