Phase III Randomized Open-Label Study of Regorafenib and Nivolumab Versus Standard Chemotherapy in Refractory Advanced Gastro-Oesophageal Cancer
- Trial ID
- 2023-505441-69-00
- Protocol
- AG0315OG/CTC0140
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **regorafenib** in combination with **nivolumab** (RegoNivo) on overall survival (OS) in patients with refractory, advanced gastro-oesophageal cancer. This is clinically relevant as it aims to improve survival outcomes in a population with limited treatment options.
Secondary objectives include:
- Assessing overall survival in the Asian sub-population.
- Evaluating progression-free survival (PFS), defined as the time to disease progression or death.
- Determining the objective tumour response rate (OTRR) based on partial or complete response according to RECIST version 1.1 and immune-related iRECIST criteria.
- Measuring quality of life (QoL) through scores from participant-completed questionnaires.
- Monitoring safety by analyzing rates of adverse events.
Participants
The clinical trial involves a total of **335 participants** diagnosed with **refractory, advanced gastro-oesophageal cancer**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on their diagnosis of metastatic or locally recurrent gastro-oesophageal cancer, specifically of adenocarcinoma or undifferentiated carcinoma histology, and their condition must be evaluable according to the Response Evaluation Criteria in Solid Tumours (RECIST Version 1.1). The trial includes individuals who have failed or been intolerant to at least two lines of prior anti-cancer therapy, which must have included a platinum agent and a fluoropyrimidine analogue. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, and must demonstrate adequate bone marrow, renal, and liver function. The ability to swallow oral medication is necessary, and participants must be willing and able to comply with all study requirements. The trial population includes vulnerable groups, and all participants have provided signed, written informed consent. The study does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase III study to evaluate the efficacy of **regorafenib** in combination with **nivolumab** compared to standard chemotherapy in patients with refractory, advanced gastro-oesophageal cancer. The primary objective is to assess the impact on overall survival, with secondary endpoints including progression-free survival, objective tumor response rate, quality of life, safety, and translational research involving prognostic and predictive biomarkers. The trial is expected to run from May 2022 to May 2026, with participant involvement lasting up to 24 months, depending on individual response and tolerance to treatment.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, cancer histology, prior treatment history, and organ function. Eligible participants will be randomized to receive either the investigational combination therapy or standard chemotherapy. Follow-up visits will occur regularly to monitor treatment response, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.
Inclusion criteria require participants to be adults with metastatic or locally recurrent gastro-oesophageal cancer, evaluable by RECIST criteria, and having failed or been intolerant to at least two prior lines of therapy. Exclusion criteria are not specified in the provided data. Participants must be able to comply with study requirements, including the ability to swallow oral medication and adequate organ function. Early termination from the study may occur due to disease progression, unacceptable toxicity, or withdrawal of consent.
Treatment
The clinical trial involves the administration of **regorafenib**, marketed under the product name BAY 734506, which is provided in the form of a **film-coated tablet**. This experimental medication is an oral multi-kinase inhibitor, chemically synthesized, and manufactured by Bayer AG. The maximum daily dose of regorafenib is 90 mg, with a total maximum dose of 160 mg over a treatment period of up to 24 weeks. The administration route is oral, and participant compliance will be monitored through regular assessments to ensure adherence to the dosing schedule.
In addition to regorafenib, the trial includes the administration of **nivolumab**, marketed as OPDIVO, which is provided as a **concentrate for solution for infusion**. This medication is a protein-based therapeutic, specifically a monoclonal antibody, produced by Bristol-Myers Squibb Pharma EEIG. Nivolumab is administered intravenously, with a maximum daily dose of 240 mg and a total maximum dose of 480 mg over a 24-week treatment period. The infusion schedule will be closely monitored to ensure proper dosing and participant compliance.
The trial aims to evaluate the combination of regorafenib and nivolumab against standard chemotherapy in patients with refractory advanced gastro-oesophageal cancer. The primary objective is to assess the effect of this combination therapy on overall survival. Compliance with the treatment regimen will be monitored through scheduled visits and assessments, ensuring that participants adhere to the prescribed dosing schedules for both medications.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Overall Survival (OS)**, defined as death from any cause, in the overall study population. This primary endpoint will provide a direct measure of the treatment's impact on survival rates among participants with refractory advanced gastro-oesophageal cancer. Secondary endpoints include overall survival in the Asian sub-population, **Progression-Free Survival (PFS)**, which accounts for disease progression or death, and the **Objective Tumour Response Rate (OTRR)**, evaluated using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and immune-related iRECIST. Additionally, quality of life will be assessed through scores from participant-completed questionnaires, and safety will be monitored by tracking the rates of adverse events.
Translational research components will explore prognostic and predictive biomarkers related to survival, response, and safety, as well as the pharmacokinetics (PK) of regorafenib in patient populations from different geographical regions. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial, with the aim of providing comprehensive insights into the therapeutic effects and safety profile of the combination treatment of regorafenib and nivolumab compared to standard chemotherapy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adults (18 years or over) with metastatic or locally recurrent gastro- oesophageal cancer which: a. has arisen in any primary gastro-oesophageal site (oesophago-gastric junction (GOJ) or stomach); and b. is of adenocarcinoma or undifferentiated carcinoma histology; and c. 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 d. 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. e.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 randomization, 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: a. curatively treated cervical carcinoma in situ, b. non-melanomatous carcinoma of the skin, c. superficial bladder tumours (T1a [Non-invasive tumour], and Tis [Carcinoma in situ]), d. 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 who require pharmacotherapy. Low dose steroids (e.g. ≤ 10 mg prednisone) are permitted
- 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 (WOCBP) 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.
- Patients with prior organ allograft or allogeneic bone marrow transplantation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 02 May 2022 | 1 |
 Germany | Not Recruiting | 02 May 2022 | 105 |
 Italy | Not Recruiting | 02 May 2022 | 14 |
 Spain | Not Recruiting | 02 May 2022 | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 240 | 24 | PRD2941375 |
BAY 734506 | Test | FILM-COATED TABLET | ORAL | 90 | 24 | PRD10079495 |