RegoNivo vs Chemotherapy for Gastroesophageal Cancer

(INTEGRATEIIb Trial)

Recruiting at 123 trial locations

Overseen By Clinical Project Manager

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Australasian Gastro-Intestinal Trials Group

Must not be taking: CYP3A4 inhibitors, inducers

Disqualifiers: Hypertension, Malabsorption, CNS metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Until disease progression

450 Participants Needed

Trial Summary

What is the purpose of this trial?

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

Will I have to stop taking my current medications?

The trial requires that you stop any previous drug therapy at least 2 weeks before starting the study treatment. Additionally, you cannot be on strong CYP3A4 inhibitors or inducers, and certain other medications may also need to be stopped. It's best to discuss your current medications with the trial team to see if any changes are needed.

What data supports the effectiveness of the drug combination of regorafenib and nivolumab for gastroesophageal cancer?

Research shows that regorafenib, when combined with nivolumab, has shown promising response rates in advanced gastroesophageal cancer, and regorafenib alone has been effective in prolonging survival in other cancers like colorectal cancer. ^{1 2 3 4 5}

Is the combination of Regorafenib and Nivolumab safe for treating gastroesophageal cancer?

Regorafenib and Nivolumab have been studied for safety in various cancers. Regorafenib can cause side effects like skin reactions, high blood pressure, diarrhea, and fatigue, but these are usually manageable with dose adjustments. Nivolumab, when added to chemotherapy, has been shown to improve survival in advanced gastroesophageal cancer, and its safety profile is generally considered acceptable. ^{1 4 5 6 7}

How is the drug combination of Nivolumab and Regorafenib unique for treating gastroesophageal cancer?

The combination of Nivolumab and Regorafenib is unique because it pairs an immune checkpoint inhibitor (Nivolumab) with a multi-targeted kinase inhibitor (Regorafenib), potentially enhancing the body's immune response against cancer cells while also inhibiting tumor growth pathways. This approach is novel for gastroesophageal cancer, where standard treatments are limited after initial therapies. ^{1 3 4 5 8}

Research Team

Nick Pavlakis, Prof

Principal Investigator

AGITG

Eligibility Criteria

Adults over 18 with advanced gastroesophageal cancer that's worsened after at least two treatments, including platinum and fluoropyrimidine drugs. They must be in good physical condition (ECOG 0 or 1), able to swallow pills, and have proper organ function. Excluded are those with allergies to trial drugs, uncontrolled blood pressure or malabsorption syndromes, recent use of certain medications or therapies, significant bleeding events or surgeries within a month prior to the trial, active infections like hepatitis B/C unless controlled by therapy.

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. 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, 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.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the RegoNivo combination or standard chemotherapy. RegoNivo involves self-administering regorafenib and receiving intravenous nivolumab until disease progression or prohibitive adverse events.

Until disease progression

Regular visits for intravenous administration and monitoring

Follow-up

Participants are monitored for safety, effectiveness, and quality of life after treatment

5 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term if beneficial

Long-term

Treatment Details

Interventions

• Nivolumab
• Regorafenib

Trial Overview The study is testing whether a combination of Regorafenib and Nivolumab (RegoNivo) can extend life more effectively than standard chemotherapy options for patients with refractory AGOC. Patients will be randomly assigned to receive either the new drug combo or one of several standard chemo drugs like Docetaxel.

Participant Groups

Group I: RegoNivo Experimental Treatment 2 Interventions

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.

Group II: Standard of Care Active Control 4 Interventions

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).

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Australasian Gastro-Intestinal Trials Group

Lead Sponsor

Trials

26

Recruited

8,000+

Syneos Health

Collaborator

Trials

181

Recruited

69,600+

Frankfurter Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Collaborator

Trials

1

Recruited

450+

Bayer

Industry Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

University of Sydney

Collaborator

Trials

208

Recruited

417,000+

Academic and Community Cancer Research United

Collaborator

Trials

54

Recruited

4,900+

Taiwanese Cooperative Oncology Group

Collaborator

Trials

1

Recruited

450+

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Collaborator

Trials

64

Recruited

20,100+

National Cancer Center Hospital East

Collaborator

Trials

14

Recruited

2,000+

Findings from Research

In a phase 2 trial involving 39 patients with advanced HER2-negative oesophagogastric adenocarcinoma, the combination of regorafenib, nivolumab, and chemotherapy resulted in 71% of patients being progression-free at 6 months, indicating promising efficacy.

The treatment was generally safe, with the most common adverse effects being fatigue and decreased neutrophil count, and no treatment-related deaths reported, suggesting that this combination could be a viable option for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial. Cytryn, SL., Moy, RH., Cowzer, D., et al.[2023]

Regorafenib is an oral multikinase inhibitor approved for treating pretreated metastatic colorectal cancer and gastrointestinal stromal tumors, showing antiangiogenic and antiproliferative effects, based on data from phase III studies.

Currently, regorafenib is being investigated in phase III trials for hepatocellular carcinoma and in several phase II studies for other gastrointestinal tumors, indicating its potential for broader applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists. Rey, JB., Launay-Vacher, V., Tournigand, C.[2021]

Regorafenib significantly improves overall survival by up to 2.5 months and progression-free survival by up to 1.5 months in patients with metastatic colorectal cancer (mCRC) who have not responded to standard therapies, based on phase 3 studies.

The treatment is generally well-tolerated, with most side effects being mild to moderate, and it does not negatively impact health-related quality of life compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. Dhillon, S.[2019]

Regorafenib is an effective treatment for advanced gastrointestinal stromal tumors (GISTs) after patients have not responded to imatinib and sunitinib, showing significant improvement in progression-free survival and disease control rates compared to placebo in the phase III GRID trial.

The drug has a manageable safety profile, with common side effects including hand-foot skin reactions, hypertension, diarrhea, and fatigue, which can often be addressed with dose adjustments or supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review of Its Use in Patients with Advanced Gastrointestinal Stromal Tumours. Shirley, M., Keating, GM.[2018]

In a study of 72 patients with microsatellite stable metastatic colorectal cancer, regorafenib or fruquintinib combined with sintilimab showed a median progression-free survival of 4.2 months and an overall survival of 10.5 months, indicating these combinations are viable third-line treatment options.

The treatment was generally well-tolerated, with only 15.3% of patients experiencing severe adverse events, and patients without liver metastasis showed better response rates and overall survival, suggesting they may benefit more from this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study. Nie, C., Lv, H., Chen, B., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Regorafenib in Combination with First-Line Chemotherapy for Metastatic Esophagogastric Cancer. [2023]

3. France pubmed.ncbi.nlm.nih.gov

Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists. [2021]

4. England pubmed.ncbi.nlm.nih.gov

INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG). [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. [2019]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review of Its Use in Patients with Advanced Gastrointestinal Stromal Tumours. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study. [2022]