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RecruitingLast updated: 27 March 2024

INTEGRATEIIb: This Phase III trial is trying to determine if a combined treatment of targeted and immunotherapy drugs (regorafenib and nivolumab) is more effective than the current standard chemotherapy treatments in people with advanced gastro-oesophageal cancerA Randomised Phase III Open Label Study of Regorafenib + Nivolumab vs Standard Chemotherapy in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)

Clinical summary

Summary

This is a randomised trial with experimental and active comparator arms. Participants in the Experimental Arm will receive regorafenib and nivolumab (RegoNivo). 90mg of Regorafenib will be self-administered orally (3 x 30mg) days 1-21 of each 28-day treatment cycle; and nivolumab will be administered intravenously (240mg) day 1 of each 14 day cycle until disease progression or prohibitive adverse events as per protocol, given in hospital by infusion. Participants in the Active Comparator group will receive Standard Of Care treatment. Participants in this group 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).

Conditions

This trial is treating patients with advanced gastro-oesophageal cancer

Cancer

Upper gastrointestinal tract Cancers Upper gastrointestinal tract

Age

People18+

Phase

III

Trial Acronym

INTEGRATEIIb

More information

Trial Identifiers

Use the hyperlinks, where available to access additional clinical trial information.

Trial sponsor

Australasian Gastro-Intestinal Trials Group (AGITG)

Scientific Title

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

Eligibility

Inclusion

  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

  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.

Inclusion

  • Your cancer has spread to other parts of the body.
  • Your cancer has not spread to other parts of the body.
  • You have had treatment but your cancer has gotten worse or has not responded to the treatment you have been given.
  • You are able to swallow medication by mouth.

Exclusion

  • You have certain types of non-cancer medical conditions.
  • You have had certain treatments, surgical procedures or drugs.
Message

Clinical trials have complex eligibility criteria.

Ask your doctor if this trial could be right for you.

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