Patient case: 54-year-old male with Gastric cancer. Genetic variant: PIK3CA (E545K). Other conditions: Depression.

Clinical trial: A Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer

Summary: Advanced Gastro-oesophageal Carcinoma (AGOC) has a poor prognosis, and there is no established standard treatment following failure of first and second line chemotherapy. Regorafenib (BAY 73-4506) is an investigational 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, and has shown activity in other solid tumours. Regorafenib was shown to prolong PFS across all regions/subgroups in INTEGRATE I The general aim of this study is to determine if regorafenib improves overall survival in refractory AGOC.


Eligibility: 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 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.
  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. Adequate cardiac function (Left Ventricular Ejection Fraction (LVEF) ≥ 50% or above the lower limit of normal (LLN) for the Institution (whichever is lower).
  Cardiac function should be assessed within 3 months prior to randomisation, but after completion of any anthracycline containing chemotherapy.
  8. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments and follow-up.
  9. Study treatment both planned and able to start within 7 days after randomisation.
  10. Signed, written informed consent.
  Exclusion Criteria:
  1. Known allergy to the investigational product drug class or excipients in the regorafenib
  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. Treatment with any previous drug therapy within 4 weeks prior to randomization. This includes any investigational therapy.
  6. Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
  7. Concurrent treatment with strong CYP3A4 inhibitors or inducers.
  8. 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 V4.03
  9. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
  10. Arterial thrombotic or ischaemic events, such as cerebrovascular accident within 6 months prior to randomization.
  11. Venous thrombotic events and pulmonary embolism within 3 months prior to randomization
  12. Any haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v4.03 within 4 weeks prior to randomization.
  13. Non-healing wound, ulcer, or bone fracture.
  14. Interstitial lung disease with ongoing signs and symptoms
  15. Abnormal thyroid function (TSH outside normal range).
  16. Persistent proteinuria of ≥ Grade 3 according to CTCAE v4.03 (Formal testing is required if initial urine analysis using dipstick is positive. A random urine protein: creatinine ratio equivalent to or greater than 3.5g of protein over 24 hour is considered ineligible.)
  17. Uncontrolled metastatic disease to the central nervous system. To be eligible, 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.
  18. 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
  19. 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.
  20. Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol.
  21. 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.

Relevance to patient case: not relevant