Adenocarcinoma of the Gastroesophageal Junction, Adenocarcinoma of the Stomach
Conditions
Keywords
adenocarcinoma, gastro-oesophageal, regorafenib
Brief summary
Trial evaluating the efficacy of regorafenib combined with irinotecan compared to irinotecan alone in second-line treatment of patients with metastatic gastro-oesophageal adenocarcinomas.
Detailed description
Comparative interventional prospective phase 2, randomised, open-label, multicentric trial comparing the combination of regorafenib and irinotecan (REGIRI) to irinotecan alone (IRI) as second line treatment of patients with metastatic gastro-oesophageal adenocarcinomas.
Interventions
COMBINATION_PRODUCTRegorafenib and Irinotecan
Irinotecan (180 mg/m² on D1 and D15 of a 4-week cycle) combined with regorafenib (160 mg daily on D2-8 and D16-22 of a 4-week cycle) administered until progression of disease or unacceptable toxicity
DRUGIrinotecan
Irinotecan (180 mg/m² on D1 and D15 of a 4-week cycle) administered until progression of disease or unacceptable toxicity
Sponsors
Bayer
UNICANCER
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient must have signed a written informed consent form prior to any study specific procedures 2. Patients aged ≥18 years old 3. Histologically confirmed diagnosis of gastro-oesophageal adenocarcinomas: gastroesophageal junction (Siewert II and III) and gastric adenocarcinomas 4. Asymptomatic primary tumour 5. Metastatic disease 6. At least one target lesion (according to RECIST v1.1): * Unidimensionally measurable on cross-sectional imaging * In an area not previously irradiated 7. Disease progression after a fluoropyrimidine and platinum agent-based chemotherapy (5-fluorouracil or 5-fluorouracil prodrugs combined with cisplatin or oxaliplatin). For example, docetaxel combined with FOLFOX, PD-L1/PD-1 inhibitors combined with FOLFOX, LV5-FU2-cisplatin or 5-fluorouracil-cisplatin are acceptable prior therapies. 8. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 9. Life expectancy \>3 months 10. Amylase ≤1.5 x upper limit of normal (ULN) and lipase ≤1.5 x ULN 11. Adequate liver function: * Total bilirubin ≤1.5 x ULN * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN (≤5 x ULN for patients with liver metastasis) * Alkaline phosphatase (ALP) ≤2.5 x ULN (≤5.0 x ULN for patients with liver or bone metastases) 12. Platelet count ≥100,000/mm³; haemoglobin (Hb) ≥9 g/dL; absolute neutrophil count (ANC) ≥1,500/mm³. The use of blood transfusion(s) to meet the inclusion criteria will not be allowed 13. International normalised ratio (INR) ≤1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g., heparin, are eligible if there is no evidence of an underlying abnormality with these parameters and if a close monitoring of at least weekly evaluations was performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care 14. Creatinine clearance (CLcr) ≥50 mL/min estimated by Cockcroft-Gault equation 15. Women of childbearing potential and men must agree to use adequate contraception during the study and for at least 3 months after the last study drug administration 16. Patients affiliated to the social security system
Exclusion criteria
1. Symptomatic brain metastases or carcinomatous meningitis 2. Bone-only metastasis 3. Known and documented UGT1A1 deficiency 4. History of Gilbert's syndrome 5. Previous or concurrent cancer with a distinct primary site, other than gastro-oesophageal cancer, within 5 years prior to randomisation (except for curatively treated cervical cancer in situ, non-melanoma skin cancer, and superficial bladder tumours) 6. Persistent proteinuria \>3.5 g/24 h measured by urine protein-creatinine ratio from a random urine sample (grade ≥3, NCI-CTCAE v 5.0) 7. Interstitial lung disease with ongoing signs and symptoms at inclusion 8. Known hypersensitivity to any of the study drugs, study drug classes, or excipients 9. Non-healing wound, non-healing ulcer, or non-healing bone fracture 10. Patients with evidence or history of any bleeding diathesis, irrespective of severity 11. Any haemorrhage or bleeding event grade ≥3 (NCI-CTCAE v.5.0) within 4 weeks before starting of the study treatment 12. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 month before starting the study treatment (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication) 13. Previous major surgical procedure, significant traumatic injury, or radiotherapy within the 4 weeks before inclusion 14. Uncontrolled hypertension (systolic blood pressure \>140 mmHg or diastolic pressure \>90 mmHg) despite optimal medical management. Congestive heart failure: New York Heart Association (NYHA) ≥ class 2 15. Unstable angina (angina symptoms at rest), new-onset angina (that started within the last 3 months) 16. Myocardial infarction less than 6 months before starting the study treatment 17. Uncontrolled cardiac arrhythmias 18. History of epileptic seizures requiring long-term anticonvulsant therapy 19. History of organ transplantation with use of immunosuppression therapy 20. Ongoing bacterial or fungal infection (grade \>2 by NCI-CTCAE v.5.0) 21. Known history of human immunodeficiency virus (HIV) infection 22. Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy 23. Use of CYP3A4 inducers or inhibitors 24. Pregnant or breast-feeding women 25. Bowel malabsorption or extended bowel resection that could affect the absorption of regorafenib, occlusive syndrome, inability to take oral medications 26. Inflammatory bowel disease with chronic diarrhoea 27. Participation in another clinical trial within the 30 days before inclusion 28. Concurrent treatment with another investigational product or anticancer therapy (other than irinotecan or regorafenib) 29. Concomitant treatment with hypericum or live attenuated vaccines 30. Gastro-intestinal fistula or perforation 31. Person kept in detention or incapable of giving consent 32. Patient unwilling or unable to comply with the medical follow-up required by the study because of geographic, social, or psychological reasons
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To compare the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of overall survival (OS) | expected duration of 10 months from randomisation | Time duration from randomisation to time of death of any cause. If a patient is alive at the database cut-off date, then the patient will be censored at the last date of follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To compare the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the overall survival rate | 6 and 12 months from randomisation | Overall survival rates at 6 and 12 months |
| To compare the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the progression-free survival (PFS) | expected duration of 6 months from randomisation | Time duration from randomisation to time of first event (locoregional or distant relapse or progression, second malignancy, death from any cause). |
| To evaluate the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the disease control rate (DCR) | expected duration of 6 months from randomisation | Percentage of patients with complete response, partial response or stable disease as best response at the database cut-off date |
| To evaluate the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the progression-free survival rate | 6 and 12 months from randomisation | Progression-free survival rates at 6 and 12 months |
| To compare treatment-related toxicity | expected 30 days after last study treatment administration | Frequency and severity of adverse events assessed by NCI-CTCAE v5.0 |
| To compare the effect of treatment on quality of life | expected 30 days after last study treatment administration | Evaluation of quality of life with EORTC quality of life questionnaire for cancer patients (QLQ-C30) |
| To compare the effect of treatment on quality of life related to gastro-oesophageal cancer | expected 30 days after last study treatment administration | Evaluation of quality of life with EORTC quality of life specific questionnaire for gastro-oesophageal tumours (QLQ-OG25) |
| To evaluate the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the objective response rate (ORR) | expected duration of 6 months from randomisation | Percentage of patients with complete response or partial response |
Countries
France
Outcome results
None listed