Regorafenib Combined With Irinotecan as Second-line in Patients With Metastatic Gastro-oesophageal Adenocarcinomas

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomised Phase 2 Trial Assessing REGorafenib Combined With IRInotecan as Second-line Treatment in Patients With Metastatic Gastro-oesophageal Adenocarcinomas

Conditions
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Adenocarcinoma of the Stomach, Adenocarcinoma of the Gastroesophageal Junction

Intervention / Treatment
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* Combination Product: Regorafenib and Irinotecan
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have signed a written informed consent form prior to any study specific procedures Patients aged ≥18 years old Histologically confirmed diagnosis of gastro-oesophageal adenocarcinomas: gastroesophageal junction (Siewert II and III) and gastric adenocarcinomas Asymptomatic primary tumour Metastatic disease At least one target lesion (according to RECIST v1.1): Unidimensionally measurable on cross-sectional imaging In an area not previously irradiated 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. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 Life expectancy >3 months Amylase ≤1.5 x upper limit of normal (ULN) and lipase ≤1.5 x ULN 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) 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 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 Creatinine clearance (CLcr) ≥50 mL/min estimated by Cockcroft-Gault equation 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 Patients affiliated to the social security system Exclusion Criteria: Symptomatic brain metastases or carcinomatous meningitis Bone-only metastasis Known and documented UGT1A1 deficiency History of Gilbert's syndrome 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) 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) Interstitial lung disease with ongoing signs and symptoms at inclusion Known hypersensitivity to any of the study drugs, study drug classes, or excipients Non-healing wound, non-healing ulcer, or non-healing bone fracture Patients with evidence or history of any bleeding diathesis, irrespective of severity Any haemorrhage or bleeding event grade ≥3 (NCI-CTCAE v.5.0) within 4 weeks before starting of the study treatment 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) Previous major surgical procedure, significant traumatic injury, or radiotherapy within the 4 weeks before inclusion 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 Unstable angina (angina symptoms at rest), new-onset angina (that started within the last 3 months) Myocardial infarction less than 6 months before starting the study treatment Uncontrolled cardiac arrhythmias History of epileptic seizures requiring long-term anticonvulsant therapy History of organ transplantation with use of immunosuppression therapy Ongoing bacterial or fungal infection (grade >2 by NCI-CTCAE v.5.0) Known history of human immunodeficiency virus (HIV) infection Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy Use of CYP3A4 inducers or inhibitors Pregnant or breast-feeding women Bowel malabsorption or extended bowel resection that could affect the absorption of regorafenib, occlusive syndrome, inability to take oral medications Inflammatory bowel disease with chronic diarrhoea Participation in another clinical trial within the 30 days before inclusion Concurrent treatment with another investigational product or anticancer therapy (other than irinotecan or regorafenib) Concomitant treatment with hypericum or live attenuated vaccines Gastro-intestinal fistula or perforation Person kept in detention or incapable of giving consent Patient unwilling or unable to comply with the medical follow-up required by the study because of geographic, social, or psychological reasons

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regorafenib and Irinotecan<br>Irinotecan 180 mg/m² on Day1 and Day 15 of a 4 week cycle combined with regorafenib 160 mg daily on Day2-8 and D16-22 of a 4 week cycle administered until progression of disease or unacceptable toxicity. | Combination Product: Regorafenib and Irinotecan<br>* 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<br>* Other names: CAMPTO;|
| Active Comparator: Irinotecan<br>Irinotecan 180 mg/m² on Day1 and Day 15 of a 4 week cycle administered until progression of disease or unacceptable toxicity | Drug: Irinotecan<br>* Irinotecan (180 mg/m² on D1 and D15 of a 4-week cycle) administered until progression of disease or unacceptable toxicity<br>* Other names: CAMPTO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of overall survival (OS) | 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. | expected duration of 10 months from randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the overall survival rate | Overall survival rates at 6 and 12 months | 6 and 12 months from randomisation | 
| To compare the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the progression-free survival (PFS) | Time duration from randomisation to time of first event (locoregional or distant relapse or progression, second malignancy, death from any cause). | expected duration of 6 months from randomisation | 
| To evaluate the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the progression-free survival rate | Progression-free survival rates at 6 and 12 months | 6 and 12 months from randomisation | 
| To evaluate the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the disease control rate (DCR) | Percentage of patients with complete response, partial response or stable disease as best response at the database cut-off date | expected duration of 6 months from randomisation | 
| To evaluate the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the objective response rate (ORR) | Percentage of patients with complete response or partial response | expected duration of 6 months from randomisation | 
| To compare treatment-related toxicity | Frequency and severity of adverse events assessed by NCI-CTCAE v5.0 | expected 30 days after last study treatment administration | 
| To compare the effect of treatment on quality of life | Evaluation of quality of life with EORTC quality of life questionnaire for cancer patients (QLQ-C30) | expected 30 days after last study treatment administration | 
| To compare the effect of treatment on quality of life related to gastro-oesophageal cancer | Evaluation of quality of life with EORTC quality of life specific questionnaire for gastro-oesophageal tumours (QLQ-OG25) | expected 30 days after last study treatment administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma, gastro-oesophageal, regorafenib