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

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

Trial evaluating the efficacy of regorafenib combined with irinotecan compared to irinotecan alone in second-line treatment of patients with metastatic gastro-oesophageal adenocarcinomas.

Study Overview

• Status: Terminated
• Conditions: Adenocarcinoma of the Gastroesophageal Junction; Adenocarcinoma of the Stomach
• Intervention / Treatment: Combination product: Regorafenib and Irinotecan; Drug: Irinotecan

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.

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Angers, France
    • Institut de Cancerologie de L'Ouest-Paul Papin
  • Brest, France
    • Hopital Morvan
  • Coudekerque-Branche, France
    • Clinique de Flandre
  • Dijon, France, 21079
    • Centre Georges Francois Leclerc
  • Levallois-Perret, France
    • Hopital Franco-Britannique
  • Lille, France
    • Hopital Claude Huriez - CHU Lille
  • Limoges, France
    • CHU Dupuytren
  • Lyon, France
    • Centre Léon Bérard
  • Marseille, France
    • Hôpital de la Timone
  • Marseille, France
    • Institut Paoli Calmette
  • Montpellier, France, 34298
    • Institut du Cancer Montpellier
  • Montpellier, France
    • Centre de Cancérologie du Grand Montpellier
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou
  • Paris, France
    • GH Diaconesses Croix Saint-Simon
  • Perpignan, France
    • CH Saint Jean
  • Poitiers, France, 86000
    • CHU de Poitiers
  • Pringy, France
    • CH Annecy Genevois
  • Reims, France, 51100
    • Institut Jean Godinot
  • Reims, France
    • Hopital Robert Debre
  • Rouen, France
    • Hopital Charles Nicolle
  • Saint-Grégoire, France
    • CHP Saint Grégoire
  • Saint-Herblain, France
    • Institut de Cancerologie de L'Ouest-Rene Gauducheau
  • Saint-Malo, France
    • CH Saint Malo
  • Strasbourg, France
    • Centre Paul Strass
  • Tours, France
    • CHRU Tours
  • Vandœuvre-lès-Nancy, France, 54500
    • CHU Nancy - Hôpital Brabois

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regorafenib and Irinotecan; 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; 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; Other Names: STIVARGA; CAMPTO
Active Comparator: Irinotecan; Irinotecan 180 mg/m² on Day1 and Day 15 of a 4 week cycle administered until progression of disease or unacceptable toxicity	Drug: Irinotecan; Irinotecan (180 mg/m² on D1 and D15 of a 4-week cycle) administered until progression of disease or unacceptable toxicity; Other Names: CAMPTO

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: UNICANCER
• Collaborators: Bayer
• Investigators: Principal Investigator: Emmanuelle SAMALIN-SCALZI, MD, Institut du Cancer Montpellier

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2019
• Primary Completion (Actual): May 19, 2022
• Study Completion (Actual): May 19, 2022

Study Registration Dates

• First Submitted: October 25, 2018
• First Submitted That Met QC Criteria: October 25, 2018
• First Posted (Actual): October 26, 2018

Study Record Updates

• Last Update Posted (Actual): October 16, 2023
• Last Update Submitted That Met QC Criteria: October 13, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: adenocarcinoma; regorafenib; gastro-oesophageal
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Irinotecan
• Other Study ID Numbers: UC-0110/1807; 2018-002374-46 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual Participant Data will not be shared at an individual level, they will be part of the study database including all enrolled patients

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No