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

Phase 1

Terminated

• Conditions: Adenocarcinoma of the Stomach; Adenocarcinoma of the Gastroesophageal Junction
• Interventions: Combination Product: Regorafenib and Irinotecan; Drug: Irinotecan

• Registration Number: NCT03722108
• Lead Sponsor: UNICANCER

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.

Study Timeline

• Study First Submitted: 2018-10-25
• Study First Submitted QC: 2018-10-25
• Study First Posted: 2018-10-26
• Study Start: 2019-02-07
• Primary Completion: 2022-05-19
• Study Completion: 2022-05-19
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-13
• Last Update Posted: 2023-10-16

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 89

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regorafenib and Irinotecan	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.
Irinotecan	Irinotecan	Irinotecan 180 mg/m² on Day1 and Day 15 of a 4 week cycle administered until progression of disease or unacceptable toxicity

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 progression-free survival rate	6 and 12 months from randomisation	Progression-free survival rates at 6 and 12 months
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 objective response rate (ORR)	expected duration of 6 months from randomisation	Percentage of patients with complete response or partial response
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)

Trial Locations

Locations (27)

Centre de Cancérologie du Grand Montpellier; 🇫🇷 Montpellier, France

CHU Dupuytren; 🇫🇷 Limoges, France

Clinique de Flandre; 🇫🇷 Coudekerque-Branche, France

Hôpital Franco-Britannique; 🇫🇷 Levallois-Perret, France

Institut de Cancérologie de l'Ouest-René Gauducheau; 🇫🇷 Saint-Herblain, France

Hopital Claude Huriez - CHU Lille; 🇫🇷 Lille, France

Hopital Charles Nicolle; 🇫🇷 Rouen, France

Centre Paul Strass; 🇫🇷 Strasbourg, France

CHU de Poitiers; 🇫🇷 Poitiers, France

Institut Jean Godinot; 🇫🇷 Reims, France

Hopital Robert Debre; 🇫🇷 Reims, France

Hopital de la Timone; 🇫🇷 Marseille, France

Institut Paoli Calmette; 🇫🇷 Marseille, France

Centre Georges François Leclerc; 🇫🇷 Dijon, France

Institut de Cancérologie de l'Ouest-Paul Papin; 🇫🇷 Angers, France

Centre Léon Bérard; 🇫🇷 Lyon, France

GH Diaconesses Croix Saint-Simon; 🇫🇷 Paris, France

Institut du Cancer Montpellier; 🇫🇷 Montpellier, France

Hopital Europeen Georges Pompidou; 🇫🇷 Paris, France

CH Saint Jean; 🇫🇷 Perpignan, France

CH Annecy Genevois; 🇫🇷 Pringy, France

CHRU Tours; 🇫🇷 Tours, France

CHP Saint Grégoire; 🇫🇷 Saint-Grégoire, France

CH Saint Malo; 🇫🇷 Saint-Malo, France

CHU Nancy - Hôpital Brabois; 🇫🇷 Vandœuvre-lès-Nancy, France

Hôpital Morvan; 🇫🇷 Brest, France

Centre Antoine Lacassagne; 🇫🇷 Nice, France