Clinical trial NCT03722108: Regorafenib Combined With Irinotecan as Second-line in Patients With Metastatic Gastro-oesophageal Adenocarcinomas
Official title: A Randomised Phase 2 Trial Assessing REGorafenib Combined With IRInotecan as Second-line Treatment in Patients With Metastatic Gastro-oesophageal Adenocarcinomas
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Adenocarcinoma of the Stomach
Adenocarcinoma of the Gastroesophageal Junction
Keywords: adenocarcinoma
gastro-oesophageal
regorafenib
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2018-10-26
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: To compare the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of overall survival (OS)
timeFrame: expected duration of 10 months from randomisation
Secondary outcomes:
measure: To compare the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the overall survival rate
timeFrame: 6 and 12 months from randomisation
measure: To compare the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the progression-free survival (PFS)
timeFrame: expected duration of 6 months from randomisation
measure: To evaluate the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the progression-free survival rate
timeFrame: 6 and 12 months from randomisation
measure: To evaluate the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the disease control rate (DCR)
timeFrame: expected duration of 6 months from randomisation
measure: To evaluate the efficacy of regorafenib combined with irinotecan versus irinotecan alone in terms of the objective response rate (ORR)
timeFrame: expected duration of 6 months from randomisation
measure: To compare treatment-related toxicity
timeFrame: expected 30 days after last study treatment administration
measure: To compare the effect of treatment on quality of life
timeFrame: expected 30 days after last study treatment administration
measure: To compare the effect of treatment on quality of life related to gastro-oesophageal cancer
timeFrame: expected 30 days after last study treatment administration
Other outcomes:
Locations:
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest-Paul Papin
city: Brest
country: France
facility: Hôpital Morvan
city: Coudekerque-Branche
country: France
facility: Clinique de Flandre
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Levallois-Perret
country: France
facility: Hôpital Franco-Britannique
city: Lille
country: France
facility: Hopital Claude Huriez - CHU Lille
city: Limoges
country: France
facility: CHU Dupuytren
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hopital de la Timone
city: Marseille
country: France
facility: Institut Paoli Calmette
city: Montpellier
country: France
facility: Institut du Cancer Montpellier
city: Montpellier
country: France
facility: Centre de Cancérologie du Grand Montpellier
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou
city: Paris
country: France
facility: GH Diaconesses Croix Saint-Simon
city: Perpignan
country: France
facility: CH Saint Jean
city: Poitiers
country: France
facility: CHU de Poitiers
city: Pringy
country: France
facility: CH Annecy Genevois
city: Reims
country: France
facility: Institut Jean Godinot
city: Reims
country: France
facility: Hopital Robert Debre
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Saint-Grégoire
country: France
facility: CHP Saint Grégoire
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest-René Gauducheau
city: Saint-Malo
country: France
facility: CH Saint Malo
city: Strasbourg
country: France
facility: Centre Paul Strass
city: Tours
country: France
facility: CHRU Tours
city: Vandœuvre-lès-Nancy
country: France
facility: CHU Nancy - Hôpital Brabois
Study officials:
affiliation: Institut du Cancer Montpellier
name: Emmanuelle SAMALIN-SCALZI, MD
role: PRINCIPAL_INVESTIGATOR
References: