REACH IN

Randomized (1/1), double blind trial, placebo versus regorafenib, 2 arms

Primary

• Progression-free survival (PFS)
• Hypothesis made is to improve median PFS by at least 50 %
• (6 weeks to 12 weeks in Regorafenib group)

Secondary

Response rate: evaluation of tumor response based on radiological RECIST criteria evaluation (thoraco-abdominal CT scan), dynamic imaging (diffusion DCE RMI) and Pet-CT.
Overall survival (OS) at one year.

Translational analysis:

• resistance to regorafenib: pAKT, pERK (on tumor sample if enough  tissue)
• angiogenesis pathway inhibition during treatment: serum levels of CXCL 12, VEGF-C, HGF, PDGF-béta, iNO, Ang2, CXCR4
• evaluation of microvascular density of the tumor (CD31 on tumor sample if enough tissue) and correlation with perfusion MRI
• stromagenesis modulation: evaluation of FGFR and PDGFR serum levels

1. histologically proven locally advanced unresectable or metastatic intra-hepatic or hilum cholangiocarcinoma or histologically proven metastatic extra-hepatic cholangiocarcinoma (common bile duct and gallbladder),
2. progression documented after GEM-CDDP (or GEM-OX), or gemcitabine alone followed or preceded by platinum (CDDP or oxaliplatin)-based chemotherapy
3. signed written informed consent
4. Male or female patients ≥ 18 years of age
5. ECOG Performance Status 0/1 at study entry
6. measurable disease according to Recist criteria version 1.1
7. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting to study treatment:
   • Serum creatinine ≤1.5x ULN
   • Total bilirubin ≤1.5x ULN
   • Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 3.0x ULN (<5x ULN for patients with liver involvement of their cancer).
   • Amylase and lipase ≤1.5x ULN
   • Alkaline phosphatase (ALP) ≤ 2.5x ULN (≤5x ULN for patients with liver involvement of their cancer and /or have bone metastases)
   • Platelets count ≥100.000/mm³, hemoglobin (Hb) ≥9 g/dL, absolute neutrophil count (ANC) ≥1500/mm³
   • Internation normalized ratio (INR) ≤1.5x 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, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care.
8. life expectancy of at least 12 weeks
9. effective contraception for both male and female patients must be used for at least 8 weeks after the last study drug administration if the risk of conception exists
10. negative pregnancy test, only applicable if there is a risk of conception
11. negative proteinuria on dipstick or 24 hours proteinuria <1000mg

1. unability to take oral medication
2. any malabsorption condition
3. patients taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg. Clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg. Carbamazepine, phenobarbital, phenytoin, rifampin, St-John’s Wort) (see section 8)
4. persistent proteinuria >3.5g/24 hours measured by urine protein-creatinine ratio from a random urine sample (persistent proteinuria >3 non-healing woud, ulcer, or bone fracture
5. patients with evidence or history of any bleeding diathesis, irrespective of severity
6. any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication
7. interstitial lung disease with ongoing signs and symptoms at the time of informed consent
8. uncontrolled concurrent CNS, cardiac, infectious diseases, hypertension
9. history of myocardial infarction (6 months before start of study drug)
10. arterial or venous thrombotic events such as cerebrovascular accident (CVA) (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication)uncontrolled cardiac arrhythmias
11. previous exposure to anti-VEGF targeting therapy and to signal transduction inhibitors
12. known hypersensitivity to any of the components of study treatments
13. previous malignancy in the last past 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix
14. pregnancy or breast feeding
15. medical or psychological conditions that would not permit the patient to complete the study or sign inform consent
16. unstable angina, congestive heart failure ≥NYHA class II
17. uncontrolled hypertension despite optimal management (systolic blood pressure >150 mmHg or diastolic pressure > 90mmHg)
18. pheochromocytoma
19. HIV infection
20. liver failure, cirrhosis Child Pugh B or C
21. active chronic hepatitis B or C with a need for antiviral treatment
22. brain metastasis
23. major surgery, open biopsy or significant traumatic injury within 4 weeks prior to the first dose of treatment
24. intra-hepatic locoregional therapy (DC Beads, SIRT)
25. history of organ allograft
26. ongoing infection > grade 2 NCI CTCAE
27. renal failure requiring dialysis
28. patients receiving or having received any investigational treatment within 4 weeks prior to study entry, or participating to another clinical study

Regorafenib 160 mg od, 3 weeks on/ one week off (one cycle= 4 weeks) + BSC, vs placebo + BSC until progression.

Start recruitment (first patient included): 14 May 2014

Planned end recruitment (Last patient In): End 2017, Follow up Period end date (Last Patient Out): end 2018

A protocol amendment was recently submitted to Competent Authorities and Ethics Committees to extend the recruitment period with one year and is awaiting full approval: updated planned end recruitment (Last patient In): End 2018, Follow up Period end date (Last Patient Out): end 2019.

All 66 planned patients have been included.

Hôpital Erasme ULB: Prof. Anne Demols

BGDO

1. ULB Erasme, Prof. A. Demols
2. UZ Antwerpen, Prof. M. Peeters
3. UCL St-Luc, Prof. I. Borbath
4. AZ Groeninge, Dr. P. Vergauwe
5. CHC St-Joseph Liège, Dr. G. Houbiers
6. UZ Gent: Prof. S. Laurent
7. Centre Hospitalier Jolimont: Dr. Th. Delaunoit
8. CHU Ambroise Paré, Mons: Dr. S. Holbrechts
9. AZ St-Lucas Brugge, Dr. J. Art
10. AZ St-Lucas Gent, Dr. J. Van Ongeval
11. Grand Hôpital de Charleroi, Dr. J. Carasco
12. Clinique Ste-Elisabeth, Dr. J-C. Goeminne