Clinical trial NCT02162914: Regorafenib Versus Placebo to Treat Cholangiocarcinoma
Official title: REGORAFENIB AFTER FAILURE OF GEMCITABINE AND PLATINUM-BASED CHEMOTHERAPY FOR LOCALLY ADVANCED (NON RESECTABLE) AND METASTATIC INTRA-HEPATIC OR HILAR CHOLANGIOCARCINOMA: A Randomized Double-blinded Phase II Trial.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Cholangiocarcinoma
Keywords: Intra-hepatic
Hilar
Locally Advanced
Non Resectable
Metastatic
Regorafenib
Placebo
Lead sponsor: Erasme University Hospital
Sponsor class: OTHER
First posted: 2014-06-13
Enrollment: 66
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: The study is a multicenter randomized (1:1) placebo-controlled, double-blinded phase II trial aiming to demonstrate an improvement of median PFS when treating locally advanced unresectable or metastatic patients suffering from an intra-hepatic or hilum (mass-forming) cholangiocarcinoma with Regorafenib as compared to placebo, and after progression after GEM-CDDP (or GEM-OX), or gemcitabine alone followed or preceded by platinum (CDDP or oxaliplatin)-based chemotherapy.

The principal objective is to investigate Regorafenib efficacy by prospectively evaluating the PFS after the administration of Regorafenib combined with BSC as compared to placebo with BSC. Hypothesis is a 50% improvement in median PFS (from 6 weeks to 12 weeks in Regorafenib group).

Detailed description: The principal objective is to investigate Regorafenib efficacy by prospectively evaluating the PFS after the administration of Regorafenib combined with BSC as compared to placebo with BSC. Hypothesis is a 50% improvement in median PFS (from 6 weeks to 12 weeks in Regorafenib group).

Eligibility criteria: Inclusion Criteria:

* histologically proven intra-hepatic or hilum cholangiocarcinoma (mass forming, not "liniting" tumor), locally advanced unresectable or metastatic
* progression documented after GEM-CDDP (or GEM-OX), or gemcitabine alone followed or preceded by platinum-based (CDDP or oxaliplatin) chemotherapy
* age \> 18 years
* ECOG PS 0/1 at study entry
* measurable disease according to RECIST version 1.1
* Adequate bone marrow, liver and renal function as assessed by the following laboratory requirementsconducted within 7 days of starting to study treatment:

oSerum creatinine \<1.5x upper reference range

oTotal bilirubin \<1.5x ULN

oAlanine transaminase (ALT) and aspartate aminotransferase (AST) \< 2.5x ULN (\<5x ULN forpatients with liver involvement of their cancer).

oAmylase and lipase \<1.5x ULN.

* life expectancy of at least 12 weeks
* effective contraception for both male and female patients if the risk of conception exists
* negative proteinuria on dipstick or 24 hours proteinuria\<1000mg
* signed written informed consent

Exclusion Criteria:

* unability to take oral medication
* any malabsorption condition
* 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)
* persistent proteinuria \>3.5g/24 hours measured by urine protein-creatinine ratio from a random urinesample (persistent proteinuria \>3 non-healing woud, ulcer, or bone fracture
* any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of studymedication
* interstitial lund disease with ongoing signs and symptoms at the time of informed consent
* uncontrolled concurrent CNS, cardiac, infectious diseases, hypertension
* history of myocardial infarction, deep venous or arterial thrombosis, cerebrovascular accident (CVA) during the last 6 months
* previous exposure to anti-VEGF targeting therapy (including Regorafenib) and to signal transduction inhibitors
* known hypersensitivity to any of the components of study treatments
* previous malignancy in the last past 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix
* pregnant or lactating women, or patients of both genders with procreative potential not using adequate contraceptive methods
* medical or psychological conditions that would not permit the patient to complete the study or sign inform consent
* unstable angina, congestive heart failure ≥NYHA class II
* uncontrolled hypertension despite optimal management (systolic blood pressure \>150 mmHg or diastolic pressure \> 90mmHg)
* pheochromocytoma
* HIV infection
* active chronic hepatitis B or C with a need for antiviral treatment
* liver failure, cirrhosis Chil Pugh B or C
* brain metastasis
* major surgery, open biopsy or significant traumatic injury within 4 weeks prior to the first dose of treatment
* intra-hepatic locoregional therapy (DC Beads, SIRT)
* history of organ allograft
* ongoing infection
* renal failure requiring dialysis
* patients receiving or having received any investigational treatment within 4 weeks prior to study entry, or participating to another clinical study

Primary outcomes:
measure: Improve median PFS
timeFrame: 6 to 12 weeks
Secondary outcomes:
measure: Evaluation of response rate
timeFrame: At pretreatment visit (14 to 1 days before treatment initiation), every 6 weeks for 3 times then every 8 weeks until progression
measure: Correlation between radiological response and metabolic response
timeFrame: At pretreatment visit (14 to 1 days before treatment initiation)
measure: Correlation between radiologic response rate and "Dynamic tumor response rate"
timeFrame: At day 1 (pre-treatment) and day 15 of cycle 1
measure: Correlation between dynamic tumor response rate and metabolic response rate
timeFrame: At cycle 1 day 15
measure: Evaluation of Overall Survival (OS)
timeFrame: After 1 year (March 2015)
Other outcomes:
Locations:
city: Haine-Saint-Paul
country: Belgium
facility: CH Jolimont
state: Hainaut
city: Antwerp
country: Belgium
facility: University Hospitals of Antwerp
city: Brugge
country: Belgium
facility: AZ St-Lucas Brugge
city: Brussels
country: Belgium
facility: Erasme University Hospital
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Charleroi
country: Belgium
facility: Grand Hôpital de Charleroi
city: Gent
country: Belgium
facility: AZ St-Lucas Gent
city: Gent
country: Belgium
facility: UZ Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge
city: Liège
country: Belgium
facility: CHC St-Joseph
city: Mons
country: Belgium
facility: Hôpital Ambroise Paré
city: Namur
country: Belgium
facility: CMSE
Study officials:
affiliation: Erasme University Hospital
name: Anne Demols, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Demols A, Borbath I, Van den Eynde M, Houbiers G, Peeters M, Marechal R, Delaunoit T, Goemine JC, Laurent S, Holbrechts S, Paesmans M, Van Laethem JL. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial. Ann Oncol. 2020 Sep;31(9):1169-1177. doi: 10.1016/j.annonc.2020.05.018. Epub 2020 May 25.