To determine the influence of esomeprazole on the AUC of regorafenib in patients with mCRC or GIST.
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the influence of esomeprazole on the AUC of regorafenib in
patients with mCRC or GIST.
Secondary outcome
1. Other pharmacokinetic outcomes (i.e. clearance (CL), maximum concentration
(Cmax) and time to Cmax (tmax)).
2. To evaluate the incidence and severity of side-effects of treatment with
regorafenib in absence and presence of esomeprazole
Background summary
Regorafenib is a novel oral multi-kinase inhibitor which targets angiogenic,
stromal and oncogenic receptor tyrosine kinases. Regorafenib shows
anti-angiogenic activity based on to its dual targeted VEGFR2-TIE2 tyrosine
kinase inhibition. It is currently registered for GIST and mCRC. When
regorafenib is co-administered with an acid suppressive agent, the intragastric
pH increases, and as a result the equilibrium of ionized/non-ionized
regorafenib may shift to the less soluble non-ionized form which reduces
regorafenib bioavailability and exposure. Since proton pump inhibitors (PPI*s)
are often used during regorafenib therapy, this drug-drug interaction (DDI)
confronts pharmacists and oncologists with challenges in clinical practice. In
this study we will therefore evaluate the impact of PPI induced intragastric pH
elevation on regorafenib pharmacokinetics in patients with GIST and mCRC.
Study objective
To determine the influence of esomeprazole on the AUC of regorafenib in
patients with mCRC or GIST.
Study design
This is a single centre, open label two-period, randomized, cross-over
pharmacokinetic study.
Intervention
Patients will start with regorafenib in a loading phase of 21 days and will be
admitted for 24 hours to the hospital for pharmacokinetic blood sampling on day
21, 49 and 77. Patients will be randomized into 2 sequence groups (respectively
sequences A-B-C or C-B-A). The patient will use regorafenib alone (phase A) or
with (Phase B and C) esomeprazole. During phase B of the study regorafenib is
given concomitantly for 5 days, while during phase C regorafenib is given 3
hours after esomeprazole for 5 days.
Study burden and risks
Patients will be admitted to the hospital for a total of three days, during
which pharmacokinetic blood withdrawals will be performed. Patients will be
randomised into 2 sequence group consisting of 3 phases. In 2 phases, prior to
one of the hospital admissions, patients are pre-treated with esomeprazole 40
mg for 5 consecutive days (concomitantly or 3 hours before regorafenib
depending on study phase). Patients do not benefit individually from this
study. Major risks to be expected are side effects of one of the
investigational medicinal products regorafenib or esomeprazole, for which
patients will be carefully observed.
Groene Hilledijk 301
Rotterdam 3075 EA
NL
Groene Hilledijk 301
Rotterdam 3075 EA
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years
2. Histological or cytological confirmed diagnosis of mCRC or GIST
3. ECOG Performance Status <= 1
4. Signed Informed Consent Form prior to screening evaluations
5. No concurrent (over the counter) use of other acid reducing drugs, other than esomeprazole 40mg (PPIs, H2As and/or antacids) once daily during the study
6. No concurrent medication or supplements which can interact with esomeprazole or regorafenib during the study period
7. Abstain from grapefruit, grapefruit juice, herbal dietary supplements, and herbal tea during the study period.
8. Adequate baseline patient characteristics
Exclusion criteria
1. Pregnant or lactating patients
2. Patients with known impaired drug absorption (e.g. gastrectomy and achlorhydria)
3. Known serious illness or medical unstable conditions that could interfere with this study
4. Patients with evidence or history of any bleeding diathesis, irrespective of severity
5. Cardiac history ( recent myocardial infarction, unstable or new-onset angina, uncontrolled cardiac arrhythmias)
6. Uwillingness to abstain from grapefruit (juice), (herbal) dietary supplements, herbals, over-the-counter medication (except for paracetamol and ibuprofen) and other drugs known to seriously interact with esomeprazole and regorafenib during the study period.
7. Unwillingness to abstain from acid beverages such as jus d*orange and other acidic beverages in the morning during regorafenib treatment in this study.
8. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
9. Symptomatic CNS metastases or history of psychiatric disorder that would prohibit the understanding and giving of informed consent.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-005784-17-NL |
| CCMO | NL56302.078.16 |