Colorectal NeoplasmsPhase 4REGORANCT02800330
The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib
A Phase 4 study testing Esomeprazole 40mg concomitantly, Esomeprazole 40mg before and Regorafenib 160mg or 120mg in people with Colorectal Neoplasms and Gastrointestinal Stromal Tumors, run by Erasmus Medical Center at 1 site in Netherlands.
Trial summary
Regorafenib is a novel oral multi-kinase inhibitor which targets angiogenic, stromal and oncogenic receptor tyrosine kinases. It is currently registered for GIST and mCRC. When regorafenib is co-administered with an acid suppressive agent, the intra-gastric pH increases, and as a result the equilibrium of… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colorectal Neoplasms, Gastrointestinal Stromal Tumors
- What is being tested?
- Esomeprazole 40mg concomitantly, Esomeprazole 40mg before and Regorafenib 160mg or 120mg
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 31 participants
- Where
- 1 siteNetherlands
- Study dates
- May 2016to Feb 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Histological or cytological confirmed diagnosis of mCRC or GIST and prior treatment specific:
- mCRC-patients who have been previously treated with, or are not considered candidates for, available therapies according to common practice.
- Irresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib.
- ECOG Performance Status ≤ 1
- Able and willing to sign the Informed Consent Form
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- No concurrent (over the counter) use of other acid reducing drugs (PPIs, H2As and/or antacids), other than esomeprazole 40mg once daily during the study.
- No concurrent medication or supplements which can interact with esomeprazole or regorafenib during the study period.
- Abstain from grapefruit, grapefruit juice, herbal dietary supplements, and herbal tea during the study period.
- Adequate baseline patient characteristics (complete blood count, and serum biochemistry which involves sodium, potassium, creatinin, calculation of creatinin clearance (MDRD), AST, ALT, gamma glutamyl transpeptidase, lipase, lactate dehydrogenase, ALP, total bilirubin, albumin, glucose, INR, thyroid function tests, and PTT or APTT within two weeks prior to the study).
Who cannot join
- Pregnant or lactating patients.
- Patients with known impaired drug absorption (e.g. gastrectomy and achlorhydria).
- Known serious illness or medical unstable conditions that could interfere with this study; requiring treatment (e.g. infection, bleedings, uncontrolled hypertension despite optimal medical management, HIV, hepatitis, organ transplants, kidney, cardiac and respiratory diseases).
- Non-healing wound, non-healing ulcer, or non-healing bone fracture
- Major surgical procedure or significant traumatic injury within 28 days before start of study medication.
- Patients with evidence or history of any bleeding diathesis, irrespective of severity
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- Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication.
- 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 the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication)
- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
- Myocardial infarction less than 6 months before start of study drug.
- Uncontrolled cardiac arrhythmias
- Symptomatic CNS metastases or history of psychiatric disorder that would prohibit the understanding and giving of informed consent.
- Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
- Known history of HIV infection, active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
- Patients on strong CYP3A4 inhibitors or inducers are not eligible for the study (see appendix B).
- The use of BCRP or P-glycoprotein substrates which leads to a clinically relevant drug-drug interaction concerning the pharmacokinetics of regorafenib.
- Unwillingness 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.
- Unwillingness to abstain from acid beverages such as orange juice and other acidic beverages (e.g. Coca-Cola, 7-UP etc.) in the morning (between 06.00-14.00u AM) during regorafenib treatment in this study.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Erasmus Medical Center
Rotterdam, South Holland, 3015 CE
About this study
Official title: The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib in Patients With Metastatic Colorectal Cancer (mCRC) or Gastrointestinal Stromal Tumour (GIST)
Regorafenib is a novel oral multi-kinase inhibitor which targets angiogenic, stromal and oncogenic receptor tyrosine kinases. It is currently registered for GIST and mCRC. When regorafenib is co-administered with an acid suppressive agent, the intra-gastric 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 (PPIs) are often used during regorafenib therapy, this drug-drug interaction (DDI) confronts pharmacists and oncologists with challenges in clinical practice. In this study the investigators will therefore evaluate the impact of PPI-induced intra-gastric pH elevation on regorafenib pharmacokinetics in patients with GIST and mCRC.
Read the detailed description
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 (± 1-2 days). Patients will be randomized into 2 sequence groups (respectively sequences phase A-B-C or phase C-B-A). The patient will use regorafenib alone (phase A) or with esomeprazole for five days (phases B and C). To (completely) rule out a pH-dependent DDI between regorafenib and esomeprazole, during phase B of the study regorafenib is given concomitantly for five days, while during phase C regorafenib is given 3 hours after esomeprazole intake for five days (when the intragastric pH is maximally elevated by esomeprazole).
- Being tested
- Esomeprazole 40mg concomitantly, Esomeprazole 40mg before, Regorafenib 160mg or 120mg
- Medical subject headings
- Colorectal Neoplasms, Gastrointestinal Stromal Tumors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Esomeprazole 40mg concomitantlyDrug
Also called phase B
During phase B the patients will use esomeprazole 40mg concomitantly with regorafenib for 5 days.
Esomeprazole 40mg beforeDrug
Also called phase C
During phase C the patients will use esomeprazole 40mg 3 hours before regorafenib for 5 days.
Regorafenib 160mg or 120mgDrug
Patients will use regorafenib 160mg or 120mg during all phases (A, B, C)
| Study group | Role | What they receive |
|---|---|---|
| Arm A (e.g. sequence phase A-B-C) | Other | In this arm patients will use regorafenib alone in the first cycle (treatment A), then regorafenib with esomeprazole concomitantly in the second cycle (treatment B) and at last they will use regorafenib with esomeprazole 3 hours before (treatment C) Receives: Drug: Esomeprazole 40mg concomitantly; Drug: Esomeprazole 40mg before; Drug: Regorafenib 160mg or 120mg |
| Arm B (e.q. sequence phase C-B-A) | Other | In this arm patients will use regorafenib with esomeprazole 3 hours before (treatment C), then regorafenib with esomeprazole concomitantly in the second cycle (treatment B) and at last they will use regorafenib alone (treatment A), Receives: Drug: Esomeprazole 40mg concomitantly; Drug: Esomeprazole 40mg before; Drug: Regorafenib 160mg or 120mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
As primary endpoint, AUC of regorafenib alone and AUC of regorafenib with esomeprazole (concomitantly and 3 hours before regorafenib intake, respectively) will be related.
The AUC of regorafenib will be determined by multiple blood samples at T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
Measured: T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
Secondary outcomes (4)
The Cmax of regorafenib alone and regorafenib with esomeprazole (concomitantly and 3 hours before regorafenib intake respectively) will be related
The Cmax of regorafenib will be determined by multiple blood samples at T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
Measured: T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
Number of participants with treatment related adverse events as assessed by CTCAE v4.0 in absence and presence of esomeprazole
Measured: Through study completion, approximately 0.5 year
The Tmax of regorafenib alone and regorafenib with esomeprazole (concomitantly and 3 hours before regorafenib intake respectively) will be related
The Tmax of regorafenib will be determined by multiple blood samples at T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
Measured: T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
The clearance of regorafenib alone and regorafenib with esomeprazole (concomitantly and 3 hours before regorafenib intake respectively) will be related
The clearance of regorafenib will be determined by multiple blood samples at T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
Measured: T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jun 2016 (estimated)
- Study startMay 2016
- Primary completionFeb 2018
- Study completionFeb 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colorectal NeoplasmsStudies of the same condition, open and under way.
- More trials run by Erasmus Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 31 participants (actual)
Sponsor and investigators
- Lead sponsor
- Erasmus Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof. R.H.J. Mathijssen, MD, PhD, Erasmus Medical Center
- Investigators
- R.H.J. Mathijssen, MD, PhD, Principal investigator, EMC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02800330
- Sponsor's protocol ID
- EMC16-165
- Acronym
- REGORA
- Status last verified
- Jul 2018
- First submitted
- 25 May 2016
- Last updated
- 2 Aug 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 2 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib in Patients With Metastatic Colorectal Cancer (mCRC) or Gastrointestinal Stromal Tumour (GIST)
- ClinicalTrials.gov ID
- NCT02800330
- Acronym / sponsor ID
- REGORA / EMC16-165
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 31 participants (actual)
- Lead sponsor
- Erasmus Medical CenterUniversity, hospital or other
- Study start
- May 2016
- Primary completion
- Feb 2018 (actual)
- Study completion
- Feb 2018 (actual)
- First posted
- 15 Jun 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Regorafenib is a novel oral multi-kinase inhibitor which targets angiogenic, stromal and oncogenic receptor tyrosine kinases. It is currently registered for GIST and mCRC. When regorafenib is co-administered with an acid suppressive agent, the intra-gastric 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 (PPIs) are often used during regorafenib therapy, this drug-drug interaction (DDI) confronts pharmacists and oncologists with challenges in clinical practice. In this study the investigators will therefore evaluate the impact of PPI-induced intra-gastric pH elevation on regorafenib pharmacokinetics in patients with GIST and mCRC.
Detailed description
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 (± 1-2 days). Patients will be randomized into 2 sequence groups (respectively sequences phase A-B-C or phase C-B-A). The patient will use regorafenib alone (phase A) or with esomeprazole for five days (phases B and C). To (completely) rule out a pH-dependent DDI between regorafenib and esomeprazole, during phase B of the study regorafenib is given concomitantly for five days, while during phase C regorafenib is given 3 hours after esomeprazole intake for five days (when the intragastric pH is maximally elevated by esomeprazole).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm A (e.g. sequence phase A-B-C) | Other | Drug: Esomeprazole 40mg concomitantly, Drug: Esomeprazole 40mg before, Drug: Regorafenib 160mg or 120mgIn this arm patients will use regorafenib alone in the first cycle (treatment A), then regorafenib with esomeprazole concomitantly in the second cycle (treatment B) and at last they will use regorafenib with esomeprazole 3 hours before (treatment C) |
| Arm B (e.q. sequence phase C-B-A) | Other | Drug: Esomeprazole 40mg concomitantly, Drug: Esomeprazole 40mg before, Drug: Regorafenib 160mg or 120mgIn this arm patients will use regorafenib with esomeprazole 3 hours before (treatment C), then regorafenib with esomeprazole concomitantly in the second cycle (treatment B) and at last they will use regorafenib alone (treatment A), |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Age ≥ 18 years
- Histological or cytological confirmed diagnosis of mCRC or GIST and prior treatment specific:
- ECOG Performance Status ≤ 1
- Able and willing to sign the Informed Consent Form
- No concurrent (over the counter) use of other acid reducing drugs (PPIs, H2As and/or antacids), other than esomeprazole 40mg once daily during the study.
Key exclusion criteria (19 listed)
- Pregnant or lactating patients.
- Patients with known impaired drug absorption (e.g. gastrectomy and achlorhydria).
- Known serious illness or medical unstable conditions that could interfere with this study; requiring treatment (e.g. infection, bleedings, uncontrolled hypertension despite optimal medical management, HIV, hepatitis, organ transplants, kidney, cardiac and respiratory diseases).
- Non-healing wound, non-healing ulcer, or non-healing bone fracture
- Major surgical procedure or significant traumatic injury within 28 days before start of study medication.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Esomeprazole 40mg concomitantlyAlso: phase BDuring phase B the patients will use esomeprazole 40mg concomitantly with regorafenib for 5 days. | Drug | Arm A (e.g. sequence phase A-B-C), Arm B (e.q. sequence phase C-B-A) |
| Esomeprazole 40mg beforeAlso: phase CDuring phase C the patients will use esomeprazole 40mg 3 hours before regorafenib for 5 days. | Drug | Arm A (e.g. sequence phase A-B-C), Arm B (e.q. sequence phase C-B-A) |
| Regorafenib 160mg or 120mgPatients will use regorafenib 160mg or 120mg during all phases (A, B, C) | Drug | Arm A (e.g. sequence phase A-B-C), Arm B (e.q. sequence phase C-B-A) |
Primary outcome
As primary endpoint, AUC of regorafenib alone and AUC of regorafenib with esomeprazole (concomitantly and 3 hours before regorafenib intake, respectively) will be related.
Time frame: T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
The AUC of regorafenib will be determined by multiple blood samples at T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
4 secondary outcomes
The Cmax of regorafenib alone and regorafenib with esomeprazole (concomitantly and 3 hours before regorafenib intake respectively) will be related
Time frame: T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
Number of participants with treatment related adverse events as assessed by CTCAE v4.0 in absence and presence of esomeprazole
Time frame: Through study completion, approximately 0.5 year
The Tmax of regorafenib alone and regorafenib with esomeprazole (concomitantly and 3 hours before regorafenib intake respectively) will be related
Time frame: T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
The clearance of regorafenib alone and regorafenib with esomeprazole (concomitantly and 3 hours before regorafenib intake respectively) will be related
Time frame: T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Aug 2018.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
R.H.J. Mathijssen, MD, PhD principal investigator
EMC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Esomeprazole 40mg concomitantly, Esomeprazole 40mg before and Regorafenib 160mg or 120mg in people with Colorectal Neoplasms and Gastrointestinal Stromal Tumors, run by Erasmus Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
As primary endpoint, AUC of regorafenib alone and AUC of regorafenib with esomeprazole (concomitantly and 3 hours before regorafenib intake, respectively) will be related. (time frame: T=0, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 24h at day 21, day 49 and day 77). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Aug 2018.