Metastatic Colorectal CancerPhase 2PARICCANCT02651415
Phase II Study of Perindopril and Regorafenib in mCRC
A Phase 2 study testing Regorafenib and Perindopril in people with Metastatic Colorectal Cancer, run by British Columbia Cancer Agency at 1 site in Canada.
Trial summary
The purpose of this study is to find out what effects the combination of regorafenib and perindopril has on hand-foot skin reaction (HFSR), on high blood pressure (hypertension) and on any other types of side-effects and compare it to the published incidence of the side-effects with regorafenib alone. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Colorectal Cancer
- What is being tested?
- Regorafenib and Perindopril
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteCanada
- Study dates
- Aug 2016to 7 Nov 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Patients with metastatic colorectal cancer (mCRC) who have progressed on/after, or are intolerant to all approved drugs for CRC and are eligible for regorafenib.
- In order to be eligible, all inclusion criteria must be met.
- A patient must:
- Understand, be willing to give consent, and sign a written informed consent form (ICF) prior to undergoing any study-specific procedure
- Be male or female and ≥ 18 years of age
- Histological or cytological documentation of adenocarcinoma of the colon or rectum.
Show all 22Show fewer
- Patients with metastatic colorectal cancer (Stage IV) previously treated with fluoropyrimidine-based chemotherapy, oxaliplatin, irinotecan, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.
- Progression during or within 3 months following the last administration of approved standard therapies, or have experienced intolerance to previous therapy.
- Metastatic CRC patients with measurable or non-measurable disease
- Life expectancy of at least 3 months
- Have an Eastern Cooperative Oncology Group performance status of 0 or 1 (within 14 days prior to the initiation of study treatment)
- Have adequate bone marrow, liver function, and renal function as measured by the following laboratory assessments conducted within 7 days prior to the initiation of study treatment:
- Total bilirubin < 1.5 times the upper limit of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 times the ULN (< 5 times ULN for patients with liver involvement of their cancer)
- Lipase < 1.5 times the ULN
- Serum creatinine < 1.5 times the ULN
- Glomerular filtration rate > 30 mL/min/1.73 m2 according to the modified diet in renal disease abbreviated formula
- International normalized ratio (INR) of prothrombin time (PT; PT-INR) and partial thromboplastin time (PTT) < 1.5 times the ULN
- Platelet count > 100000 /mm3, hemoglobin > 9 g/dL, absolute neutrophil count > 1500/mm3.
- Alkaline phosphatase limit ≤ 2.5 times the ULN (< 5 times ULN for patients with liver involvement of their cancer)
- If female and of childbearing potential, have a NEGATIVE result on a pregnancy test performed a maximum of 7 days before initiation of study treatment.
- If female and of childbearing potential or if male, must agree to use adequate contraception (e.g., abstinence, intrauterine device, oral contraceptive, or double-barrier method) based on the judgment of the investigator or a designated associate from the date on which the ICF is signed until 6 months after the last dose of study drug.
Who cannot join
- Patients who meet the following criteria at the time of screening will be excluded:
- Patients with hypotension (less than 90/60mm Hg) or at risk of symptomatic hypotension (fainting or dizziness) will be excluded.
- Prior treatment with regorafenib or any VEGFR-targeting kinase inhibitor.
- Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
- Concurrent cancer requiring treatment that is distinct in primary site or histology from colorectal cancer.
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication.
Show all 36Show fewer
- Unstable/uncontrolled cardiac disease including: congestive heart failure > New York Heart Association (NYHA) class 2; 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; cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
- Uncontrolled hypertension. (Systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
- Patients with phaeochromocytoma.
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication.
- Ongoing infection > grade 2 NCI-CTCAE version 4.03
- Known history of human immunodeficiency virus (HIV) infection.
- Known history of chronic hepatitis B or C.
- Patients with seizure disorder requiring medication.
- Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies)
- History of organ allograft
- Patients with evidence or history of bleeding diasthesis, including patients who have had a transfusion and/or radiographic endoscopic or elective operative interaction to control the bleeding or hemorrhage event within four weeks prior to the study
- Non-healing wound, ulcer, or bone fracture.
- Renal impairment or failure requiring hemo-or peritoneal dialysis.
- Patients with severe hepatic impairment.
- Dehydration NCI-CTC version 4.03 grade > 1.
- Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
- Any illness or medical conditions that are unstable or could jeopardize the safety of the study
- Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
- Persistent proteinuria of Common Terminology Criteria (CTC) Grade 3 or higher. Quantification of proteinuria done by urinary protein/creatinine ratio on a random urine sample preferably taken at mid-morning. If protein/creatinine ratio is greater than 30g/mol Creat, then a 24-hour urine protein test should be performed to confirmed Grade 3 or higher proteinuria (> 3.5 g/24 hours).
- Patients unable to swallow oral medications
- Any malabsorption condition
- Unresolved toxicity higher than NCI-CTCAE (version 4.03) Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity ≤Grade 2
- Patients who are hypersensitive to perindopril, as well as those hypersensitive to regorafenib, sorafenib, drugs in the same class or any ingredient in the formulation.
- Patients who cannot tolerate the full dose of perindopril (4 mg) for any reason.
- Patients receiving systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, hormonal therapy and experimental or approved therapies during this trial or within 14 days before starting to receive study medication.
- In addition, patients will be excluded for the following reasons (From perindopril monograph).
- Patients with a history of hereditary/idiopathic angioedema, or angioedema related to previous treatment with an angiotensin converting enzyme inhibitor.
- Pregnant women or those planning to become pregnant, nursing women.
- Patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp lactase deficiency.
- Patients with pre-existing anti-hypertension treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) are to be excluded. Co-administration of ACE inhibitors, including COVERSYL®, with other agents blocking the Renin-Angiotensin System (RAS), such as ARBs or aliskiren-containing drugs, will not be allowed, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia.
Trial locations and contacts
1 site in 1 country.
Canada1 site
BC Cancer Agency - Vancouver Cancer Centre
Vancouver, British Columbia, V5Z 4E6
About this study
Official title: A Phase II Trial of the Effect of Perindopril on HFSR Incidence and Severity in Patients Receiving Regorafenib With Refractory Metastatic Colorectal Carcinoma (mCRC)
The purpose of this study is to find out what effects the combination of regorafenib and perindopril has on hand-foot skin reaction (HFSR), on high blood pressure (hypertension) and on any other types of side-effects and compare it to the published incidence of the side-effects with regorafenib alone.
This research is being done in an attempt to reduce the side-effects associated with regorafenib.
Read the detailed description
The investigators hypothesize that treatment of regorafenib-treated mCRC patients with perindopril may reduce HFSR compared to reported incidence and severity.
The investigators also hypothesize that treatment of regorafenib-treated mCRC patients with perindopril will likely reduce hypertension, a known adverse effect of vascular endothelial growth factor/receptor (VEGF/VEGFR) inhibition.
According to the 2014 Canadian Cancer Statistics, colorectal cancer is the second most frequently diagnosed cancer in Canadian males and the third most frequently diagnosed cancer in Canadian females, accounting for 13.9% and 11.6% of new diagnoses, respectively. Although mortality rates are declining very slightly, colorectal cancer is the second most frequent cause of cancer deaths in males and the third most frequent cause of cancer death in females, at 12.8% and 11.5% respectively.
Metastatic colorectal cancers are generally not curable. Median overall survival for patients with unresectable mCRC who receive best supportive care (BSC) is five to six months. Palliative treatment with systemic chemotherapy is the best option prolonging survival and maintaining quality of life. Patients who are exposed to all active drugs can sometimes extend survival past two years.
For many years 5 Fluorouracil (FU) was the only treatment, but the approval of irinotecan, oxaliplatin, fluoropyrimidines, as well as various monoclonal antibodies targeting VEGF and epidermal growth factor receptor (EGFR) growth factors led to the development of a number of different regimens. The ideal combination and sequence of the different agents is still not determined.
Recently, Regorafenib has shown efficacy in patients pretreated with all these options in a large phase III trial, where it prolonged overall survival (OS) compared with placebo (Grothey, et al 2013). In addition, the results were confirmed in a smaller randomised trial in the Asian population, with patients being less intensively pre-treated (Li et al, 2014). Therefore, regorafenib is now considered a standard option in pre-treated patients.
The intended outcome of successfully and significantly mitigating regorafenib-induced HFSR is that patients will be able to stay on the regorafenib for a longer period to increase efficacy. The hypothesis underlying this trial is that the co-administration of perindopril with regorafenib will mitigate HFSR symptoms.
This may not be the case, and if the HFSR is more severe with the addition of perindopril than with regorafenib alone, the study will be discontinued.
As a secondary endpoint, hypertension will also be followed.
- Conditions
- Metastatic Colorectal Cancer
- Being tested
- Regorafenib, Perindopril
- Keywords
- Metastatic colorectal cancer, Metastatic colorectal carcinoma, mCRC, Regorafenib, Stivarga, Perindopril, Perindopril erbumine, Coversyl
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RegorafenibDrug
Also called Stivarga (regorafenib) or "regorafenib"
Stivarga® will be used as per the marketed indication ("on label"), Coversyl will be used off-label and as such a Clinical Trial Application will be filed with Health Canada.
Regorafenib will be administered 160 mg daily for 21 days of a 28 day cycle. Regorafenib will be administered with low fat breakfast, one hour after perindopril. A low fat breakfast as defined by the Stivarga ® (regorafenib) Product Monograph is one that is <30% fat, ~300-550 calories.
PerindoprilDrug
Also called COVERSYL (perindopril erbumine) or "perindopril"
COVERSYL® (perindopril erbumine) 4 mg will be administered daily for 21 days of a 28 day cycle. Perindopril will be administered orally, first thing in the morning on an empty stomach.
| Study group | Role | What they receive |
|---|---|---|
| Regorafenib and Perindopril | Experimental | Phase II, open label, single arm trial of patient with refractory mCRC treated with regorafenib (10 mg/day) and perindopril (4 mg/day). There will be no stratification in this study. Receives: Drug: Regorafenib; Drug: Perindopril |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants That Have Any Grade HFSR Toxicity
The trial will measure the toxicities of HFSR in participants receiving both perindopril and regorafenib using the CTCAE v4.03 criteria.
The toxicity of HFSR will be expressed based on the number of participants in the study (N=10) who are experiencing HFSR of all grades.
Measured: Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)
Secondary outcomes (5)
The Number of Participants That Experienced Any Grade of Hypertension as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril
All grades of hypertension will be evaluated using CTCAE v4.03, weekly for the first six weeks while they are on the study drug, then every second week and during the 30-day follow-up period (Post therapy).
Measured: Weekly for the first six weeks while on the study drug, then every second week and during the 30-day follow-up period
The Number of Participants That Experienced All Grade Toxicities as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril
All grades of adverse events (including HFSR) will be evaluated using CTCAE v4.03, at baseline and at D1 of each cycle while they are on the study drug and during the 30-day follow-up period (Post therapy).
Measured: At baseline and at D1 of each cycle while on the study drug and during the 30-day follow-up period
Number of Participants With Maximal Severity of HFSR as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril
The number of participants that experienced an HFSR of grade 3 or above as assessed by CTCAE v4.03 criteria when treated with a combination of regorafenib and perindopril.
Measured: Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)
Median Time Course to Development of Worst Grade (Grade 3) HFSR as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril
Median time course for participants to develop worst grade 3 HFSR toxicity is defined as the time (days) from start date of study drug to date of first documented grade 3 HFSR toxicity and will be calculated only for patients who had a HFSR toxicity grade 3.
Measured: p to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)
Median Time to Progression Free Survival (PFS)
Median time (in months) to PFS. PFS is defined as the time from start date of study drugs to the date of first documented disease progression (radiological or clinical) or death due to any cause, if death occurs before progression is documented. PFS will be evaluated based on RECIST v1.1 criteria, 20% progression or any new lesion.
Measured: From start date of study drugs to the date of first documented disease progression or death due to any cause.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jan 2016 (estimated)
- Study startAug 2016
- Primary completionMar 2018
- Study completion7 Nov 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Metastatic Colorectal CancerStudies of the same condition, open and under way.
- More trials run by British Columbia Cancer AgencyThe 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- British Columbia Cancer Agency
- Sponsor type
- University, hospital or other
- Collaborators
- Bayer
- Responsible party
- Sponsor
- Investigators
- Daniel J Renouf, MD, Principal investigator, British Columbia Cancer Agency
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02651415
- Sponsor's protocol ID
- H15-02424
- Acronym
- PARICCA
- Status last verified
- Sep 2019
- First submitted
- 6 Jan 2016
- Last updated
- 12 Sep 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000 Jan;35(1):60-6. doi: 10.1016/s0735-1097(99)00537-9.
PubMed 10636260Ceconi C, Fox KM, Remme WJ, Simoons ML, Bertrand M, Parrinello G, Kluft C, Blann A, Cokkinos D, Ferrari R; EUROPA Investigators; PERTINENT Investigators and the Statistical Committee. ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res. 2007 Jan 1;73(1):237-46. doi: 10.1016/j.cardiores.2006.10.021. Epub 2006 Nov 10.
PubMed 17140552Ceconi C, Francolini G, Olivares A, Comini L, Bachetti T, Ferrari R. Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol. 2007 Dec 22;577(1-3):1-6. doi: 10.1016/j.ejphar.2007.07.061. Epub 2007 Aug 3.
PubMed 17716647Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
PubMed 19097774Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A, Vajkoczy P. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004 Feb;18(2):338-40. doi: 10.1096/fj.03-0271fje. Epub 2003 Dec 4.
PubMed 14657001Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.
PubMed 23177514Grothey A, George S, van Cutsem E, Blay JY, Sobrero A, Demetri GD. Optimizing treatment outcomes with regorafenib: personalized dosing and other strategies to support patient care. Oncologist. 2014 Jun;19(6):669-80. doi: 10.1634/theoncologist.2013-0059. Epub 2014 May 12.
PubMed 24821824Li J, Qin S, Yau T et al. CONCUR: a randomized double-blind placebo controlled phase 3 study of regorafenib monotherapy in Asian patients with previously treated metastatic colorectal cancer (mCRC). Ann Oncol 2014; 25 (Suppl 2): ii114-ii115.
Miller KK, Gorcey L, McLellan BN. Chemotherapy-induced hand-foot syndrome and nail changes: a review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol. 2014 Oct;71(4):787-94. doi: 10.1016/j.jaad.2014.03.019. Epub 2014 May 1.
PubMed 24795111Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, Pautier P, Wechsler J, Lhomme C, Escudier B, Boige V, Armand JP, Le Chevalier T. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005 Jul;6(7):491-500. doi: 10.1016/S1470-2045(05)70243-6.
PubMed 15992698Taddei S: New evidence for entothelial protection. Medicographia, a Servier publication Vol 34:17-23, 2012
Zhuo JL, Mendelsohn FA, Ohishi M. Perindopril alters vascular angiotensin-converting enzyme, AT(1) receptor, and nitric oxide synthase expression in patients with coronary heart disease. Hypertension. 2002 Feb;39(2 Pt 2):634-8. doi: 10.1161/hy0202.103417.
PubMed 11882622
Study at a glance
From the registry record, last updated by the sponsor on 12 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Trial of the Effect of Perindopril on HFSR Incidence and Severity in Patients Receiving Regorafenib With Refractory Metastatic Colorectal Carcinoma (mCRC)
- ClinicalTrials.gov ID
- NCT02651415
- Acronym / sponsor ID
- PARICCA / H15-02424
- Conditions
- Metastatic Colorectal Cancer
- Keywords
- Metastatic colorectal cancer, Metastatic colorectal carcinoma, mCRC, Regorafenib, Stivarga, Perindopril, Perindopril erbumine, Coversyl
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- British Columbia Cancer AgencyUniversity, hospital or other
- Collaborators
- Bayer
- Study start
- Aug 2016 (actual)
- Primary completion
- Mar 2018 (actual)
- Study completion
- 7 Nov 2018 (actual)
- First posted
- 11 Jan 2016 (estimated)
- Results
- Posted 12 Sep 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to find out what effects the combination of regorafenib and perindopril has on hand-foot skin reaction (HFSR), on high blood pressure (hypertension) and on any other types of side-effects and compare it to the published incidence of the side-effects with regorafenib alone.
This research is being done in an attempt to reduce the side-effects associated with regorafenib.
Detailed description
The investigators hypothesize that treatment of regorafenib-treated mCRC patients with perindopril may reduce HFSR compared to reported incidence and severity.
The investigators also hypothesize that treatment of regorafenib-treated mCRC patients with perindopril will likely reduce hypertension, a known adverse effect of vascular endothelial growth factor/receptor (VEGF/VEGFR) inhibition.
According to the 2014 Canadian Cancer Statistics, colorectal cancer is the second most frequently diagnosed cancer in Canadian males and the third most frequently diagnosed cancer in Canadian females, accounting for 13.9% and 11.6% of new diagnoses, respectively. Although mortality rates are declining very slightly, colorectal cancer is the second most frequent cause of cancer deaths in males and the third most frequent cause of cancer death in females, at 12.8% and 11.5% respectively.
Metastatic colorectal cancers are generally not curable. Median overall survival for patients with unresectable mCRC who receive best supportive care (BSC) is five to six months. Palliative treatment with systemic chemotherapy is the best option prolonging survival and maintaining quality of life. Patients who are exposed to all active drugs can sometimes extend survival past two years.
For many years 5 Fluorouracil (FU) was the only treatment, but the approval of irinotecan, oxaliplatin, fluoropyrimidines, as well as various monoclonal antibodies targeting VEGF and epidermal growth factor receptor (EGFR) growth factors led to the development of a number of different regimens. The ideal combination and sequence of the different agents is still not determined.
Recently, Regorafenib has shown efficacy in patients pretreated with all these options in a large phase III trial, where it prolonged overall survival (OS) compared with placebo (Grothey, et al 2013). In addition, the results were confirmed in a smaller randomised trial in the Asian population, with patients being less intensively pre-treated (Li et al, 2014). Therefore, regorafenib is now considered a standard option in pre-treated patients.
The intended outcome of successfully and significantly mitigating regorafenib-induced HFSR is that patients will be able to stay on the regorafenib for a longer period to increase efficacy. The hypothesis underlying this trial is that the co-administration of perindopril with regorafenib will mitigate HFSR symptoms.
This may not be the case, and if the HFSR is more severe with the addition of perindopril than with regorafenib alone, the study will be discontinued.
As a secondary endpoint, hypertension will also be followed.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Regorafenib and Perindopril | Experimental | Drug: Regorafenib, Drug: PerindoprilPhase II, open label, single arm trial of patient with refractory mCRC treated with regorafenib (10 mg/day) and perindopril (4 mg/day). There will be no stratification in this study. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Patients with metastatic colorectal cancer (mCRC) who have progressed on/after, or are intolerant to all approved drugs for CRC and are eligible for regorafenib.
- In order to be eligible, all inclusion criteria must be met.
- Understand, be willing to give consent, and sign a written informed consent form (ICF) prior to undergoing any study-specific procedure
- Be male or female and ≥ 18 years of age
- Histological or cytological documentation of adenocarcinoma of the colon or rectum.
Key exclusion criteria (36 listed)
- Patients with hypotension (less than 90/60mm Hg) or at risk of symptomatic hypotension (fainting or dizziness) will be excluded.
- Prior treatment with regorafenib or any VEGFR-targeting kinase inhibitor.
- Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
- Concurrent cancer requiring treatment that is distinct in primary site or histology from colorectal cancer.
- Major surgical procedure, open biopsy, 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 |
|---|---|---|
| RegorafenibAlso: Stivarga (regorafenib) or "regorafenib"Stivarga® will be used as per the marketed indication ("on label"), Coversyl will be used off-label and as such a Clinical Trial Application will be filed with Health Canada. Regorafenib will be administered 160 mg daily for 21 days of a 28 day cycle. Regorafenib will be administered with low fat breakfast, one hour after perindopril. A low fat breakfast as defined by the Stivarga ® (regorafenib) Product Monograph is one that is <30% fat, ~300-550 calories. | Drug | Regorafenib and Perindopril |
| PerindoprilAlso: COVERSYL (perindopril erbumine) or "perindopril"COVERSYL® (perindopril erbumine) 4 mg will be administered daily for 21 days of a 28 day cycle. Perindopril will be administered orally, first thing in the morning on an empty stomach. | Drug | Regorafenib and Perindopril |
Primary outcome
Number of Participants That Have Any Grade HFSR Toxicity
Time frame: Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)
The trial will measure the toxicities of HFSR in participants receiving both perindopril and regorafenib using the CTCAE v4.03 criteria. The toxicity of HFSR will be expressed based on the number of participants in the study (N=10) who are experiencing HFSR of all grades.
5 secondary outcomes
The Number of Participants That Experienced Any Grade of Hypertension as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril
Time frame: Weekly for the first six weeks while on the study drug, then every second week and during the 30-day follow-up period
The Number of Participants That Experienced All Grade Toxicities as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril
Time frame: At baseline and at D1 of each cycle while on the study drug and during the 30-day follow-up period
Number of Participants With Maximal Severity of HFSR as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril
Time frame: Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)
Median Time Course to Development of Worst Grade (Grade 3) HFSR as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril
Time frame: p to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)
Median Time to Progression Free Survival (PFS)
Time frame: From start date of study drugs to the date of first documented disease progression or death due to any cause.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Sep 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 10636260Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000 Jan;35(1):60-6. doi: 10.1016/s0735-1097(99)00537-9.
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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.
Daniel J Renouf, MD principal investigator
British Columbia Cancer Agency
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Regorafenib and Perindopril in people with Metastatic Colorectal Cancer, run by British Columbia Cancer Agency at 1 site in Canada.
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 22 inclusion and 36 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 12 Sep 2019. 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 Canada. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Sep 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Number of Participants That Have Any Grade HFSR Toxicity (time frame: Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02651415, which also lists 12 linked publications.
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 12 Sep 2019.