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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.

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.

Regorafenib

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.

Daniel J Renouf, MD

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.

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.

Phase II Study of Perindopril and Regorafenib in mCRC

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 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.

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).

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).

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.

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.

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.

Bayer

British Columbia Cancer Agency

All patients in this single-arm trial will receive treatment with regorafenib and perindopril.

Single Arm Trial

Phase II, open label, single arm trial of patient with refractory metastatic colorectal carcinoma (mCRC) treated with regorafenib (10 mg/day) and perindopril (4 mg/day). There will be no stratification in this study.

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.

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.

Regorafenib and Perindopril

Number of participants aged less than or equal to 18 years, between 18 and 65 years, and greater than or equal to 65 years.

12 participants were enrolled but only 10 participants were evaluable.

Age, Categorical

Age, Continuous

Sex: Female, Male

Asian

Black

Caucasian

Number of Asian, Black, and Caucasian participants.

Race/Ethnicity, Customized

Canada

Number of participants for which regional information was collected.

Region of Enrollment

Dr. Barbara Melosky

Number of Participants That Have Any Grade HFSR Toxicity

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

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

Number of Participants With Maximal Severity of HFSR as Assessed by CTCAE v4.03 Criteria When Treated With a Combination of Regorafenib and Perindopril

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

Spots Global Cancer Trial Database for perindopril erbumine