Phase II Study of Perindopril and Regorafenib in mCRC (PARICCA)
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.
Metastatic Colorectal Cancer
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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)|
- Proportion of Participants that have Any Grade HFSR Toxicity 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) ] [ Designated as safety issue: Yes ]
The trial will measure the incidence and severity of HFSR in participants receiving both perindopril and regorafenib using the CTCAE v4.03 criteria.
The incidence of HFSR will be expressed as the number of participants out of study (N=34) who are experiencing HFSR of all grades.
- Proportion of All Grades 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 ] [ Designated as safety issue: Yes ]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).
- Proportion of 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 ] [ Designated as safety issue: Yes ]All grades of AE (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).
- 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) ] [ Designated as safety issue: Yes ]
- Time Course to Development of Worst Grade (stage 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) ] [ Designated as safety issue: Yes ]Time to 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 patient who had a HFSR toxicity grade 3.
- Progression-Free Survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
Progression-free survival (PFS) will be evaluated based on RECIST v1.1 criteria.
PFS is defined as the time (days) from start date of study drugs to date of first documented disease progression (radiological or clinical) or death due to any cause, if death occurs before progression is documented.
|Study Start Date:||August 2016|
|Estimated Primary Completion Date:||December 2017 (Final data collection date for primary outcome measure)|
Experimental: Regorafenib and Perindopril
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.
Other Name: Stivarga (regorafenib) or "regorafenib"Drug: 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.
Other Name: COVERSYL (perindopril erbumine) or "perindopril"
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 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 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 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02651415
|Contact: Daniel J Renouf, MD||604-877-6000 ext email@example.com|
|Contact: Barbara Melosky, MD||604-877-6000||BMelosky@bccancer.bc.ca|
|Canada, British Columbia|
|BC Cancer Agency - Vancouver Cancer Centre||Recruiting|
|Vancouver, British Columbia, Canada, V5Z 4E6|
|Contact: Daniel J Renouf, MD 604-877-6000 firstname.lastname@example.org|
|Contact: Barbara Melosky, MD 604-877-6000 BMelosky@bccancer.bc.ca|
|Principal Investigator: Daniel J Renouf, MD|
|Sub-Investigator: Barbara Melosky, MD|
|Sub-Investigator: Winson Cheung, MD|
|Sub-Investigator: Howard Lim, MD|
|Sub-Investigator: Christian Kollmannsberger, MD|
|Sub-Investigator: Sharlene Gill, MD|
|Sub-Investigator: Janine Davies, MD|
|Sub-Investigator: Corey Metcalf, MD|
|Sub-Investigator: Hagen Kennecke, MD|
|Principal Investigator:||Daniel J Renouf, MD||British Columbia Cancer Agency|