Phase II Study of Perindopril and Regorafenib in mCRC

NCT02651415 | Completed Phase 2 Results

• 1 other identifier: H15-02424
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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. This research is being done in an attempt to reduce the side-effects associated with regorafenib.

Conditions

Metastatic Colorectal Cancer

Keywords

Metastatic colorectal cancer; Metastatic colorectal carcinoma; mCRC; Regorafenib; Stivarga; Perindopril; Perindopril erbumine; Coversyl

Outcome Measures

Primary Outcomes (1)

• 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.

  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

  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

  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

  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

  p to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)

• Median Time to Progression Free Survival (PFS)

  From start date of study drugs to the date of first documented disease progression or death due to any cause.

Study Arms (1)

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.

Drug: Regorafenib; Drug: Perindopril

Interventions

Regorafenib DRUG

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.

Also known as: Stivarga (regorafenib) or "regorafenib"

Regorafenib and Perindopril

Perindopril DRUG

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.

Also known as: COVERSYL (perindopril erbumine) or "perindopril"

Regorafenib and Perindopril

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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

You may not qualify if:

• 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.
• 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)

Sponsors & Collaborators

• British Columbia Cancer Agency: lead
• Bayer: collaborator

Study Sites (1)

BC Cancer Agency - Vancouver Cancer Centre

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Related Publications (12)

• 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.

  PMID: 10636260 BACKGROUND

• Ceconi 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.

  PMID: 17140552 BACKGROUND

• Ceconi 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.

  PMID: 17716647 BACKGROUND

• Eisenhauer 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.

  PMID: 19097774 BACKGROUND

• Erber 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.

  PMID: 14657001 BACKGROUND

• Grothey 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.

  PMID: 23177514 BACKGROUND

• Grothey 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.

  PMID: 24821824 BACKGROUND

• Li 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.

  BACKGROUND

• 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.

  PMID: 24795111 BACKGROUND

• Robert 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.

  PMID: 15992698 BACKGROUND

• Taddei S: New evidence for entothelial protection. Medicographia, a Servier publication Vol 34:17-23, 2012

  BACKGROUND

• 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.

  PMID: 11882622 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

regorafenib; Perindopril

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Barbara Melosky
• Organization: BC Cancer

bmelosky@bccancer.bc.ca

604-877-6000

Study Officials

• Daniel J Renouf, MD

  British Columbia Cancer Agency

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2016
• First Posted: January 11, 2016
• Study Start: August 1, 2016
• Primary Completion: March 1, 2018
• Study Completion: November 7, 2018
• Last Updated: September 12, 2019
• Results First Posted: September 12, 2019

Record last verified: 2019-09

Locations

CA (1)