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Study to Determine the Efficacy of Regorafenib in Metastatic Colorectal Cancer Patients and to Discover Biomarkers

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ClinicalTrials.gov Identifier: NCT01949194
Recruitment Status : Recruiting
First Posted : September 24, 2013
Last Update Posted : August 21, 2017
Quebec Clinical Research Organization in Cancer
Information provided by (Responsible Party):
Gerald Batist, Jewish General Hospital

Brief Summary:

In recent years, anti-angiogenic agents have been incorporated into clinical practice for the treatment of metastatic CRC, leading to improvements in progression-free survival and overall survival. Regorafenib is an oral multi-kinase inhibitor that targets angiogenic and oncogenic kinases. Although structurally similar to another multi-kinase inhibitor, sorafenib, it appears to be pharmacologically more potent and possesses broader antiangiogenic properties.

Both sorafenib and regorafenib target BRAF wild-type and BRAF V600E mutant but the inhibition of p38 MAP kinase is a peculiar characteristic of regorafenib. A Phase I study of regorafenib as a single agent in patients with heavily pretreated CRC showed promising clinical activity with a disease control rate (PR + SD) of 59% in evaluable patients. In the Phase III trial (CORRECT), which was a randomized double-blind, placebo-controlled study comparing either regorafenib plus best supportive care (BSC) or placebo plus BSC, it was shown that regorafenib significantly increased overall survival (OS), progression-free survival (PFS) and disease control rate (DCR), independently of KRAS status. A major interest, given the data presented in the CORRECT trial, is to determine predictive biomarkers to indicate patients likely to benefit, or to be resistant to this anti-angiogenic compound.

This study aims to determine the efficacy of regorafenib as single-agent treatment for the treatment of second-line metastatic colorectal cancer and to identify predictive biomarkers in the actual metastatic tumors to be treated. In the case of metastatic CRC patients, liver lesions are frequently the most common site of metastatic deposit and these lesions can be biopsied to assess putative biomarkers. Patients will be asked to undergo a biopsy of a metastatic lesion prior to treatment, and an optional liver biopsy at the time of relapse. Using several high-throughput discovery platforms, biomarkers will be identified in the metastatic tumor specimens and in blood samples collected throughout the treatment. This will allow us to evaluate putative biomarkers and monitor tumor biomarker dynamics using serial blood collection.

The objectives of this trial are to help identify the patient subgroup most likely to be responsive or resistant to regorafenib, so that future treatment with regorafenib can be directed to the more responsive but as yet identified patient population.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: Regorafenib Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Exploratory Study to Identify Biomarkers Predictive of Clinical Response to Regorafenib in Patients With Metastatic Colorectal Cancer Who Have Failed First-line Therapy
Actual Study Start Date : September 2013
Estimated Primary Completion Date : February 2018
Estimated Study Completion Date : February 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Regorafenib
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Regorafenib
Single-agent regorafenib
Drug: Regorafenib
The dose of regorafenib given will be 160 mg once a day (od) oral (po), using a 21 days on / 7 days off treatment schedule. This equates to four (4) tablets once a day for three (3) weeks. The patient should take the dose at the same time each day, with a full glass of water, and following a light meal. A "light meal"consists of less than 30% fat and around 300-550 calories.
Other Name: BAY 73-4506

Primary Outcome Measures :
  1. A biomarker (in blood or tissue) that may be predictive of level of response to regorafenib [ Time Frame: 4 years ]
    A biopsy from a liver metastasis will be taken at baseline for discovery of biomarkers that correlate with response to regorafenib. Genomic material (DNA and RNA) will be isolated from all biopsies. Those that pass quality control (high quality DNA, RNA and >60% tumor content) will be considered evaluable. Batched analysis will be performed at the end of the study with the evaluable samples for multiplex biomarker discovery. Patient's biomarker status at baseline will be correlated with treatment effect on PFS and response (including response rate and disease control rate) to explore which biological targets may be particularly important in defining the appropriate treatment population for regorafenib.

Secondary Outcome Measures :
  1. Number of participants with adverse events [ Time Frame: Up to 3 years ]
    Assessment of safety profile of regorafenib in treated patients : report of Adverse Events according to the The NCI's Common Toxicity Criteria version 4.0

  2. Progression free survival (PFS) time [ Time Frame: Time from registration to progressive disease (up to 3 years) ]
    The time from the date of registration until the date of radiological disease progression assessed by RECIST 1.1 or until death due to any cause, even in the absence of radiological progression.

  3. Objective Response Rate (RR) [ Time Frame: Up to 3 years ]
    Determination of the objective response rate (ORR: CR (complete response) +PR (partial response) +SD (stable disease)) of treated patients according to RECIST 1.1 criteria.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Signed informed consent.
  2. Age ≥18 years.
  3. Histological documentation of adenocarcinoma of the colon or rectum, with at least one liver metastatic site available for biopsy.
  4. Metastatic disease not suitable for upfront curative-intent surgery.
  5. Patients must have received one (and no more than one) prior treatment regimen for metastatic CRC.
  6. Measurable disease according to RECIST v.1.1.
  7. ECOG status ≤1.
  8. Life expectancy ≥ 3 months.
  9. Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last study drug administration.
  10. Adequate bone-marrow, liver, and renal function:

    • Total bilirubin ≤1.5 × ULN
    • ALT and AST ≤5 × ULN (since liver involvement of their cancer)
    • Alkaline phosphatase limit ≤5 × ULN, since liver involvement of their cancer
    • Amylase and lipase ≤1.5 × ULN
    • Serum creatinine ≤1.5 × ULN
    • INR and PTT ≤1.5 × ULN.
    • Platelet count ≥100 x 10^9/L, hemoglobin ≥90 g/L, absolute neutrophil count (ANC) >1.5 x 10^9/L

Exclusion Criteria:

  1. Previous treatment with regorafenib.
  2. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years before randomization, EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumours.
  3. Extended field radiotherapy within 4 weeks or limited field radiotherapy within 2 weeks prior to registration. Patients must have recovered from all therapy-related toxicities. The site of irradiation should have evidence of progressive disease (new lesions or increase in lesion size) if this is the only site of disease.
  4. Major surgical procedure or significant traumatic injury within 28 days before starting the study treatment.
  5. Female patients that are pregnant or breast-feeding.
  6. Congestive heart failure ≥ Class 2 according to the NYHA.
  7. 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
  8. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
  9. Uncontrolled hypertension
  10. Phaeochromocytoma
  11. Pleural effusion or ascites that causes respiratory compromise.
  12. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 3 months before starting the study treatment.
  13. Ongoing uncontrolled infection > Grade 2 per CTCAE v. 4.0.
  14. Known history of HIV infection.
  15. Active hepatitis B or C, or chronic hepatitis B or C requiring antiviral therapy.
  16. Seizure disorder requiring medication.
  17. Any history of or currently known brain metastases (patients with stable brain metastases ≥ 3 months may be eligible for the study).
  18. History of organ allograft.
  19. Evidence or history of severe bleeding diathesis.
  20. Non-healing wound, ulcer, or bone fracture.
  21. Renal failure requiring haemodialysis or peritoneal dialysis
  22. Dehydration ≥ 2 per CTCAE v. 4.0.
  23. Substance abuse or medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
  24. Known hypersensitivity to regorafenib, regorafenib class of drugs, or excipients in the formulation.
  25. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient in the opinion of the investigator.
  26. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
  27. Persistent proteinuria ≥ Grade 3 per CTCAE v. 4.0 (i.e. >3.5g/24 hours).
  28. Inability to swallow oral medications.
  29. Any malabsorption condition.
  30. Unresolved toxicity > Grade 1, attributed to any prior therapy/procedure, excluding alopecia and oxaliplatin neurotoxicity ≤ Grade 2, per CTCAE v. 4.0.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01949194

Contact: Gerald Batist, MD 514 340-8222 ext 5418 gerald.batist@mcgill.ca
Contact: Petr Kavan, MD, PhD 514 340-8222 ext 5074 petr.kavan@mcgill.ca

Canada, New Brunswick
The Moncton Hospital (Horizon Health Network) Recruiting
Moncton, New Brunswick, Canada, E1C 6Z8
Contact: Mrudula Avileli    506 857-5669    Mrudula.Avileli@horizonnb.ca   
Principal Investigator: Mahmoud Abdelsalam, MD         
Canada, Quebec
CSSS Alphonse-Desjardins Recruiting
Lévis, Quebec, Canada, G6V3Z1
Contact: Pierre Bédard, BSN    418 835-7121 ext 3048    pierre_bedard@ssss.gouv.qc.ca   
Principal Investigator: Félix Couture, MD         
Jewish General Hospital Recruiting
Montreal, Quebec, Canada, H3T 1E2
Contact: Claudia Schanz    514 340-8222 ext 23651    cschanz@jgh.mcgill.ca   
Principal Investigator: Gerald Batist, MD         
Principal Investigator: Petr Kavan, MD, PhD         
St-Mary's Hospital Centre Recruiting
Montreal, Quebec, Canada, H3T 1M5
Contact: Rajesh Sharma    514 345-3511 ext 3981    rajesh.sharma.comtl@ssss.gouv.qc.ca   
Principal Investigator: Adrian Langleben, MD         
McGill University Health Centre Recruiting
Montréal, Quebec, Canada, H4A 3J1
Contact: Dianna Leroux    514-934-1934 ext 35161    dianna.leroux@muhc.mcgill.ca   
Principal Investigator: Thierry Alcindor, MD         
Hopital Maisonneuve-Rosemont Active, not recruiting
Montreal, Canada, H1T 2M4
Sponsors and Collaborators
Gerald Batist
Quebec Clinical Research Organization in Cancer
Principal Investigator: Gerald Batist, MD Jewish General Hospital
Principal Investigator: Petr Kavan, MD, PhD McGill University Health Center

Responsible Party: Gerald Batist, Medical Oncologist, Director Segal Cancer Center, Jewish General Hospital
ClinicalTrials.gov Identifier: NCT01949194     History of Changes
Other Study ID Numbers: QCROC-06
First Posted: September 24, 2013    Key Record Dates
Last Update Posted: August 21, 2017
Last Verified: August 2017

Keywords provided by Gerald Batist, Jewish General Hospital:
liver metastases

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases