Identification of Predictive Biomarker of Regorafenib in Refractory Colorectal Cancer
Primary Purpose
Metastatic Colorectal Cancer
Status
Completed
Phase
Not Applicable
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Regorafenib
Sponsored by
About this trial
This is an interventional screening trial for Metastatic Colorectal Cancer focused on measuring metastatic colorectal cancer, refractory, regorafenib, biomarker, gene sequencing
Eligibility Criteria
Inclusion Criteria:
- Signed informed consent obtained before any study-specific procedures.
- Age ≥ 20
- Pathologically confirmed metastatic adenocarcinoma of colon or rectum
- Failure of standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan. Failure is defined as progression during or within 3 months following the last administration of therapy. Patients who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent before progression of disease will also be allowed into the study. Patients treated with oxaliplatin in an adjuvant setting who have progressed during or within 6 months of completion of adjuvant therapy are regarded as failure of oxaliplatin. Patients may or may not have received bevacizumab or cetuximab.
- Measurable or nonmeasurable disease according to RECIST criteria, version 1.1.
- Adequate tissue for gene sequencing (surgical FFPE specimen or fresh-frozen biopsy specimen)
- ECOG PS 0 or 1
- Life expectancy of at least 3 months
Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 14 days of starting to study treatment
- Total bilirubin ≤1.5 × ULN
- Alanine aminotransferase and aspartate aminotransferase ≤2 × ULN (≤5 × ULN for patients with liver involvement of cancer)
- Amylase and lipase ≤1.5 × ULN
- Serum creatinine ≤1.5 × ULN
- Glomerular filtration rate ≥30 ml/min/1.73 m2 according to the Modified Diet in Renal Disease abbreviated formula
- International normalised ratio (INR) and partial thromboplastin time (PTT) ≤1.5 × ULN. Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of an underlying abnormality in coagulation parameters exists.
- Platelet count ≥100,000/mm3, haemoglobin >9 g/dl, absolute neutrophil count >1,500/mm3
- Alkaline phosphatase limit ≤2.5 × ULN (≤5 × ULN for patients with liver involvement of their cancer)
Exclusion Criteria:
- Prior treatment with regorafenib
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication
- Pregnancy or breast-feeding. Women of childbearing potential must have a negative pregnancy test performed a maximum of 7 days before start of treatment
- Congestive heart failure of NYHA class 2 or worse
- Unstable angina, 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 >90 mmHg despite optimal medical management)
- Arterial or venous thrombotic or embolic events within the 6 months before start of study medication
- Ongoing infection higher than NCI-CTCAE v4.0 grade 2
- Known history of HIV infection
- Active hepatitis B or C virus infection
- Seizure disorder requiring medication
- Symptomatic metastatic brain or meningeal tumors
- History of organ allograft
- Non-healing wound, ulcer, or bone fracture
- Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
- Persistent proteinuria of NCI-CTCAE v4.0 grade 3 or higher
- Inability to swallow oral medications
- Any malabsorption condition
- Unresolved toxicity higher than NCI-CTCAE v4.0 grade 1 attributed to any prior therapy/procedure, excluding alopecia and oxaliplatin-induced neurotoxicity of grade 2 or less
Sites / Locations
- Seoul National University Hospital
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
Regorafenib
Arm Description
This study is a single arm study with biomarker analysis
Outcomes
Primary Outcome Measures
Predictive biomarker in terms of disease control rate
This study aims at identifying potential molecular subgroup of colorectal cancer that may benefit from regorafenib treatment in terms of disease control rate.
Secondary Outcome Measures
Disease control rate
Disease control rate in all treated population
Progression-free survival
Progression-free survival in all treated population
Overall survival
Overall survival in all treated population
number of participants with adverse events
adverse events according to NCI-CTCAE v.4.0
Progression-free survival according to biomarker status
Progression-free survivals will be compared according to biomarker status
Overall survival according to biomarker status
Overall survivals will be compared according to biomarker status
Assessment of adequate response evaluation modality after regorafenib treatment
Changes in size, CT attenuation (HFU) and PET metabolism (SUV) will be evaluated and assessed in relation to survival outcomes
Full Information
NCT ID
NCT01996969
First Posted
October 24, 2013
Last Updated
February 20, 2019
Sponsor
Seoul National University Hospital
Collaborators
Bayer
1. Study Identification
Unique Protocol Identification Number
NCT01996969
Brief Title
Identification of Predictive Biomarker of Regorafenib in Refractory Colorectal Cancer
Official Title
Identification of Predictive Biomarker of Regorafenib in Refractory Colorectal Cancer: A Prospective Explorative Study
Study Type
Interventional
2. Study Status
Record Verification Date
February 2019
Overall Recruitment Status
Completed
Study Start Date
October 2013 (undefined)
Primary Completion Date
June 2015 (Actual)
Study Completion Date
May 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Seoul National University Hospital
Collaborators
Bayer
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Regorafenib is a valuable treatment option for metastatic colorectal cancer patients who have progressed after prior standard treatments. Prior progression-free survival data suggest that there could be a distinct subgroup of patients that may benefit from regorafenib. The aim of this study is to identify predictive biomarker of regorafenib in terms of its efficacy.
Detailed Description
Regorafenib is a multi-tyrosine kinase inhibitor which has been shown to increase survival in metastatic colorectal cancer patients who have progressed after prior standard treatments. Progression-free survival data suggest that there could be a distinct subgroup of patients that may benefit from regorafenib. Therefore, it would be important to identify predictive biomarker of efficacy of regorafenib. Considering that regorafenib is a multi-tyrosine kinase inhibitor, comprehensive approach is required to discover predictive biomarker.
NGS-based sequencing allows generating large amount of data regarding multiple genes and multiple genetic alterations within a single experiment. Also, it requires less amount of DNA or tissue and cost compared to currently used individual gene testing techniques such as direct sequencing or FISH. Moreover, superior sensitivity over Sanger sequencing can be obtained by increasing coverage depth, especially in cases with low tumor purity. Wide range of genes targeted by regorafenib and genes in the major oncogenic pathway of colorectal cancer influenced by regorafenib can be efficiently assessed using NGS-based sequencing.
The aim of this study is to identify predictive biomarker of efficacy of regorafeinib in metastatic, refractory colorectal cancer patients using NGS technology.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer
Keywords
metastatic colorectal cancer, refractory, regorafenib, biomarker, gene sequencing
7. Study Design
Primary Purpose
Screening
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
117 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Regorafenib
Arm Type
Other
Arm Description
This study is a single arm study with biomarker analysis
Intervention Type
Drug
Intervention Name(s)
Regorafenib
Intervention Description
Regorafenib will be given 160mg once daily for 3 weeks, followed by a 1 week rest. Treatment will be continued until disease progression or unacceptable toxicity occurs. Response evaluation (CT scans) will be performed every 2 cycles.
Primary Outcome Measure Information:
Title
Predictive biomarker in terms of disease control rate
Description
This study aims at identifying potential molecular subgroup of colorectal cancer that may benefit from regorafenib treatment in terms of disease control rate.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Disease control rate
Description
Disease control rate in all treated population
Time Frame
1 year
Title
Progression-free survival
Description
Progression-free survival in all treated population
Time Frame
1 year
Title
Overall survival
Description
Overall survival in all treated population
Time Frame
1 year
Title
number of participants with adverse events
Description
adverse events according to NCI-CTCAE v.4.0
Time Frame
1 year
Title
Progression-free survival according to biomarker status
Description
Progression-free survivals will be compared according to biomarker status
Time Frame
1 year
Title
Overall survival according to biomarker status
Description
Overall survivals will be compared according to biomarker status
Time Frame
1 year
Title
Assessment of adequate response evaluation modality after regorafenib treatment
Description
Changes in size, CT attenuation (HFU) and PET metabolism (SUV) will be evaluated and assessed in relation to survival outcomes
Time Frame
1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Signed informed consent obtained before any study-specific procedures.
Age ≥ 20
Pathologically confirmed metastatic adenocarcinoma of colon or rectum
Failure of standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan. Failure is defined as progression during or within 3 months following the last administration of therapy. Patients who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent before progression of disease will also be allowed into the study. Patients treated with oxaliplatin in an adjuvant setting who have progressed during or within 6 months of completion of adjuvant therapy are regarded as failure of oxaliplatin. Patients may or may not have received bevacizumab or cetuximab.
Measurable or nonmeasurable disease according to RECIST criteria, version 1.1.
Adequate tissue for gene sequencing (surgical FFPE specimen or fresh-frozen biopsy specimen)
ECOG PS 0 or 1
Life expectancy of at least 3 months
Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 14 days of starting to study treatment
Total bilirubin ≤1.5 × ULN
Alanine aminotransferase and aspartate aminotransferase ≤2 × ULN (≤5 × ULN for patients with liver involvement of cancer)
Amylase and lipase ≤1.5 × ULN
Serum creatinine ≤1.5 × ULN
Glomerular filtration rate ≥30 ml/min/1.73 m2 according to the Modified Diet in Renal Disease abbreviated formula
International normalised ratio (INR) and partial thromboplastin time (PTT) ≤1.5 × ULN. Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of an underlying abnormality in coagulation parameters exists.
Platelet count ≥100,000/mm3, haemoglobin >9 g/dl, absolute neutrophil count >1,500/mm3
Alkaline phosphatase limit ≤2.5 × ULN (≤5 × ULN for patients with liver involvement of their cancer)
Exclusion Criteria:
Prior treatment with regorafenib
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication
Pregnancy or breast-feeding. Women of childbearing potential must have a negative pregnancy test performed a maximum of 7 days before start of treatment
Congestive heart failure of NYHA class 2 or worse
Unstable angina, 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 >90 mmHg despite optimal medical management)
Arterial or venous thrombotic or embolic events within the 6 months before start of study medication
Ongoing infection higher than NCI-CTCAE v4.0 grade 2
Known history of HIV infection
Active hepatitis B or C virus infection
Seizure disorder requiring medication
Symptomatic metastatic brain or meningeal tumors
History of organ allograft
Non-healing wound, ulcer, or bone fracture
Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
Persistent proteinuria of NCI-CTCAE v4.0 grade 3 or higher
Inability to swallow oral medications
Any malabsorption condition
Unresolved toxicity higher than NCI-CTCAE v4.0 grade 1 attributed to any prior therapy/procedure, excluding alopecia and oxaliplatin-induced neurotoxicity of grade 2 or less
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tae-You Kim, M.D., Ph.D
Organizational Affiliation
Seoul National University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sae-Won Han, M.D.,Ph.D
Organizational Affiliation
Seoul National University Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
12. IPD Sharing Statement
Learn more about this trial
Identification of Predictive Biomarker of Regorafenib in Refractory Colorectal Cancer
We'll reach out to this number within 24 hrs