Regorafenib+FOLFIRI Versus Placebo+FOLFIRI as 2nd Line Tx in Metastatic Colorectal Cancer

December 10, 2020 updated by: UNC Lineberger Comprehensive Cancer Center

Multi-Center, Randomized, Placebo-Controlled Phase II Study of Regorafenib in Combination With FOLFIRI Versus Placebo With FOLFIRI as Second-Line Therapy in Patients With Metastatic Colorectal Cancer

This randomized (2:1), multi-center, placebo-controlled, phase II efficacy study is designed to compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients with mCRC previously treated with a FOLFOX regimen.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This randomized (2:1 ratio), multi-center, placebo-controlled, phase II efficacy study is designed to compare progression-free survival (PFS) between regorafenib + FOLFIRI (5-fluorouracil + leucovorin + irinotecan [ARM A] versus placebo + FOLFIRI [ARM B]) in patients with metastatic colorectal carcinoma (mCRC) previously treated with a FOLFOX (5-fluorouracil + leucovorin + oxaliplatin) regimen. Secondary objectives include objective response (OR) rates, disease control (DC) rates, and overall survival (OS). A pharmacokinetic (PK) evaluation of irinotecan will be conducted in a subset of patients at selected sites. This trial also incorporates a number of exploratory analyses designed to evaluate potential correlations between blood and tissue biomarkers and clinical benefit.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
181

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Ireland
      • Dublin, Ireland
        • Ireland Cooperative Clinical Research Group
  • United States
    • Colorado
      • Denver, Colorado, United States, 80218
        • Rocky Mountain Cancer Centers
    • Florida
      • Miami, Florida, United States, 33140
        • Mount Sinai Medical Center-Miami
      • Tampa, Florida, United States, 33612
        • Moffitt Cancer Center
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University
      • Atlanta, Georgia, United States, 30341
        • Georgia Cancer Specialists
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana University Simon Cancer Center
    • Kentucky
      • Louisville, Kentucky, United States, 40202
        • University of Louisville James Brown Cancer Center
    • New York
      • Manhasset, New York, United States, 11030
        • North Shore Long Island Jewish Health System
      • New York, New York, United States, 10016
        • New York University Langone Medical Center
    • North Carolina
      • Boone, North Carolina, United States, 28607
        • Seby B. Jones Cancer Center
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina
      • Charlotte, North Carolina, United States, 28262
        • Carolinas Healthcare System
      • Goldsboro, North Carolina, United States, 27534
        • Southeast Medical Oncology Center
      • Greensboro, North Carolina, United States, 27403
        • The Moses Cone Regional Cancer Center
      • Greenville, North Carolina, United States, 27834
        • Leo W. Jenkins Cancer Center at ECU Medical School
      • Pinehurst, North Carolina, United States, 28374
        • First Health of the Carolinas, Moore Regional Hospital
      • Raleigh, North Carolina, United States, 27607
        • Rex Cancer Center at Rex Hospital
      • Winston-Salem, North Carolina, United States, 27157-1096
        • Wake Forest University Comprehensive Cancer Center
    • Ohio
      • Cincinnati, Ohio, United States, 45267
        • University of Cincinnati
      • Columbus, Ohio, United States, 43221
        • Ohio State University Comprehensive Cancer Center
    • Virginia
      • Charlottesville, Virginia, United States, 22903
        • University of Virginia
      • Portsmouth, Virginia, United States, 23708
        • Portsmouth Naval Medical Center
    • Washington
      • Tacoma, Washington, United States, 98405
        • MultiCare Regional Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria

Subject must meet all of the inclusion criteria to participate in this study:

  1. Age ≥18 years of age (no upper age limit)
  2. Histological or cytological documentation of adenocarcinoma of the colon or rectum
  3. Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies required
  4. Metastatic disease not amenable to surgical resection with curative intent

  5. Progression during or within 6 months following administration of a standard regimen[2] for treatment of metastatic disease that included oxaliplatin with any of the following agents with or without bevacizumab:

    • 5-fluorouracil (F-FU) with or without leucovorin or levoleucovorin
    • Capecitabine

    Note: In patients receiving FOLFOX, oxaliplatin is sometimes discontinued due to toxicity or as part of maintenance therapy strategy. If such patients progress while on 5-FU alone, they are eligible for this trial. As an example, a patient who is begun on FOLFOX or CapeOx (capecitabine with oxaliplatin, with or without bevacizumab), whose oxaliplatin is held for neurotoxicity and who is switched to capecitabine monotherapy or capecitabine with bevacizumab, would be considered to have had one prior therapy.

    OR

    Patients who develop metastatic disease within 9 months of adjuvant FOLFOX for stage II or III colon cancer

  6. Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1.
  7. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix C)
  8. Life expectancy of at least 3 months

  9. Adequate bone marrow, renal, and hepatic function, as evidenced by the following:

    • absolute neutrophil count (ANC) ≥1,500/mm3
    • platelets ≥100,000/mm3
    • hemoglobin ≥9.0 g/dL
    • serum creatinine ≤1.5 x upper limit of normal (ULN)
    • Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 (see Appendix A)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer
    • Bilirubin ≤1.5 X ULN
    • Alkaline phosphatase ≤3 x ULN (≤5 x ULN with liver involvement of their cancer)
    • Amylase and lipase ≤1.5 x ULN
    • Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urine analysis.If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours
    • International normalized ratio (INR)/Partial thromboplastin time (PTT) ≤1.5 x ULN

    Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.

  10. Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care.
  11. The subject is capable of understanding and complying with parameters as outlined in the protocol
  12. Signed, Institutional Review Board (IRB)-approved written informed consent

Exclusion Criteria

Any subject meeting any of the following exclusion criteria at baseline will be ineligible for study participation:

  1. Prior treatment with regorafenib
  2. More than 1 prior chemotherapy regimen for mCRC (see section 3.1.5) Previous adjuvant FOLFOX based chemotherapy is allowed. Prior FOLFIRI or single agent irinotecan is prohibited.
  3. Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator
  4. Pregnant or breastfeeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of FOLFIRI treatment, and a negative result must be documented before start of treatment.
  5. History of Gilbert's syndrome
  6. Known Dihydropyrimidine dehydrogenase (DPD) deficiency
  7. Pernicious anemia or other anemias due to vitamin B12 deficiency (due to potential masking of deficiency with leucovorin)
  8. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of Day 1 of treatment with FOLFIRI
  9. Radiotherapy within 4 weeks prior to first dose of FOLFIRI

  10. Active cardiac disease including any of the following:

    • Congestive heart failure (New York Heart Association (NYHA)) ≥Class 2 (see Appendix D)
    • Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of Day 1 of FOLFIRI
    • 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)
  11. Patients with pheochromocytoma
  12. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of FOLFIRI
  13. Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0)
  14. Known history of human immunodeficiency virus (HIV) infection
  15. Known history of chronic hepatitis B or C
  16. Patients with seizure disorder requiring medication
  17. Symptomatic metastatic brain or meningeal tumors unless the patient is >6 months from definitive therapy, has a negative imaging study within 4 weeks of FOLFIRI initiation, 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)
  18. History of organ allograft
  19. Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 4 within 4 weeks of start of FOLFIRI
  20. Non-healing wound, ulcer, or bone fracture
  21. Renal failure requiring hemo- or peritoneal dialysis
  22. Dehydration according to NCI-CTC v 4.0 Grade >1
  23. Substance abuse, 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 any of the study drugs, study drug classes, or excipients in the formulation
  25. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
  26. Inability to swallow oral medications
  27. Any malabsorption condition
  28. Unresolved toxicity higher than CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin-induced neurotoxicity (which must be ≤Grade 2)
  29. Patients unable or unwilling to discontinue (and substitute if necessary) use of prohibited drugs for at least 30 days prior to Day 1 of FOLFIRI initiation (see Appendix B for list of prohibited drugs)
  30. Unwilling to provide consent for genetic studies of tumor, whole blood, or plasma specimens

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
ACTIVE_COMPARATOR: Regorafenib + FOLFIRI
regorafenib 160 mg + FOLFIRI
Drug: Regorafenib (BAY 73-4506)
Regorafenib, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle
Drug: FOLFIRI
FOLFIRI (Irinotecan,180 mg/m2 IV over 90 minutes; 5-Fluorouracil l400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours; Leucovorin 200-400c mg/m2 IV over 2 hours) Day 1 and Day 15 of each 28 day cycle.
Other Names:
  • FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin)
PLACEBO_COMPARATOR: Placebo + FOLFIRI
Drug: FOLFIRI
FOLFIRI (Irinotecan,180 mg/m2 IV over 90 minutes; 5-Fluorouracil l400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours; Leucovorin 200-400c mg/m2 IV over 2 hours) Day 1 and Day 15 of each 28 day cycle.
Other Names:
  • FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin)
Drug: Placebo
Placebo, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: 5.5 years
To compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients failing one prior oxaliplatin-containing regimen for metastatic colorectal cancer. PFS is defined as the time from randomization until metastatic colorectal cancer (mCRC) progression or death as a result of any cause. Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
5.5 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Overall Response(OR)Rate
Time Frame: 3 years
To compare overall response (OR) rates (OR= CR + PR) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
3 years
Disease Control (DC) Rate
Time Frame: 3 years
To compare Disease Control (DC) Rate (DC= CR + PR + SD) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions and Stable Disease (SD) ), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
3 years
Overall Survival (OS)
Time Frame: 5.5 years
To compare overall survival (OS) between ARM A and ARM B. OS is defined as the time from randomization until death as a result of any cause.
5.5 years
Drug Metabolism
Time Frame: 28 days
To compare the pharmacokinetic (PK) profile of FOLFIRI between a subset of patients receiving regorafenib (ARM A) and patients receiving placebo (Arm B). The Area Under the Curve (AUC) levels of the irinotecan metabolite SN-38 were compared.
28 days
Percentage of Patients With Severe Adverse Events
Time Frame: 3 years
Toxicity Assessments were made according to NCI CTCAE v. 4.0 . Severe events (grades 3-4) that occurred in a higher percentage of regorafenib treated participants as compared to placebo are reported below.
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
UNC Lineberger Comprehensive Cancer Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Bayer

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 7, 2011

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 15, 2016

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 2, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 16, 2011

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 16, 2011

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 17, 2011

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 6, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 10, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • LCCC 1029
  • 10-2176 (OTHER: UNC IRB)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Colorectal Cancer Metastatic

Clinical Trials on Regorafenib (BAY 73-4506)

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings