We updated the design of this site on December 18, 2017. Learn more.
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01298570
Recruitment Status : Active, not recruiting
First Posted : February 17, 2011
Last Update Posted : March 21, 2017
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Metastatic Drug: Regorafenib (BAY 73-4506) Drug: FOLFIRI Drug: Placebo Phase 2

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 : Interventional  (Clinical Trial)
Actual Enrollment : 181 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : February 2011
Primary Completion Date : November 15, 2016
Estimated Study Completion Date : February 2021

Resource links provided by the National Library of Medicine

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

Arm Intervention/treatment
Active Comparator: Arm A
regorafenib 160 mg + FOLFIRI
Drug: Regorafenib (BAY 73-4506)
Regorafenib, 160 mg, PO, daily, per 7 day cycle
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 Name: FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin)
Placebo Comparator: Arm B
Placebo + FOLFIRI
Drug: Placebo
Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle +
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 Name: FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin)

Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 7 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

Secondary Outcome Measures :
  1. Overall Response(OR)rate [ Time Frame: 7 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)

  2. disease control (DC) rate [ Time Frame: 7 years ]
    To compare the disease control (DC) rate (DC; CR + PR + SD) between ARM A and ARM B as defined via RECIST 1.1

  3. Overall Survival (OS) [ Time Frame: 7 years ]
    To compare overall survival (OS) between ARM A and ARM B

  4. Drug Metabolism [ Time Frame: 3 years ]
    To evaluate the PK profile of irinotecan in a subset of patients receiving regorafenib (ARM A)

  5. Toxicity Assessments According to NCI CTCAE v. 4.0 [ Time Frame: 5 years ]
    Specific to this trial of regorafenib and FOLFIRI, special attention should be paid to any overlaps in toxicity. The most frequent toxicities caused by 5-fluorouracil (5-FU) are myelosuppression, nausea, vomiting, diarrhea, mucositis, alopecia, and HFSR.Based upon the nonclinical and clinical toxicology data, patients on regorafenib should be monitored closely for liver, kidney, thyroid, bone marrow, blood coagulation, and pancreas function.The dose-limiting toxicities (DLTs) of irinotecan are myelosuppression (primarily neutropenia) and diarrhea.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

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 (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.


    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)
    • AST and 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
    • INR/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, 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 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

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): NCT01298570

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

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01298570     History of Changes
Other Study ID Numbers: LCCC 1029
10-2176 ( Other Identifier: UNC IRB )
First Posted: February 17, 2011    Key Record Dates
Last Update Posted: March 21, 2017
Last Verified: March 2017

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
Metastatic Colorectal Cancer
K-RAS mutation
BRAF mutation
BAY 73-4506
Phase II
North Carolina Cancer Hospital

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
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs