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Colorectal Cancer MetastaticPhase 2NCT01298570

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

A Phase 2 study testing Regorafenib (BAY 73-4506) and FOLFIRI in people with Colorectal Cancer Metastatic, run by UNC Lineberger Comprehensive Cancer Center at 24 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Colorectal Cancer Metastatic
What is being tested?
Regorafenib (BAY 73-4506) and FOLFIRI
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
181 participants
Where
24 sitesin 2 countries
Study dates
7 Apr 2011to 2 Oct 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Subject must meet all of the inclusion criteria to participate in this study:
  • Age ≥18 years of age (no upper age limit)
  • Histological or cytological documentation of adenocarcinoma of the colon or rectum
  • Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies required
  • Metastatic disease not amenable to surgical resection with curative intent
  • 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:
Show all 30Show fewer
  • 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
  • Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix C)
  • Life expectancy of at least 3 months
  • 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.
  • 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.
  • The subject is capable of understanding and complying with parameters as outlined in the protocol
  • Signed, Institutional Review Board (IRB)-approved written informed consent

Who cannot join

  • Any subject meeting any of the following exclusion criteria at baseline will be ineligible for study participation:
  • Prior treatment with regorafenib
  • 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.
  • Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator
  • 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.
  • History of Gilbert's syndrome
Show all 35Show fewer
  • Known Dihydropyrimidine dehydrogenase (DPD) deficiency
  • Pernicious anemia or other anemias due to vitamin B12 deficiency (due to potential masking of deficiency with leucovorin)
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of Day 1 of treatment with FOLFIRI
  • Radiotherapy within 4 weeks prior to first dose of FOLFIRI
  • 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)
  • Patients with pheochromocytoma
  • Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of FOLFIRI
  • Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0)
  • 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 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)
  • History of organ allograft
  • Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 4 within 4 weeks of start of FOLFIRI
  • Non-healing wound, ulcer, or bone fracture
  • Renal failure requiring hemo- or peritoneal dialysis
  • Dehydration according to NCI-CTC v 4.0 Grade >1
  • Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
  • Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
  • Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
  • Inability to swallow oral medications
  • Any malabsorption condition
  • 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)
  • 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)
  • Unwilling to provide consent for genetic studies of tumor, whole blood, or plasma specimens

Trial locations and contacts

24 sites in 2 countries.

24 sites in 2 countries

United States23 sites

  • Emory University

    Atlanta, Georgia, 30322

  • Georgia Cancer Specialists

    Atlanta, Georgia, 30341

  • Seby B. Jones Cancer Center

    Boone, North Carolina, 28607

  • University of North Carolina

    Chapel Hill, North Carolina, 27599

  • Carolinas HealthCare System

    Charlotte, North Carolina, 28262

  • University of Virginia

    Charlottesville, Virginia, 22903

  • University of Cincinnati

    Cincinnati, Ohio, 45267

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43221

  • Rocky Mountain Cancer Centers

    Denver, Colorado, 80218

  • Southeast Medical Oncology Center

    Goldsboro, North Carolina, 27534

  • The Moses Cone Regional Cancer Center

    Greensboro, North Carolina, 27403

  • Leo W. Jenkins Cancer Center at ECU Medical School

    Greenville, North Carolina, 27834

  • Indiana University Simon Cancer Center

    Indianapolis, Indiana, 46202

  • University of Louisville James Brown Cancer Center

    Louisville, Kentucky, 40202

  • North Shore Long Island Jewish Health System

    Manhasset, New York, 11030

  • Mount Sinai Medical Center-Miami

    Miami, Florida, 33140

  • New York University Langone Medical Center

    New York, New York, 10016

  • First Health of the Carolinas, Moore Regional Hospital

    Pinehurst, North Carolina, 28374

  • Portsmouth Naval Medical Center

    Portsmouth, Virginia, 23708

  • Rex Cancer Center at Rex Hospital

    Raleigh, North Carolina, 27607

  • Multicare Regional Cancer Center

    Tacoma, Washington, 98405

  • Moffitt Cancer Center

    Tampa, Florida, 33612

  • Wake Forest University Comprehensive Cancer Center

    Winston-Salem, North Carolina, 27157-1096

Other trials in United States

Ireland1 site

  • Ireland Cooperative Clinical Research Group

    Dublin

Other trials in Ireland

About this study

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

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.

Read the 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.

Being tested
Regorafenib (BAY 73-4506), FOLFIRI, Placebo
Keywords
Metastatic Colorectal Cancer, K-RAS mutation, BRAF mutation, Regorafenib, BAY 73-4506, FOLFIRI, Irinotecan, 5-FU, Leucovorin, Placebo, Phase II, Multi-Center, Randomized, Lineberger, North Carolina Cancer Hospital, UNC
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Regorafenib (BAY 73-4506)Drug

    Regorafenib, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle

  • FOLFIRIDrug

    Also called FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin)

    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.

  • PlaceboDrug

    Placebo, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle

  • FOLFIRIDrug

    Also called FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin)

    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.

Study groups in NCT01298570
Study groupRoleWhat they receive
Regorafenib + FOLFIRIActive comparatorregorafenib 160 mg + FOLFIRI
Receives: Drug: Regorafenib (BAY 73-4506); Drug: FOLFIRI
Placebo + FOLFIRIPlacebo comparatorPlacebo + FOLFIRI
Receives: Drug: Placebo; Drug: FOLFIRI

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression Free Survival (PFS)

    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.

    Measured: 5.5 years

Secondary outcomes (5)

  1. Overall Response(OR)Rate

    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.

    Measured: 3 years

  2. Disease Control (DC) Rate

    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.

    Measured: 3 years

  3. Overall Survival (OS)

    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.

    Measured: 5.5 years

  4. Drug Metabolism

    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.

    Measured: 28 days

  5. Percentage of Patients With Severe Adverse Events

    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.

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Feb 2011 (estimated)
  2. Study start7 Apr 2011
  3. Primary completion15 Nov 2016
  4. Study completion2 Oct 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
181 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01298570
Sponsor's protocol ID
LCCC 1029
Other IDs
10-2176
Status last verified
Dec 2020
First submitted
16 Feb 2011
Last updated
6 Jan 2021
Data monitoring committee
Yes

Publications

  • Quintanilha JCF, Geyer S, Etheridge AS, Racioppi A, Hammond K, Crona DJ, Pena CE, Jacobson SB, Marmorino F, Rossini D, Cremolini C, Sanoff HK, Abou-Alfa GK, Innocenti F. KDR genetic predictor of toxicities induced by sorafenib and regorafenib. Pharmacogenomics J. 2022 Dec;22(5-6):251-257. doi: 10.1038/s41397-022-00279-3. Epub 2022 Apr 28.

    PubMed 35484400

  • Schultheis B, Folprecht G, Kuhlmann J, Ehrenberg R, Hacker UT, Kohne CH, Kornacker M, Boix O, Lettieri J, Krauss J, Fischer R, Hamann S, Strumberg D, Mross KB. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol. 2013 Jun;24(6):1560-7. doi: 10.1093/annonc/mdt056. Epub 2013 Mar 13.

    PubMed 23493136

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Regorafenib (BAY 73-4506) and FOLFIRI in people with Colorectal Cancer Metastatic, run by UNC Lineberger Comprehensive Cancer Center at 24 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 30 inclusion and 35 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in United States, Ireland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Feb 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression Free Survival (PFS) (time frame: 5.5 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01298570, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jan 2021.

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