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

• Sponsor: UNC Lineberger Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01298570
• Collaborator: Bayer (Industry)
• Enrollment: 181
• Locations: 24
• Arms: 2
• Actual Duration (Months): 113.9
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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; Drug: FOLFIRI	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 Design

• Study Type: Interventional
• 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
• Actual Study Start Date: Apr 7, 2011
• Actual Primary Completion Date: Nov 15, 2016
• Actual Study Completion Date: Oct 2, 2020

Arms and Interventions

Arm	Intervention/Treatment
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 Placebo + FOLFIRI	Drug: Placebo; Placebo, 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)

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [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.

Secondary Outcome Measures

1. Overall Response(OR)Rate [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.

2. Disease Control (DC) Rate [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. Overall Survival (OS) [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.

4. Drug Metabolism [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.

5. Percentage of Patients With Severe Adverse Events [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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 (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

1. Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1.

2. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix C)

3. Life expectancy of at least 3 months

4. 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.

1. 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.

2. The subject is capable of understanding and complying with parameters as outlined in the protocol

3. 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)

1. Patients with pheochromocytoma

2. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of FOLFIRI

3. Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0)

4. Known history of human immunodeficiency virus (HIV) infection

5. Known history of chronic hepatitis B or C

6. Patients with seizure disorder requiring medication

7. 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)

8. History of organ allograft

9. Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 4 within 4 weeks of start of FOLFIRI

10. Non-healing wound, ulcer, or bone fracture

11. Renal failure requiring hemo- or peritoneal dialysis

12. Dehydration according to NCI-CTC v 4.0 Grade >1

13. Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results

14. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation

15. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent

16. Inability to swallow oral medications

17. Any malabsorption condition

18. 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)

19. 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)

20. Unwilling to provide consent for genetic studies of tumor, whole blood, or plasma specimens

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rocky Mountain Cancer Centers	Denver	Colorado	United States	80218
2	Mount Sinai Medical Center-Miami	Miami	Florida	United States	33140
3	Moffitt Cancer Center	Tampa	Florida	United States	33612
4	Emory University	Atlanta	Georgia	United States	30322
5	Georgia Cancer Specialists	Atlanta	Georgia	United States	30341
6	Indiana University Simon Cancer Center	Indianapolis	Indiana	United States	46202
7	University of Louisville James Brown Cancer Center	Louisville	Kentucky	United States	40202
8	North Shore Long Island Jewish Health System	Manhasset	New York	United States	11030
9	New York University Langone Medical Center	New York	New York	United States	10016
10	Seby B. Jones Cancer Center	Boone	North Carolina	United States	28607
11	University of North Carolina	Chapel Hill	North Carolina	United States	27599
12	Carolinas HealthCare System	Charlotte	North Carolina	United States	28262
13	Southeast Medical Oncology Center	Goldsboro	North Carolina	United States	27534
14	The Moses Cone Regional Cancer Center	Greensboro	North Carolina	United States	27403
15	Leo W. Jenkins Cancer Center at ECU Medical School	Greenville	North Carolina	United States	27834
16	First Health of the Carolinas, Moore Regional Hospital	Pinehurst	North Carolina	United States	28374
17	Rex Cancer Center at Rex Hospital	Raleigh	North Carolina	United States	27607
18	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
19	University of Cincinnati	Cincinnati	Ohio	United States	45267
20	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43221
21	University of Virginia	Charlottesville	Virginia	United States	22903
22	Portsmouth Naval Medical Center	Portsmouth	Virginia	United States	23708
23	Multicare Regional Cancer Center	Tacoma	Washington	United States	98405
24	Ireland Cooperative Clinical Research Group	Dublin		Ireland

Sponsors and Collaborators

• UNC Lineberger Comprehensive Cancer Center
• Bayer

Investigators

• Principal Investigator: Hanna Sanoff, MD, UNC Lineberger Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lineberger Comprehensive Cancer Center website

Publications

None provided.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01298570
• Other Study ID Numbers: LCCC 1029; 10-2176
• First Posted: Feb 17, 2011
• Last Update Posted: Jan 6, 2021
• Last Verified: Dec 1, 2020

• Keywords provided by UNC Lineberger Comprehensive Cancer Center: 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
• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Fluorouracil; Irinotecan; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	224 participants were consented to the study from 39 institutions from 4/7/11 - 8/10/15.
Pre-assignment Detail	30 participants were ineligible, 7 withdrew prior to beginning protocol therapy, 3 could not participate due to study closure, 2 were unable to participate for financial reasons, 1 did not provide a reason for non-participation; 181 patients were enrolled and went on treatment.

Arm/Group Title	Arm A	Arm B
Arm/Group Description	regorafenib 160 mg + FOLFIRI Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle 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.	Placebo + FOLFIRI Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle + 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.
Period Title: Overall Study
STARTED	120	61
COMPLETED	0	0
NOT COMPLETED	120	61

Baseline Characteristics

Arm/Group Title	Arm A	Arm B	Total
Arm/Group Description	regorafenib 160 mg + FOLFIRI Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle 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.	Placebo + FOLFIRI Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle + 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.	Total of all reporting groups
Overall Participants	120	61	181
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62	62	62
Sex: Female, Male (Count of Participants)
Female	52 43.3%	29 47.5%	81 44.8%
Male	68 56.7%	32 52.5%	100 55.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	20 16.7%	11 18%	31 17.1%
White	99 82.5%	48 78.7%	147 81.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.8%	2 3.3%	3 1.7%
Region of Enrollment (count of participants) [Number]
United States	84 70%	43 70.5%	127 70.2%
Ireland	36 30%	18 29.5%	54 29.8%
ECOG Performance Status (Count of Participants)
0	52 43.3%	23 37.7%	75 41.4%
1	68 56.7%	38 62.3%	106 58.6%
Stage at diagnosis (Count of Participants)
I	3 2.5%	0 0%	3 1.7%
II	4 3.3%	4 6.6%	8 4.4%
III	24 20%	11 18%	35 19.3%
IV	86 71.7%	46 75.4%	132 72.9%
Unknown	3 2.5%	0 0%	3 1.7%
Prior Biologic Agent (Count of Participants)
None	33 27.5%	16 26.2%	49 27.1%
Bevacizumab	76 63.3%	41 67.2%	117 64.6%
EGFR inhibitor	11 9.2%	4 6.6%	15 8.3%
Locally Reported RAS (Count of Participants)
Wildtype	49 40.8%	18 29.5%	67 37%
Mutated	54 45%	37 60.7%	91 50.3%
Unknown	17 14.2%	6 9.8%	23 12.7%
Locally Reported BRAF (Count of Participants)
Wildtype	22 18.3%	12 19.7%	34 18.8%
Mutated	10 8.3%	2 3.3%	12 6.6%
Unknown	88 73.3%	47 77%	135 74.6%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	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.
Time Frame	5.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B
Arm/Group Description	regorafenib 160 mg + FOLFIRI Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle 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.	Placebo + FOLFIRI Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle + 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.
Measure Participants	120	61
Median (95% Confidence Interval) [Months]	6.1	5.3

2. Secondary Outcome

Title	Overall Response(OR)Rate
Description	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.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

Only evaluable participants (those who had RECIST measurements after baseline) were included in this analysis

Arm/Group Title	Arm A	Arm B
Arm/Group Description	regorafenib 160 mg + FOLFIRI Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle 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.	Placebo + FOLFIRI Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle + 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.
Measure Participants	102	58
Complete Response (CR)	0 0%	0 0%
Partial Response (PR)	35 29.2%	12 19.7%
Other	67 55.8%	46 75.4%

3. Secondary Outcome

Title	Disease Control (DC) Rate
Description	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.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

Only evaluable participants (those who had RECIST measurements after baseline) were included in this analysis

Arm/Group Title	Arm A	Arm B
Arm/Group Description	regorafenib 160 mg + FOLFIRI Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle 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.	Placebo + FOLFIRI Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle + 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.
Measure Participants	102	58
Disease Control Total (CR+PR+SD)	84 70%	43 70.5%
Progression	18 15%	15 24.6%

4. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	5.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B
Arm/Group Description	regorafenib 160 mg + FOLFIRI Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle 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.	Placebo + FOLFIRI Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle + 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.
Measure Participants	120	61
Median (Full Range) [Months]	13.8	11.7

5. Secondary Outcome

Title	Drug Metabolism
Description	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.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

This objective was designed to only look at a small subset of participants (11 on each arm)

Arm/Group Title	Arm A	Arm B
Arm/Group Description	regorafenib 160 mg + FOLFIRI Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle 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.	Placebo + FOLFIRI Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle + 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.
Measure Participants	11	11
Cycle 1	0.68	0.63
Cycle 2	0.59	0.72

6. Secondary Outcome

Title	Percentage of Patients With Severe Adverse Events
Description	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.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

All patients who received treatment

Arm/Group Title	Arm A	Arm B
Arm/Group Description	regorafenib 160 mg + FOLFIRI Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle 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.	Placebo + FOLFIRI Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle + 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.
Measure Participants	120	61
neutropenia	41 34.2%	30 49.2%
diarrhea	15 12.5%	5 8.2%
hypophosphatemia	14 11.7%	0 0%
hypertension	8 6.7%	2 3.3%
elevated lipase	8 6.7%	3 4.9%

Adverse Events

Arm/Group Title	Arm A		Arm B
Arm/Group Description	regorafenib 160 mg + FOLFIRI Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle 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.		Placebo + FOLFIRI Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle + 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.
All Cause Mortality
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/120 (93.3%)		59/61 (96.7%)
Serious Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/120 (50%)		20/61 (32.8%)
Blood and lymphatic system disorders
Anemia	2/120 (1.7%)		3/61 (4.9%)
Febrile neutropenia	7/120 (5.8%)		3/61 (4.9%)
Cardiac disorders
Chest pain - cardiac	2/120 (1.7%)		1/61 (1.6%)
Atrial fibrillation	1/120 (0.8%)		0/61 (0%)
Sinus bradicardia	1/120 (0.8%)		0/61 (0%)
Left ventricular systolic dysfunction	1/120 (0.8%)		0/61 (0%)
Palpitations	1/120 (0.8%)		0/61 (0%)
Ventricular tachycardia	1/120 (0.8%)		0/61 (0%)
Endocrine disorders
Hypothyroidism	0/120 (0%)		1/61 (1.6%)
Gastrointestinal disorders
Abdominal pain	9/120 (7.5%)		2/61 (3.3%)
Ascites	0/120 (0%)		1/61 (1.6%)
Colitis	1/120 (0.8%)		0/61 (0%)
Constipation	1/120 (0.8%)		2/61 (3.3%)
Colonic hemorrhage	1/120 (0.8%)		0/61 (0%)
Colonic obstruction	1/120 (0.8%)		0/61 (0%)
Colonic perforation	1/120 (0.8%)		0/61 (0%)
Diarrhea	10/120 (8.3%)		1/61 (1.6%)
Esophageal varices hemorrhage	0/120 (0%)		1/61 (1.6%)
Ileus	3/120 (2.5%)		0/61 (0%)
Mucositis oral	3/120 (2.5%)		1/61 (1.6%)
Nausea	2/120 (1.7%)		1/61 (1.6%)
Vomiting	0/120 (0%)		2/61 (3.3%)
Rectal hemorrhage	4/120 (3.3%)		0/61 (0%)
Small intestinal perforation	1/120 (0.8%)		0/61 (0%)
General disorders
Chills	0/120 (0%)		1/61 (1.6%)
Death NOS	2/120 (1.7%)		2/61 (3.3%)
Fatigue	2/120 (1.7%)		1/61 (1.6%)
Fever	9/120 (7.5%)		3/61 (4.9%)
flu like symptoms	1/120 (0.8%)		0/61 (0%)
Pressure in Head	1/120 (0.8%)		0/61 (0%)
Rigors	1/120 (0.8%)		0/61 (0%)
Generalized muscle weakness	1/120 (0.8%)		0/61 (0%)
Pain	1/120 (0.8%)		1/61 (1.6%)
Infusion related reaction	1/120 (0.8%)		0/61 (0%)
Non-cardiac chest pain	1/120 (0.8%)		0/61 (0%)
Hepatobiliary disorders
Cholecystitis	3/120 (2.5%)		1/61 (1.6%)
Hepatic failure	1/120 (0.8%)		0/61 (0%)
Cholangitis	1/120 (0.8%)		0/61 (0%)
Infections and infestations
Abdominal infection	1/120 (0.8%)		0/61 (0%)
Anorectal infection	0/120 (0%)		1/61 (1.6%)
Catheter related infection	1/120 (0.8%)		0/61 (0%)
Cecal infection	1/120 (0.8%)		0/61 (0%)
Enterocolitis infectious	0/120 (0%)		1/61 (1.6%)
Infections and infestations - Other, specify	0/120 (0%)		1/61 (1.6%)
Lung infection	0/120 (0%)		1/61 (1.6%)
Skin infection	0/120 (0%)		1/61 (1.6%)
Urinary tract infection	0/120 (0%)		1/61 (1.6%)
Infection of unknown source	1/120 (0.8%)		0/61 (0%)
Lung infection	2/120 (1.7%)		0/61 (0%)
Sepsis	2/120 (1.7%)		0/61 (0%)
Soft tissue infection	2/120 (1.7%)		0/61 (0%)
Upper respiratory infection	1/120 (0.8%)		0/61 (0%)
Injury, poisoning and procedural complications
Fall	2/120 (1.7%)		0/61 (0%)
Intestinal stoma site bleeding	1/120 (0.8%)		0/61 (0%)
Stomal ulcer	1/120 (0.8%)		0/61 (0%)
Investigations
Alanine aminotransferase increased	1/120 (0.8%)		0/61 (0%)
Alkaline phosphatase increased	1/120 (0.8%)		0/61 (0%)
Aspartate aminotransferase increased	1/120 (0.8%)		0/61 (0%)
Blood bilirubin increased	1/120 (0.8%)		0/61 (0%)
GGT increased	1/120 (0.8%)		0/61 (0%)
Obstructive Jaundice	1/120 (0.8%)		0/61 (0%)
Deteriorating LFT's	1/120 (0.8%)		0/61 (0%)
Elevated INR	1/120 (0.8%)		0/61 (0%)
Neutrophil count decreased	6/120 (5%)		0/61 (0%)
Platelet count decreased	2/120 (1.7%)		0/61 (0%)
Metabolism and nutrition disorders
Anorexia	3/120 (2.5%)		1/61 (1.6%)
Dehydration	5/120 (4.2%)		3/61 (4.9%)
Hypoalbuminemia	1/120 (0.8%)		0/61 (0%)
severely elevated lipase level	1/120 (0.8%)		0/61 (0%)
Malnutrician	1/120 (0.8%)		0/61 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/120 (0.8%)		0/61 (0%)
Muscle weakness lower limb	0/120 (0%)		1/61 (1.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/120 (0.8%)		0/61 (0%)
Nervous system disorders
Headache	1/120 (0.8%)		0/61 (0%)
Movements involuntary	0/120 (0%)		1/61 (1.6%)
Syncope	1/120 (0.8%)		0/61 (0%)
Psychiatric disorders
Insomnia	1/120 (0.8%)		0/61 (0%)
Psychosis	1/120 (0.8%)		0/61 (0%)
Renal and urinary disorders
Acute kidney injury	1/120 (0.8%)		0/61 (0%)
Reproductive system and breast disorders
Pelvic pain	0/120 (0%)		1/61 (1.6%)
Respiratory, thoracic and mediastinal disorders
Aspiration	0/120 (0%)		1/61 (1.6%)
Cough	1/120 (0.8%)		0/61 (0%)
Dyspnea	3/120 (2.5%)		1/61 (1.6%)
Pneumonitis	0/120 (0%)		1/61 (1.6%)
Pleural effusion	1/120 (0.8%)		0/61 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/120 (0.8%)		0/61 (0%)
Palmar-plantar erythrodysesthesia syndrome	1/120 (0.8%)		0/61 (0%)
right hip abscess	1/120 (0.8%)		0/61 (0%)
Surgical and medical procedures
Surgical and medical procedures - Other, specify	0/120 (0%)		1/61 (1.6%)
Vascular disorders
Hypertension	1/120 (0.8%)		0/61 (0%)
Thromboembolic event	3/120 (2.5%)		2/61 (3.3%)
Other (Not Including Serious) Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	118/120 (98.3%)		61/61 (100%)
Blood and lymphatic system disorders
Anemia	67/120 (55.8%)		38/61 (62.3%)
Febrile neutropenia	7/120 (5.8%)		1/61 (1.6%)
Cardiac disorders
Sinus tachycardia	6/120 (5%)		2/61 (3.3%)
Endocrine disorders
Hypothyroidism	8/120 (6.7%)		1/61 (1.6%)
Gastrointestinal disorders
Abdominal pain	41/120 (34.2%)		9/61 (14.8%)
Constipation	41/120 (34.2%)		17/61 (27.9%)
Diarrhea	63/120 (52.5%)		28/61 (45.9%)
Dysgeusia	6/120 (5%)		2/61 (3.3%)
Dyspepsia	9/120 (7.5%)		1/61 (1.6%)
Dysphagia	6/120 (5%)		1/61 (1.6%)
Hemorrhoids	10/120 (8.3%)		2/61 (3.3%)
Mucositis oral	65/120 (54.2%)		20/61 (32.8%)
Nausea	60/120 (50%)		34/61 (55.7%)
Oral pain	8/120 (6.7%)		0/61 (0%)
Rectal pain	10/120 (8.3%)		1/61 (1.6%)
Vomiting	40/120 (33.3%)		10/61 (16.4%)
General disorders
Edema limbs	5/120 (4.2%)		4/61 (6.6%)
Fatigue	76/120 (63.3%)		33/61 (54.1%)
Fever	18/120 (15%)		3/61 (4.9%)
Flu like symptoms	7/120 (5.8%)		1/61 (1.6%)
Pain	26/120 (21.7%)		4/61 (6.6%)
Infections and infestations
Urinary tract infection	11/120 (9.2%)		3/61 (4.9%)
Investigations
Activated partial thromboplastin time prolonged	7/120 (5.8%)		3/61 (4.9%)
Alanine aminotransferase increased	30/120 (25%)		9/61 (14.8%)
Alkaline phosphatase increased	35/120 (29.2%)		14/61 (23%)
Aspartate aminotransferase increased	28/120 (23.3%)		10/61 (16.4%)
Blood bilirubin increased	22/120 (18.3%)		4/61 (6.6%)
Creatinine increased	6/120 (5%)		5/61 (8.2%)
INR increased	6/120 (5%)		5/61 (8.2%)
Lipase increased	21/120 (17.5%)		13/61 (21.3%)
Lymphocyte count decreased	15/120 (12.5%)		11/61 (18%)
Neutrophil count decreased	69/120 (57.5%)		36/61 (59%)
Platelet count decreased	34/120 (28.3%)		9/61 (14.8%)
Serum amylase increased	16/120 (13.3%)		8/61 (13.1%)
Weight loss	27/120 (22.5%)		5/61 (8.2%)
White blood cell decreased	35/120 (29.2%)		23/61 (37.7%)
Metabolism and nutrition disorders
Anorexia	43/120 (35.8%)		7/61 (11.5%)
Dehydration	15/120 (12.5%)		5/61 (8.2%)
Hyperglycemia	17/120 (14.2%)		16/61 (26.2%)
Hypertriglyceridemia	25/120 (20.8%)		19/61 (31.1%)
Hypoalbuminemia	37/120 (30.8%)		14/61 (23%)
Hyperuricemia	5/120 (4.2%)		7/61 (11.5%)
Hypocalcemia	29/120 (24.2%)		10/61 (16.4%)
Hypokalemia	40/120 (33.3%)		19/61 (31.1%)
Hypomagnesemia	16/120 (13.3%)		9/61 (14.8%)
Hyponatremia	20/120 (16.7%)		13/61 (21.3%)
Hypophosphatemia	38/120 (31.7%)		6/61 (9.8%)
Musculoskeletal and connective tissue disorders
Back pain	12/120 (10%)		4/61 (6.6%)
Bone pain	6/120 (5%)		0/61 (0%)
Pain in extremity	8/120 (6.7%)		3/61 (4.9%)
Nervous system disorders
Dizziness	9/120 (7.5%)		1/61 (1.6%)
Headache	24/120 (20%)		6/61 (9.8%)
Peripheral sensory neuropathy	28/120 (23.3%)		8/61 (13.1%)
Psychiatric disorders
Anxiety	6/120 (5%)		1/61 (1.6%)
Depression	9/120 (7.5%)		5/61 (8.2%)
Insomnia	13/120 (10.8%)		3/61 (4.9%)
Renal and urinary disorders
Hematuria	9/120 (7.5%)		3/61 (4.9%)
Proteinuria	18/120 (15%)		14/61 (23%)
Respiratory, thoracic and mediastinal disorders
Cough	15/120 (12.5%)		4/61 (6.6%)
Dyspnea	22/120 (18.3%)		7/61 (11.5%)
Epistaxis	9/120 (7.5%)		2/61 (3.3%)
Hoarseness	15/120 (12.5%)		0/61 (0%)
Sore throat	11/120 (9.2%)		1/61 (1.6%)
Skin and subcutaneous tissue disorders
Alopecia	30/120 (25%)		15/61 (24.6%)
Dry skin	15/120 (12.5%)		5/61 (8.2%)
Palmar-plantar erythrodysesthesia syndrome	35/120 (29.2%)		6/61 (9.8%)
Rash maculo-papular	18/120 (15%)		5/61 (8.2%)
Rash acneiform	12/120 (10%)		2/61 (3.3%)
Vascular disorders
Hypertension	23/120 (19.2%)		9/61 (14.8%)
Hypotension	10/120 (8.3%)		3/61 (4.9%)
Thromboembolic event	10/120 (8.3%)		1/61 (1.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.