First Line Treatment of Metastatic Colorectal Cancer With mFOLFOX6 in Combination With Regorafenib

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01289821
• Collaborator: (none)
• Enrollment: 54
• Locations: 18
• Arm: 1
• Duration (Months): 40
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a study to evaluate the efficacy (effectiveness) and the safety of regorafenib when given in combination with chemotherapy mFOLFOX6 as first line therapy in patients with metastatic colorectal cancer (CRC). mFOLFOX6 is an approved chemotherapy. Regorafenib is an oral (i.e. taken by mouth) multi-targeted kinase inhibitor. A kinase inhibitor targets certain key proteins that are essential for the survival of the cancer cell. By specifically targeting these proteins, regorafenib may stop cancer growth. The growth of the tumor may be decreased by preventing these specific proteins from functioning.

The primary endpoint (the most meaningful result to be tracked) of this study is based on the rate of response, i.e. the disease getting smaller. The aim is to show that the therapy of colorectal cancer with mFOLFOX6 in combination with regorafenib improves the response rate observed for the standard therapy only.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Neoplasms	Drug: Regorafenib (Stivarga, BAY73-4506); Drug: Oxaliplatin; Drug: Folinic acid; Drug: 5-FU (mFOLFOX6)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Uncontrolled, Open-label, Phase II Study in Subjects With Metastatic Adenocarcinoma of the Colon or Rectum Who Are Receiving First Line Chemotherapy With mFOLFOX6 (Oxaliplatin/ Folinic Acid/5-fluorouracil [5-FU]) in Combination With Regorafenib
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Regorafenib + oxaliplatin/folinic acid/5-FU (mFOLFOX6) On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.

Drug: Regorafenib (Stivarga, BAY73-4506); Subjects will receive regorafenib 160 mg od on days 4 to 10 and days 18 to 24 as four 40 mg coprecipitate tablets. In case of administration as a single agent during the study, regorafenib will be administered 160 mg od for 3 weeks on/1 week off. Each cycle consists of 28 days.; Drug: Oxaliplatin; On day 1 and day 15 of each cycle, participants will receive 85 mg/m^2 oxaliplatin as a 2 hour i.v. infusion.; Drug: Folinic acid; On day 1 and day 15 of each cycle, participants will receive folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2 hour i.v. infusion.; Drug: 5-FU (mFOLFOX6); Participants will receive a 400 mg/m^2 5 FU i.v. bolus injection immediately followed by a 2400 mg/m^2 5 FU 46 hour i.v. infusion.

Outcome Measures

Primary Outcome Measures

1. Objective Response (OR) [From start of treatment until 30 days after termination of study medication, an average of 47 weeks. Assessed every 8 weeks.]

   OR was defined as the best tumor response (confirmed complete response [CR] or partial response [PR]) observed by MRI or CT scan assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. CR and PR were confirmed not earlier than 4 weeks following the initial detection of response. CR = Disappearance of all clinical and radiological evidence of tumor (both target and no-target). Any pathological lymph nodes (whether target or non target) must have a reduction in short axis to < 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing nontarget lesions and no appearance of new lesions.

Secondary Outcome Measures

1. Overall Survival (OS) [From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks]

   OS was calculated as the time from first date of receiving study treatment to date of death due to any cause. Participants alive at the time of analysis were censored at their last date of follow-up.

2. Progression-free Survival (PFS) [From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks]

   PFS was defined as time from the date of start of study treatment to the date of first observed disease progression (radiological according to central assessment or clinical), or death due to any cause, if death occurred before progression was documented. PFS for participants without disease progression or death at the date of database cutoff were right-censored at the last date of tumor assessment. Participants who had no tumor evaluation after baseline and no clinical progression post baseline and who did not die were censored at Day 1 in the analysis. PD = At least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non target lesions or the appearance of one or more new lesions will also constitute PD.

3. Disease Control (DC) [From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks]

   DC was defined as the proportion of participants who had a best response rating of CR, PR, or stable disease (SD) according to RECIST criteria that was achieved during treatment or within 30 days after termination of study treatment. CR and PR were confirmed not earlier than 4 weeks following the initial detection of response. A minimum of 8 weeks (allowing a minus 7-day time window) between start of study treatment and the first follow-up tumor assessment with SD as response was required to assign SD as best overall response.

4. Duration of Response (DOR) [From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks]

   DOR was defined as the time from the date of first documented objective response of PR or CR, whichever was noted earlier, to first subsequent disease progression or death (if death occurred before progression was documented). DOR was defined for responders only (that is, subjects with CR or PR). DOR for subjects without disease progression or death before progression was right censored at the date of their last tumor assessment.

5. Duration of Stable Disease (DOSD) [From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks]

   DOSD was only evaluated in participants failing to achieve a best response of CR or PR, but who achieved SD. DOSR was defined as the time (in days) from date of start of study treatment to the date at which disease progression or death (if death occurred before progression was first documented). The date the tumor scan was performed was used for this calculation. DOSD for participants without disease progression or death before progression at the time of analysis were censored at the date of their last tumor assessment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female subjects aged ≥ 18 years

• Histological or cytological documentation of adenocarcinoma of the colon or rectum

• Suitable to receive mFOLFOX6 regimen as first line metastatic treatment

• At least 1 measurable lesion as per RECIST version 1.1

• Unresectable or unlikely becoming resectable metastatic disease

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Life expectancy of at least 3 months

• Adequate bone marrow, liver, and renal function

Exclusion Criteria:

• Prior systemic anticancer therapy for metastatic colorectal cancer (CRC). Adjuvant chemotherapy for CRC (Stage I, II, III) is permitted, if the adjuvant therapy ended > 6 months before screening and recurrent disease was documented.

• Prior treatment with antivascular endothelial growth factor (anti-VEGF) agents and any signal transduction inhibitors (STIs)

• Uncontrolled hypertension

• Subjects with symptoms, signs, or history of brain metastases

• Any hemorrhage or bleeding event ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 within 4 weeks of start of study treatment

• Sensory neuropathy (> CTCAE Grade 1), unresolved toxicity > CTCAE Grade 1 attributed to any prior therapy/procedure excluding alopecia

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Chicago	Illinois	United States	60611-2906
2		Concord	New South Wales	Australia	2139
3		Woodville South	South Australia	Australia	5011
4		Bruxelles - Brussel		Belgium	1070
5		Edegem		Belgium	2650
6		Leuven		Belgium	3000
7		Stuttgart	Baden-Württemberg	Germany	70199
8		Oldenburg	Niedersachsen	Germany	26133
9		Herne	Nordrhein-Westfalen	Germany	44625
10		Dresden	Sachsen	Germany	01307
11		Napoli	Campania	Italy	80131
12		Genova	Liguria	Italy	16132
13		Ancona	Marche	Italy	60126
14		Santander	Cantabria	Spain	39008
15		Barcelona		Spain	08035
16		Madrid		Spain	28034
17		Glasgow		United Kingdom	G12 0YN
18		Manchester		United Kingdom	M20 4BX

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01289821
• Other Study ID Numbers: 11728; 2010-020121-41
• First Posted: Feb 4, 2011
• Last Update Posted: Mar 15, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Folic Acid; Oxaliplatin; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	Male or female participants with histological or cytological documentation of adenocarcinoma of the colon or rectum that was unresectable or unlikely of becomining resectable, who were at least 18 years of age and were suitable to receive mFOLFOX6 regimen as first line treatment could participate in this study at 16 centers in 7 countries.
Pre-assignment Detail	Of 66 enrolled participants, 54 received study medication, 4 withdrew consent during screening, and 8 were screen failures due to no measurable lesion, not suitable to receive mFOLFOX as 1st line regimen (2), uncontrolled hypertension, symptoms/signs/history of brain metastases, glomerular filtration rate too low (2), and protein in spot urine

Arm/Group Title	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
Arm/Group Description	On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.
Period Title: Treatment Period
STARTED	54
Participants Received Regorafenib	54
COMPLETED	0
NOT COMPLETED	54
Period Title: Treatment Period
STARTED	54
COMPLETED	49
NOT COMPLETED	5
Period Title: Treatment Period
STARTED	52
COMPLETED	34
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
Arm/Group Description	On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.
Overall Participants	54
Age, Customized (Number) [Number]
< 65 years	33 61.1%
65 - 75 years	18 33.3%
> 75 years	3 5.6%
Sex/Gender, Customized (Paricipants) [Number]
Female	26
Male	28
Caucasian (Number) [Number]
Number [Participants]	54 100%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at study entry (Number) [Number]
0	35 64.8%
1	19 35.2%
Stage at initial diagnosis (Number) [Number]
I	1 1.9%
IIA	5 9.3%
IIIB	3 5.6%
IIIC	4 7.4%
IV	41 75.9%

Outcome Measures

1. Primary Outcome

Title	Objective Response (OR)
Description	OR was defined as the best tumor response (confirmed complete response [CR] or partial response [PR]) observed by MRI or CT scan assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. CR and PR were confirmed not earlier than 4 weeks following the initial detection of response. CR = Disappearance of all clinical and radiological evidence of tumor (both target and no-target). Any pathological lymph nodes (whether target or non target) must have a reduction in short axis to < 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing nontarget lesions and no appearance of new lesions.
Time Frame	From start of treatment until 30 days after termination of study medication, an average of 47 weeks. Assessed every 8 weeks.

Outcome Measure Data

Analysis Population Description

Primary analysis set (PAS, N=41) was a subset of the PPS and included the first 41 subjects, who were assigned to treatment

Arm/Group Title	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
Arm/Group Description	On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.
Measure Participants	41
Number [Proportion of participants]	0.4390 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
	Comments	Null hypothesis: "True probability p of objective tumor response does not exceed p0, p0=0.4." H0: p<=0.4 One-sided type I error probability of alpha=10%
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	One-sample exact binomial test
	Comments
Method of Estimation	Estimation Parameter	Percentage of Participants
	Estimated Value	43.90
	Confidence Interval	(2-Sided) 80%; 33.19 to 55.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was calculated as the time from first date of receiving study treatment to date of death due to any cause. Participants alive at the time of analysis were censored at their last date of follow-up.
Time Frame	From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS, N=54) included all subjects who received treatment.

Arm/Group Title	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
Arm/Group Description	On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.
Measure Participants	54
Median (95% Confidence Interval) [Days]	772

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was defined as time from the date of start of study treatment to the date of first observed disease progression (radiological according to central assessment or clinical), or death due to any cause, if death occurred before progression was documented. PFS for participants without disease progression or death at the date of database cutoff were right-censored at the last date of tumor assessment. Participants who had no tumor evaluation after baseline and no clinical progression post baseline and who did not die were censored at Day 1 in the analysis. PD = At least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non target lesions or the appearance of one or more new lesions will also constitute PD.
Time Frame	From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS)

Arm/Group Title	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
Arm/Group Description	On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.
Measure Participants	54
Median (95% Confidence Interval) [Days]	258

4. Secondary Outcome

Title	Disease Control (DC)
Description	DC was defined as the proportion of participants who had a best response rating of CR, PR, or stable disease (SD) according to RECIST criteria that was achieved during treatment or within 30 days after termination of study treatment. CR and PR were confirmed not earlier than 4 weeks following the initial detection of response. A minimum of 8 weeks (allowing a minus 7-day time window) between start of study treatment and the first follow-up tumor assessment with SD as response was required to assign SD as best overall response.
Time Frame	From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks

Outcome Measure Data

Analysis Population Description

PAS

Arm/Group Title	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
Arm/Group Description	On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.
Measure Participants	41
Number [Proportion of participants]	0.8537 1.6%

5. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR was defined as the time from the date of first documented objective response of PR or CR, whichever was noted earlier, to first subsequent disease progression or death (if death occurred before progression was documented). DOR was defined for responders only (that is, subjects with CR or PR). DOR for subjects without disease progression or death before progression was right censored at the date of their last tumor assessment.
Time Frame	From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol set (PPS)

Arm/Group Title	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
Arm/Group Description	On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.
Measure Participants	20
Median (95% Confidence Interval) [Days]	257

6. Secondary Outcome

Title	Duration of Stable Disease (DOSD)
Description	DOSD was only evaluated in participants failing to achieve a best response of CR or PR, but who achieved SD. DOSR was defined as the time (in days) from date of start of study treatment to the date at which disease progression or death (if death occurred before progression was first documented). The date the tumor scan was performed was used for this calculation. DOSD for participants without disease progression or death before progression at the time of analysis were censored at the date of their last tumor assessment.
Time Frame	From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks

Outcome Measure Data

Analysis Population Description

Per protocol set (PPS)

Arm/Group Title	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
Arm/Group Description	On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.
Measure Participants	22
Median (95% Confidence Interval) [Days]	231

Adverse Events

Time Frame	From start of study treatment until 4 weeks following the last dose of study treatment.
Adverse Event Reporting Description	Of 54 treated subjects, 53 subjects were valid for safety population. One subject was excluded from the SAF. The reason for the exclusion "never received regorafenib" is only enumerated once, under the reasons for exclusion from the SAF.
Arm/Group Title	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
Arm/Group Description	On Day 1, participants received 85 mg/m2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m2 D/L folinic acid or 200 mg/m2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m2 IV bolus injection immediately followed by a 5-FU 2400 mg/m2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days.
All Cause Mortality
	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
	Affected / at Risk (%)	# Events
Total	25/53 (47.2%)
Blood and lymphatic system disorders
Febrile neutropenia	1/53 (1.9%)	1
Lymph node pain	1/53 (1.9%)	1
Cardiac disorders
Acute coronary syndrome	1/53 (1.9%)	1
Atrial fibrillation	1/53 (1.9%)	1
Atrial flutter	1/53 (1.9%)	2
Gastrointestinal disorders
Abdominal pain	1/53 (1.9%)	1
Colonic obstruction	1/53 (1.9%)	1
Constipation	1/53 (1.9%)	1
Diarrhea	3/53 (5.7%)	3
Gastrointestinal disorders - Other, specify	1/53 (1.9%)	1
Pancreatitis	1/53 (1.9%)	1
Small intestinal obstruction	3/53 (5.7%)	3
Vomiting	1/53 (1.9%)	1
General disorders
Fever	3/53 (5.7%)	3
Infusion related reaction	1/53 (1.9%)	2
General disorders and administration site conditions - Other, specify	1/53 (1.9%)	1
Hepatobiliary disorders
Cholecystitis	1/53 (1.9%)	1
Infections and infestations
Catheter related infection	1/53 (1.9%)	1
Infections and infestations - Other, specify	1/53 (1.9%)	1
Sepsis	1/53 (1.9%)	1
Skin infection	1/53 (1.9%)	1
Investigations
Blood bilirubin increased	1/53 (1.9%)	1
Metabolism and nutrition disorders
Dehydration	1/53 (1.9%)	1
Hypokalemia	1/53 (1.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/53 (1.9%)	1
Tumor pain	1/53 (1.9%)	1
Nervous system disorders
Dizziness	1/53 (1.9%)	1
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	1/53 (1.9%)	1
Surgical and medical procedures
Surgical and medical procedures - Other, specify	7/53 (13.2%)	9
Vascular disorders
Hypertension	1/53 (1.9%)	1
Thromboembolic event	3/53 (5.7%)	3
Other (Not Including Serious) Adverse Events
	Regorafenib + Oxaliplatin/Folinic Acid/5-FU (mFOLFOX6)
	Affected / at Risk (%)	# Events
Total	53/53 (100%)
Blood and lymphatic system disorders
Anemia	12/53 (22.6%)	25
Cardiac disorders
Conduction disorder	4/53 (7.5%)	8
Sinus bradycardia	3/53 (5.7%)	3
Endocrine disorders
Hypothyroidism	6/53 (11.3%)	8
Eye disorders
Conjunctivitis	3/53 (5.7%)	4
Eye disorders - Other, specify	3/53 (5.7%)	4
Gastrointestinal disorders
Abdominal pain	28/53 (52.8%)	47
Constipation	17/53 (32.1%)	26
Diarrhea	37/53 (69.8%)	124
Dyspepsia	6/53 (11.3%)	7
Mucositis oral	24/53 (45.3%)	65
Nausea	28/53 (52.8%)	70
Gastrointestinal disorders - Other, specify	4/53 (7.5%)	4
Rectal pain	4/53 (7.5%)	4
Vomiting	16/53 (30.2%)	29
General disorders
Fatigue	34/53 (64.2%)	92
Fever	10/53 (18.9%)	18
Infusion related reaction	3/53 (5.7%)	7
Injection site reaction	4/53 (7.5%)	4
General disorders and administration site conditions - Other, specify	3/53 (5.7%)	4
Pain	13/53 (24.5%)	15
Immune system disorders
Allergic reaction	5/53 (9.4%)	5
Infections and infestations
Catheter related infection	3/53 (5.7%)	5
Infections and infestations - Other, specify	4/53 (7.5%)	4
Paronychia	3/53 (5.7%)	3
Upper respiratory infection	6/53 (11.3%)	10
Urinary tract infection	5/53 (9.4%)	7
Injury, poisoning and procedural complications
Intestinal stoma site bleeding	3/53 (5.7%)	3
Investigations
Alanine aminotransferase increased	10/53 (18.9%)	27
Alkaline phosphatase increased	3/53 (5.7%)	3
Aspartate aminotransferase increased	12/53 (22.6%)	29
Blood bilirubin increased	9/53 (17%)	15
GGT increased	8/53 (15.1%)	17
Lipase increased	14/53 (26.4%)	19
Neutrophil count decreased	35/53 (66%)	88
Investigations - Other, specify	3/53 (5.7%)	3
Platelet count decreased	25/53 (47.2%)	61
Serum amylase increased	5/53 (9.4%)	8
White blood cell decreased	6/53 (11.3%)	8
Weight loss	5/53 (9.4%)	7
Metabolism and nutrition disorders
Anorexia	21/53 (39.6%)	41
Hypocalcemia	6/53 (11.3%)	7
Hypokalemia	6/53 (11.3%)	9
Hyponatremia	4/53 (7.5%)	4
Hypophosphatemia	14/53 (26.4%)	35
Hyperglycemia	6/53 (11.3%)	10
Musculoskeletal and connective tissue disorders
Back pain	10/53 (18.9%)	15
Chest wall pain	3/53 (5.7%)	3
Musculoskeletal and connective tissue disorder - Other, specify	3/53 (5.7%)	4
Pain in extremity	5/53 (9.4%)	6
Nervous system disorders
Dizziness	6/53 (11.3%)	6
Dysgeusia	16/53 (30.2%)	18
Dysesthesia	7/53 (13.2%)	14
Headache	8/53 (15.1%)	15
Lethargy	10/53 (18.9%)	29
Paresthesia	28/53 (52.8%)	71
Peripheral sensory neuropathy	24/53 (45.3%)	47
Somnolence	3/53 (5.7%)	4
Psychiatric disorders
Insomnia	5/53 (9.4%)	6
Renal and urinary disorders
Hematuria	3/53 (5.7%)	4
Respiratory, thoracic and mediastinal disorders
Cough	5/53 (9.4%)	8
Dyspnea	3/53 (5.7%)	3
Epistaxis	7/53 (13.2%)	12
Hoarseness	7/53 (13.2%)	11
Sore throat	4/53 (7.5%)	4
Voice alteration	12/53 (22.6%)	29
Skin and subcutaneous tissue disorders
Alopecia	15/53 (28.3%)	15
Dry skin	5/53 (9.4%)	6
Hyperhidrosis	3/53 (5.7%)	5
Skin and subcutaneous tissue disorders - Other, specify	6/53 (11.3%)	7
Palmar-plantar erythrodysesthesia syndrome	19/53 (35.8%)	47
Pruritus	4/53 (7.5%)	5
Rash acneiform	5/53 (9.4%)	5
Rash maculo-papular	6/53 (11.3%)	10
Vascular disorders
Flushing	5/53 (9.4%)	8
Hypotension	5/53 (9.4%)	5
Hypertension	30/53 (56.6%)	134
Phlebitis	3/53 (5.7%)	3
Thromboembolic event	3/53 (5.7%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI has to submit a draft manuscript of the publication or abstract to Bayer for review and approval at least 60 days before submission. Possible discrepancies will be discussed to find solution which satifies both parties. Bayer may delay publication for up to three months after analyzing the results.