Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Bayer

ClinicalTrials.gov Identifier:

NCT01103323

First received: April 8, 2010

Last updated: May 28, 2015

Last verified: May 2015

History of Changes

Results First Received: October 19, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Metastatic Colorectal Cancer
Interventions:	Drug: Regorafenib (Stivarga, BAY73-4506) Drug: Placebo Other: Best Supportive Care (BSC)

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Regorafenib (Stivarga, BAY73-4506)+BSC	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Placebo+BSC	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). Period 1 is placebo and placebo-regorafenib with placebo period only before unblinding. Period 2 is placebo-regorafenib with regorafenib period only.

Participant Flow for 2 periods

Period 1: Without/Before Drug Switch

	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC
STARTED	505	255
Participants Received Treatment	500	253
COMPLETED	429	237
NOT COMPLETED	76	18
Adverse Event	50	7
Withdrawal by Subject	17	5
Protocol Violation	2	0
Physician Decision	2	0
did not receive study treatment	5	2
Switch to Regorafenib	0	4

Period 2: Switched From Placebo to Regorafenib

	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC
STARTED	0	4 ^[1]
COMPLETED	0	3
NOT COMPLETED	0	1
Adverse Event	0	1

[1]	Participants in the placebo+BSC group switched to Regorafenib treatment after unblinding.

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Regorafenib (Stivarga, BAY73-4506)+BSC	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Placebo+BSC	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Total	Total of all reporting groups

Baseline Measures

	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC	Total
Number of Participants [units: participants]	505	255	760
Age ^[1] [units: Years] Mean (Full Range)	60.7 (22 to 82)	60.1 (25 to 85)	60.5 (22 to 85)
Gender [units: Participants]
Female	194	102	296
Male	311	153	464
Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment ^[2] [units: Participants]
0	265	146	411
1	240	109	349
KRAS mutation ^[3] [units: Participants]
No	205	94	299
Yes	273	157	430
Unknown	27	4	31

[1]	The age of the patient in years at enrollment in the study.
[2]	ECOG PS is a scale that measures how cancer affects the daily life of a patient on an ordinal scale from grade 0 (best) to grade 5 (worst). 0=Fully active without restriction; 1= Restricted in physically strenuous activity; 2= Ambulatory, capable of all selfcare; 3= Capable of limited selfcare; 4= Completely disabled; 5= Dead
[3]	KRAS - Kirsten rat sarcoma viral oncogene homolog (protein), member of the RAS family of GTPases (guanosine triphosphate hydrolases)

Outcome Measures

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1. Primary:

Overall Survival [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA). ]

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Measure Type	Primary
Measure Title	Overall Survival
Measure Description	Overall survival (OS) was defined as the time (days) from randomization to death due to any cause. Patients alive at the time of analysis were censored at the last date known to be alive. If a patient was lost to follow-up and there was no contact after randomization, this patient was censored at Day 1.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA).
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to treat (ITT)

Reporting Groups

	Description
Regorafenib (Stivarga, BAY73-4506)+BSC	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Placebo+BSC	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)

Measured Values

	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC
Number of Participants Analyzed [units: participants]	505	255
Overall Survival [units: Days] Median (95% Confidence Interval)	196 (178 to 222)	151 (134 to 177)

Statistical Analysis 1 for Overall Survival

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	0.005178
Hazard Ratio (HR) ^[4]	0.774
95% Confidence Interval	0.636 to 0.942

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Sample size based on primary efficacy endpoint of OS. The study was designed to have 90% power to detect 33.3% increase in median OS (i.e. hazard ratio of 0.75, Regorafenib / Placebo). Assuming 1-sided overall alpha of 0.025, randomization ratio of 2:1 for Regorafenib and Placebo, and 2 formal interim analyses of OS using an O’Brien-Fleming-type error spending function, a total of 582 death events were required for primary completion. Results based on 2nd planned formal IA with 432 total events.
[2]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	According to protocol specified O'Brien-Fleming type alpha spending function and 432 death events at 2nd IA, the pre-specified alpha (false positive rate) for this analysis was 0.009279 (1-sided).
[4]	Other relevant estimation information:
	Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (Regorafenib / Placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.

2. Secondary:

Progression-free Survival (Based on Investigator’s Assessment) [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

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3. Secondary:

Objective Tumor Response [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

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4. Secondary:

Disease Control [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

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5. Secondary:

Tumor Response [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

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Serious Adverse Events

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Time Frame	AE was collected up to 30 days after end of study treatment (per protocol) over a period of approximately 3.7 years.
Additional Description	Disseminated Intravascular Coagulation (DIC), International Normalized Ratio (INR), Cardiac Troponin T (cTnT), Gastroihntestina (GI), Not Otherwise Specified (NOS), Aspartate Aminotransferase (AST), Genitourinary (GU), Alanine Aminotransferase (ALT), Acute Respiratory Distress Syndrome (ARDS), Absolute Neutrophil Count (ANC)

Reporting Groups

	Description
Regorafenib (BAY73-4506)+BSC	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Placebo+BSC	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). It is for placebo period only before unblinding.
Placebo - Regorafenib After Unblinding	Participants in the placebo+BSC group switched to treatment with Regorafenib after unblinding. It is for Regorafenib treatment period only

Serious Adverse Events

	Regorafenib (BAY73-4506)+BSC	Placebo+BSC	Placebo - Regorafenib After Unblinding
Total, serious adverse events
# participants affected / at risk	232/500 (46.40%)	103/253 (40.71%)	2/4 (50.00%)
Blood and lymphatic system disorders
DIC ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Edema: Limb ^{* 1}
# participants affected / at risk	1/500 (0.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	1	1	0
Edema: Trunk/Genital ^{* 1}
# participants affected / at risk	0/500 (0.00%)	2/253 (0.79%)	0/4 (0.00%)
# events	0	4	0
Edema: Viscera ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	3	0
Hemoglobin ^{* 1}
# participants affected / at risk	4/500 (0.80%)	2/253 (0.79%)	0/4 (0.00%)
# events	8	2	0
INR ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	5	0	0
Neutrophils ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Platelets ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Thrombotic microangiopathy ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Cardiac disorders
Cardiac arrhythmia - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Cardiac ischemia/infarction ^{* 1}
# participants affected / at risk	6/500 (1.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	6	2	0
Hypertension ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Hypotension ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Left ventricular systolic dysfunction ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	3	0	0
Supraventricular arrhythmia, Atrial fibrillation ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
cTnT ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Eye disorders
Diplopia ^{* 1}
# participants affected / at risk	1/500 (0.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	1	1	0
Ocular - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Gastrointestinal disorders
Anorexia ^{* 1}
# participants affected / at risk	5/500 (1.00%)	2/253 (0.79%)	0/4 (0.00%)
# events	8	2	0
Ascites ^{* 1}
# participants affected / at risk	1/500 (0.20%)	2/253 (0.79%)	1/4 (25.00%)
# events	2	2	1
Constipation ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Dehydration ^{* 1}
# participants affected / at risk	3/500 (0.60%)	2/253 (0.79%)	0/4 (0.00%)
# events	3	2	0
Diarrhea ^{* 1}
# participants affected / at risk	8/500 (1.60%)	0/253 (0.00%)	0/4 (0.00%)
# events	9	0	0
Distension ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Enteritis ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Fistula, GI, Abdomen NOS ^{* 1}
# participants affected / at risk	1/500 (0.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	2	1	0
Fistula, GI, Anus ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Fistula, GI, Small bowel NOS ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
GI - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	1	1	0
Hemorrhoids ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Ileus ^{* 1}
# participants affected / at risk	2/500 (0.40%)	3/253 (1.19%)	0/4 (0.00%)
# events	3	3	0
Mucositis (functional/symptomatic), Small bowel ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Necrosis, GI, Peritoneal cavity ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Obstruction, GI, Colon ^{* 1}
# participants affected / at risk	9/500 (1.80%)	6/253 (2.37%)	0/4 (0.00%)
# events	11	8	0
Obstruction, GI, Ileum ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Obstruction, GI, Small bowel NOS ^{* 1}
# participants affected / at risk	4/500 (0.80%)	7/253 (2.77%)	0/4 (0.00%)
# events	5	9	0
Obstruction, GI, Stomach ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Perforation, GI, Colon ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Stricture, GI, Biliary tree ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Ulcer, GI, Duodenum ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Vomiting ^{* 1}
# participants affected / at risk	3/500 (0.60%)	0/253 (0.00%)	1/4 (25.00%)
# events	3	0	1
General disorders
Constitutional symptoms - Other ^{* 1}
# participants affected / at risk	34/500 (6.80%)	23/253 (9.09%)	0/4 (0.00%)
# events	49	39	0
Death not associated with CTCAE term, Disease progression NOS ^{* 1}
# participants affected / at risk	16/500 (3.20%)	6/253 (2.37%)	1/4 (25.00%)
# events	17	6	1
Death not associated with CTCAE term, Multi-Organ Failure ^{* 1}
# participants affected / at risk	4/500 (0.80%)	1/253 (0.40%)	0/4 (0.00%)
# events	4	1	0
Death not associated with CTCAE term, Sudden death ^{* 1}
# participants affected / at risk	2/500 (0.40%)	2/253 (0.79%)	0/4 (0.00%)
# events	2	2	0
Fatigue ^{* 1}
# participants affected / at risk	5/500 (1.00%)	5/253 (1.98%)	0/4 (0.00%)
# events	6	5	0
Fever ^{* 1}
# participants affected / at risk	17/500 (3.40%)	2/253 (0.79%)	0/4 (0.00%)
# events	21	2	0
Pain, Abdomen NOS ^{* 1}
# participants affected / at risk	13/500 (2.60%)	2/253 (0.79%)	0/4 (0.00%)
# events	21	2	0
Pain, Back ^{* 1}
# participants affected / at risk	4/500 (0.80%)	4/253 (1.58%)	0/4 (0.00%)
# events	6	5	0
Pain, Buttock ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	4	0	0
Pain, Cardiac/Heart ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Pain, Chest wall ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Pain, Chest/Thorax NOS ^{* 1}
# participants affected / at risk	4/500 (0.80%)	1/253 (0.40%)	0/4 (0.00%)
# events	4	1	0
Pain, Extremity - limb ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	6	0	0
Pain, Head/Headache ^{* 1}
# participants affected / at risk	2/500 (0.40%)	1/253 (0.40%)	0/4 (0.00%)
# events	2	1	0
Pain, Joint ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Pain, Liver ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Pain, Neuralgia/Peripheral nerve ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Pain, Pain NOS ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Pain, Tumor pain ^{* 1}
# participants affected / at risk	3/500 (0.60%)	1/253 (0.40%)	0/4 (0.00%)
# events	3	1	0
Syndromes - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Tumor flare ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Weight loss ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Hepatobiliary disorders
Cholecystitis ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Hepatobiliary - Other ^{* 1}
# participants affected / at risk	2/500 (0.40%)	1/253 (0.40%)	0/4 (0.00%)
# events	2	1	0
Liver dysfunction ^{* 1}
# participants affected / at risk	17/500 (3.40%)	5/253 (1.98%)	0/4 (0.00%)
# events	28	11	0
Immune system disorders
Allergic reaction ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	4	0	0
Infections and infestations
Infection (documented clinically), Abdomen NOS ^{* 1}
# participants affected / at risk	4/500 (0.80%)	0/253 (0.00%)	0/4 (0.00%)
# events	4	0	0
Infection (documented clinically), Anal/perianal ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection (documented clinically), Appendix ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection (documented clinically), Bladder (urinary) ^{* 1}
# participants affected / at risk	2/500 (0.40%)	1/253 (0.40%)	0/4 (0.00%)
# events	2	1	0
Infection (documented clinically), Blood ^{* 1}
# participants affected / at risk	3/500 (0.60%)	2/253 (0.79%)	0/4 (0.00%)
# events	5	2	0
Infection (documented clinically), Bronchus ^{* 1}
# participants affected / at risk	3/500 (0.60%)	0/253 (0.00%)	0/4 (0.00%)
# events	3	0	0
Infection (documented clinically), Catheter-related ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Infection (documented clinically), Kidney ^{* 1}
# participants affected / at risk	1/500 (0.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	1	1	0
Infection (documented clinically), Lung (Pneumonia) ^{* 1}
# participants affected / at risk	9/500 (1.80%)	3/253 (1.19%)	0/4 (0.00%)
# events	11	4	0
Infection (documented clinically), Skin (Cellulitis) ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection (documented clinically), Soft tissue NOS ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection (documented clinically), Urinary tract NOS ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Infection (documented clinically), Wound ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection - Other ^{* 1}
# participants affected / at risk	5/500 (1.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	6	2	0
Infection with normal ANC, Blood ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Infection with normal ANC, Catheter-related ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection with normal ANC, Colon ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection with normal ANC, Gallbladder (Cholecystitis) ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection with normal ANC, Kidney ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection with normal ANC, Lung (Pneumonia) ^{* 1}
# participants affected / at risk	1/500 (0.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	1	1	0
Infection with normal ANC, Soft tissue NOS ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Infection with unknown ANC, Kidney ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Infection with unknown ANC, Lung (Pneumonia) ^{* 1}
# participants affected / at risk	1/500 (0.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	1	1	0
Metabolism and nutrition disorders
AST ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Bilirubin (Hyperbilirubinemia) ^{* 1}
# participants affected / at risk	8/500 (1.60%)	3/253 (1.19%)	0/4 (0.00%)
# events	11	3	0
Hypoalbuminemia ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Hypocalcemia ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Hyponatremia ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Metabolic/Lab - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Musculoskeletal and connective tissue disorders
Fracture ^{* 1}
# participants affected / at risk	4/500 (0.80%)	2/253 (0.79%)	0/4 (0.00%)
# events	4	3	0
Gait/Walking ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Muscle weakness left-sided ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Muscle weakness, Extremity - lower ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Muscle weakness, Whole body/generalized ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Musculoskeletal - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Myositis ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy (possibly related to cancer treatment) ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Nervous system disorders
Ataxia ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
CNS ischemia ^{* 1}
# participants affected / at risk	1/500 (0.20%)	2/253 (0.79%)	0/4 (0.00%)
# events	2	2	0
Cognitive disturbance ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Confusion ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Dizziness ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Encephalopathy ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Mood Alteration, Anxiety ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Neurology - Other ^{* 1}
# participants affected / at risk	3/500 (0.60%)	2/253 (0.79%)	0/4 (0.00%)
# events	4	2	0
Neuropathy: Cranial, CN III Pupil, upper eyelid, extra ocular mov ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Neuropathy: motor ^{* 1}
# participants affected / at risk	3/500 (0.60%)	0/253 (0.00%)	0/4 (0.00%)
# events	3	0	0
Seizure ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Somnolence ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Speech impairment ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Syncope (Fainting) ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Renal and urinary disorders
Cystitis ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Fistula, GU, Bladder ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Obstruction, GU, Ureter ^{* 1}
# participants affected / at risk	2/500 (0.40%)	1/253 (0.40%)	0/4 (0.00%)
# events	2	1	0
Renal - Other ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Renal failure ^{* 1}
# participants affected / at risk	5/500 (1.00%)	3/253 (1.19%)	0/4 (0.00%)
# events	6	5	0
Urinary retention ^{* 1}
# participants affected / at risk	0/500 (0.00%)	2/253 (0.79%)	0/4 (0.00%)
# events	0	2	0
Respiratory, thoracic and mediastinal disorders
ARDS ^{* 1}
# participants affected / at risk	1/500 (0.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	1	1	0
Cough ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Dyspnea (Shortness of breath) ^{* 1}
# participants affected / at risk	12/500 (2.40%)	4/253 (1.58%)	0/4 (0.00%)
# events	18	4	0
Pleural effusion ^{* 1}
# participants affected / at risk	1/500 (0.20%)	4/253 (1.58%)	0/4 (0.00%)
# events	2	4	0
Pneumonitis ^{* 1}
# participants affected / at risk	1/500 (0.20%)	1/253 (0.40%)	0/4 (0.00%)
# events	2	1	0
Pneumothorax ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	3	0	0
Pulmonary - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Skin and subcutaneous tissue disorders
Dermatology - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	2/253 (0.79%)	0/4 (0.00%)
# events	2	3	0
Erythema multiforme ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Hand-foot skin reaction ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	3	0	0
Rash/Desquamation ^{* 1}
# participants affected / at risk	4/500 (0.80%)	1/253 (0.40%)	0/4 (0.00%)
# events	7	1	0
Wound complication, non-infectious ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Vascular disorders
Hematoma ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Hemorrhage - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Hemorrhage pulmonary, Bronchus ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Hemorrhage pulmonary, Mediastinum ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Hemorrhage, GI, Abdomen NOS ^{* 1}
# participants affected / at risk	2/500 (0.40%)	0/253 (0.00%)	0/4 (0.00%)
# events	4	0	0
Hemorrhage, GI, Anus ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Hemorrhage, GI, Lower GI NOS ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Hemorrhage, GI, Rectum ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Hemorrhage, GI, Stoma ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Hemorrhage, GI, Upper GI NOS ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Hemorrhage, GI, Varices (esophageal) ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Hemorrhage, GI, Varices (rectal) ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	1	0	0
Hemorrhage, GU, Vagina ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0
Thrombosis/Embolism (vascular access) ^{* 1}
# participants affected / at risk	0/500 (0.00%)	1/253 (0.40%)	0/4 (0.00%)
# events	0	1	0
Thrombosis/Thrombus/Embolism ^{* 1}
# participants affected / at risk	6/500 (1.20%)	3/253 (1.19%)	0/4 (0.00%)
# events	6	5	0
Vascular - Other ^{* 1}
# participants affected / at risk	1/500 (0.20%)	0/253 (0.00%)	0/4 (0.00%)
# events	2	0	0

*	Events were collected by non-systematic assessment
1	Term from vocabulary, NCI-CTCAE v.3.0

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
At 2nd IA, pre-specified O’Brien-Fleming-type efficacy boundary was crossed. DMC concluded OS result positive and after positive risk benefit assessment, recommended unblinding of study. OS from 2nd IA are the final formal and definitive results.

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