Axitinib For The Treatment Of Advanced Hepatocellular Carcinoma

• ClinicalTrials.gov Identifier: NCT01210495
• Recruitment Status: Completed
• First Posted: September 28, 2010
• Results First Posted: May 27, 2015
• Last Update Posted: January 9, 2019
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Hepatocellular Carcinoma
• Interventions: Drug: Axitinib (AG-013736); Other: Best Supportive Care; Drug: Placebo
• Enrollment: 224

Participant Flow

Recruitment Details	Total 224 participants were enrolled in the study. Randomized portion enrolled 202 participants in 2 arms (134 in axitinib, 68 in placebo) in 70 centers (13 countries). Non-randomized portion enrolled 22 participants in 2 cohorts (15 in Child-Pugh Class A, 7 in Child-Pugh Class B score 7) according to Child-Pugh score in 13 centers (4 countries).
Pre-assignment Details	Participants with Child-Pugh Class A (score 5 or 6) could have been enrolled into either non-randomized or to randomized portion. Participants with Child-Pugh Class B (score 7) were initially enrolled into non-randomized portion but following determination of recommended axitinib starting dose they could have been enrolled in randomized portion.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B	Axitinib	Placebo
Arm/Group Description	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 milligrams (mg) twice daily (BID).	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non-randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child-Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Period Title: Overall Study
Started	15	7	134	68
Completed	0	0	0	0
Not Completed	15	7	134	68
Reason Not Completed
Participant Refused Further Follow-Up	1	0	11	2
Death	14	7	112	54
Study Terminated by Sponsor	0	0	4	11
Lost to Follow-up	0	0	1	1
Other unspecified	0	0	6	0

Baseline Characteristics

Arm/Group Title		Child-Pugh Class A	Child-Pugh Class B	Axitinib	Placebo	Total
Arm/Group Description		Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.	Total of all reporting groups
Overall Number of Baseline Participants		15	7	134	68	224
Baseline Analysis Population Description		Full analysis set (FAS) included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	15 participants	7 participants	134 participants	68 participants	224 participants
<18 years		0	0	0	0	0
18-44 years		4	0	7	4	15
45-64 years		5	5	74	32	116
>=65 years		6	2	53	32	93
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	7 participants	134 participants	68 participants	224 participants
	Female	3 20.0%	2 28.6%	24 17.9%	12 17.6%	41 18.3%
	Male	12 80.0%	5 71.4%	110 82.1%	56 82.4%	183 81.7%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) - Stratified Analysis, Randomized Portion
Description	OS was defined as the time from the date of randomization to the date of death due to any cause. OS (in months) was calculated as (date of death - first randomization date +1)/30.4. For participants still alive at the time of the analysis, the OS time was censored on the last date they were known to be alive. All participants were followed up for survival at least every 3 months after discontinuing study treatment until at least two years after randomization of the last participant.
Time Frame	From randomization until at least two years after the last participant has been randomized (up to 6 years)

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Median (95% Confidence Interval); Unit of Measure: months
	12.7; (10.2 to 14.9)	9.7; (5.9 to 11.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	The study was designed to test the null hypothesis that the true median OS was 5 months vs. the alternative hypothesis that the true median OS was at least 8.3 months (i.e., 66 percent [%] improvement in median OS).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2872
	Comments	For the overall stratified analysis the p-value is from a 1-sided log-rank test of treatment stratified by tumor invasion and geographic region.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.907
	Confidence Interval	(2-Sided) 95%; 0.646 to 1.274
	Estimation Comments	Assuming proportional hazards, a hazard ratio less than (<) 1 indicated reduction in hazard rate to favor Axitinib; hazard ratio greater than (>) 1 indicated reduction to favor Placebo.

2. Secondary Outcome

Title	Progression-Free Survival (PFS) - Stratified Analysis, Randomized Portion
Description	PFS was defined as time from randomization to first documented objective tumor progression or to death due to any cause, whichever occurred first. PFS (in months) was calculated as (first event date - first randomization date +1)/30.4. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was death). As per response evaluation criteria in solid tumors (RECIST) 1.1, progression was defined as greater than or equal to (>=) 20% increase in sum of longest dimensions of target lesions or appearance of one or more new target lesions and unequivocal progression of existing non-target lesions, or appearance of 1 new non-target lesions. Participants discontinuing study treatment without documented evidence of PD were to be followed up at least every 8 weeks after discontinuing study treatment until disease progression, or initiation of another anticancer treatment.
Time Frame	Every 8 weeks until disease progression/death or start of new treatment or until at least two years after the last participant has been randomized, whatever occurs first

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Median (95% Confidence Interval); Unit of Measure: months
	3.6; (2.3 to 4.6)	1.9; (1.9 to 3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0039
	Comments	For the overall stratified analysis the p-value is from a 1-sided log-rank test of treatment stratified by tumor invasion and geographic region.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.618
	Confidence Interval	(2-Sided) 95%; 0.438 to 0.871
	Estimation Comments	Assuming proportional hazards, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Placebo.

3. Secondary Outcome

Title	Objective Response Rate (ORR) - Percentage of Participants With Objective Response by Stratified Analysis, Randomized Portion
Description	ORR was defined as the percentage of participants with confirmed complete response (CR) or confirmed partial response (PR) according to the RECIST 1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis <10 millimetres [mm]). PR was defined as a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Time Frame	Every 8 weeks until at least two years after the last participant has been randomized

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	9.7; (5.3 to 16.0)	2.9; (0.4 to 10.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0914
	Comments	ORR for the 2 treatment arms was compared with a significance level of 0.025 using Cochran-Mantel-Haenszel (CMH) test for stratified analyses.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	3.172
	Confidence Interval	(2-Sided) 95%; 0.759 to 13.265
	Estimation Comments	Risk ratio and confidence interval (CI) were based on the Mantel-Haenszel estimator; risk ratio was adjusted for geographical region and vascular invasion and extra hepatic spread.

4. Secondary Outcome

Title	Time to Tumor Progression (TTP) - Stratified Analysis, Randomized Portion
Description	TTP was defined as the time from randomization to first documentation of objective tumor progression. If tumor progression data included more than 1 date, the first date was used. TTP (in months) was calculated as (first event date - first randomization date +1)/30.4.
Time Frame	Every 8 weeks until disease progression/death or start of new treatment or until at least two years after the last participant has been randomized, whatever occurs first

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Median (95% Confidence Interval); Unit of Measure: months
	3.7; (2.8 to 5.6)	1.9; (1.9 to 3.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.006
	Comments	For the overall stratified analysis the p-value is from a 1-sided log-rank test of treatment stratified by tumor invasion and geographic region.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.621
	Confidence Interval	(2-Sided) 95%; 0.434 to 0.889
	Estimation Comments	Assuming proportional hazards, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Placebo.

5. Secondary Outcome

Title	Duration of Response (DR) by Unstratified Analysis, Randomized Portion
Description	DR was defined as the time from the first documentation of objective tumor response (CR or PR) that was subsequently confirmed to the first documentation of PD or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, the first date was to be used. DR (in months) was to be calculated as (the end date for DR - first CR or PR that was subsequently confirmed +1)/30.4.
Time Frame	From objective response to date of progression or death

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received. DR was calculated for the subgroup of FAS participants with objective response.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	13	2
Median (95% Confidence Interval); Unit of Measure: months
	6.4; (3.7 to 9.3)	NA [1]; (NA to NA)

[1]

Not reached

6. Secondary Outcome

Title	Percentage of Participants With Overall Clinical Benefit Response (CBR) - Stratified Analysis, Randomized Portion
Description	CBR was defined as the percentage of participants with confirmed CR or confirmed PR or a best response of stable disease >=8 weeks according to RECIST 1.1 criteria, relative to all randomized participants who had baseline measurable disease. Confirmed responses were defined as those that persisted on repeat imaging study >=4 weeks after the initial documentation of response. Participants who did not have on study radiographic tumor re-evaluation or who died, progressed, or dropped out for any reason prior to reaching a CR, PR, or stable disease were counted as non-responders in the assessment of CBR. A participant who initially met the criteria for a PR and then subsequently became a confirmed CR was to be assigned a best response of CR.
Time Frame	From Baseline up to end of treatment

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	31.3; (23.6 to 39.9)	11.8; (5.2 to 21.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0025
	Comments	For the overall stratified analysis the p-value is from Cochran-Mantel-Haenszel test of treatment stratified by geographical region and vascular invasion and extra hepatic spread.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	2.650
	Confidence Interval	(2-Sided) 95%; 1.319 to 5.326
	Estimation Comments	Risk Ratio and CI based on the Mantel-Haenszel estimator; risk ratio was adjusted for geographical region and vascular invasion and extra hepatic spread.

7. Secondary Outcome

Title	Axitinib Steady-State Pharmacokinetic (PK) Parameter - Maximum Observed Plasma Concentration (Cmax), Non-Randomized Portion
Description	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK concentration set included all participants who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B
Arm/Group Description:	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
Overall Number of Participants Analyzed	12	7
Geometric Mean (95% Confidence Interval); Unit of Measure: nanograms per milliliter (ng/mL)
	35.74; (21.84 to 58.50)	21.16; (11.10 to 40.33)

8. Secondary Outcome

Title	Axitinib Steady-State PK Parameter - Area Under the Plasma Concentration Versus Time Curve From 0 to 24 Hour (AUC0-24), Non-Randomized Portion
Description	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. In the below table, 4 participants in Child-Pugh A and 1 participant in Child-Pugh B were not reported due to nonestimable half-life.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK concentration set included all participants who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B
Arm/Group Description:	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
Overall Number of Participants Analyzed	8	6
Geometric Mean (95% Confidence Interval); Unit of Measure: nanograms*hour per milliliter (ng*hr/mL)
	310.76; (175.02 to 551.75)	316.20; (162.96 to 613.55)

9. Secondary Outcome

Title	Axitinib Steady-State Pharmacokinetic Parameter - Time to First Occurrence of Cmax (Tmax), Non-Randomized Portion
Description	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK concentration set included all participants who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B
Arm/Group Description:	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
Overall Number of Participants Analyzed	12	7
Median (Full Range); Unit of Measure: hours
	2.50; (0.00 to 7.98)	1.05; (0.00 to 4.00)

10. Secondary Outcome

Title	Axitinib Steady-State Pharmacokinetic Parameter - Apparent Oral Clearance (CL/F), Non-Randomized Portion
Description	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. In the below table, 4 participants in Child-Pugh A and 1 participant in Child-Pugh B were not reported due to nonestimable half-life.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK concentration set included all participants who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B
Arm/Group Description:	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
Overall Number of Participants Analyzed	8	6
Geometric Mean (95% Confidence Interval); Unit of Measure: liters per hour (L/hr)
	32.18; (18.12 to 57.13)	12.65; (6.52 to 24.55)

11. Secondary Outcome

Title	Axitinib Steady-State Pharmacokinetic Parameter - Terminal Plasma Elimination Half-Life (t1/2), Non-Randomized Portion
Description	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. In the below table, 4 participants in Child-Pugh A and 1 participant in Child-Pugh B were not reported due to nonestimable half-life.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK concentration set included all participants who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B
Arm/Group Description:	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
Overall Number of Participants Analyzed	8	6
Mean (Standard Deviation); Unit of Measure: hours
	4.12 (3.55)	4.79 (2.42)

12. Secondary Outcome

Title	Axitinib Steady-State Pharmacokinetic Parameter - Apparent Oral Volume of Distribution of the Drug During the Elimination Phase (Vz/F), Non-Randomized Portion
Description	Axitinib samples were to be collected from all participants on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. The PK parameter, Vz/F has been presented in this outcome measure. In the below table, 4 participants in Child-Pugh A and 1 participant in Child-Pugh B were not reported due to nonestimable half-life.
Time Frame	Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK concentration set included all participants who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B
Arm/Group Description:	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
Overall Number of Participants Analyzed	8	6
Geometric Mean (95% Confidence Interval); Unit of Measure: liters
	150.01; (94.67 to 237.68)	81.16; (47.70 to 138.08)

13. Secondary Outcome

Title	Concentration of Soluble Proteins at Baseline in Randomized Portion
Description	Plasma soluble proteins interleukin-6 (IL-6), E-Selectin, interleukin-8 (IL-8), hepatocyte growth factor (HGF), matrix metalloproteinase-2 (MMP-2), stem cell factor (SCF), angiopoietin-2 (Ang-2), vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor-C (VEGF-C), soluble vascular endothelial growth factor receptor 2 (sVEGFR2), soluble vascular endothelial growth factor receptor 3 (sVEGFR3), stromal cell-derived factor-1 (SDF1), neutrophil gelatinase-associated lipocalin (NGAL), migration inhibitory factor (MIF), c-MET, regulated upon activation normal T cell expressed and presumably secreted (RANTES), and monocyte chemotactic protein-3 (MCP-3) were only measured in randomized participants.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The soluble protein analysis set included all participants in the safety analysis set who had a Baseline soluble protein assessment. Safety analysis population included all randomized participants who received at least 1 dose of study drug with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	120	61
Mean (Standard Deviation); Unit of Measure: picograms per milliliter (pg/mL)
IL-6	50.67 (102.86)	50.72 (106.74)
E-Selectin	52313.94 (32603.18)	55430.76 (26723.43)
IL-8	33.35 (47.72)	27.23 (44.46)
HGF	478.84 (712.43)	406.06 (376.04)
MMP-2	355715.66 (137663.04)	350979.72 (146323.29)
SCF	1352.75 (1534.41)	1439.71 (2260.89)
Ang-2	662.40 (623.87)	577.82 (354.42)
VEGF-A	102.56 (128.09)	173.59 (472.19)
VEGF-C	NA [1] (NA)	NA [2] (NA)
sVEGFR2	17675.76 (7218.95)	18273.65 (6836.16)
sVEGFR3	287429.28 (117583.24)	290338.69 (97830.36)
SDF1	1190.08 (823.03)	1150.10 (681.04)
NGAL	134861.80 (152492.96)	141383.00 (121747.35)
MIF	33057.15 (28256.00)	32302.99 (21485.01)
c-MET ELISA	1664.96 (834.36)	1641.08 (704.38)
RANTES	26412.12 (38682.81)	26917.76 (27094.12)
MCP-3	NA [2] (NA)	NA [2] (NA)

[1]

Not available as the % < LLQ (lower limit of quantification) was greater than 75%.

[2]

Not available as the % < LLQ was greater than 75%.

14. Secondary Outcome

Title	Percentage of Participants With Specific Micro-Ribonucleic Acid (miRNA) Transcript Present in Circulation in Randomized Portion
Description	A 5 millilitres (mL) whole blood sample was collected from all randomized participants to evaluate the miRNA transcripts.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The miRNA analysis set included all participants in the safety analysis set who had a baseline miRNA assessment. Safety analysis population included all randomized participants who received at least 1 dose of study drug with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	111	59
Measure Type: Number; Unit of Measure: percentage of participants
hsa-let-7a-5p	100.0	100.0
hsa-let-7b-5p	100.0	100.0
hsa-let-7c	100.0	100.0
hsa-let-7d-5p	100.0	100.0
hsa-let-7f-5p	100.0	100.0
hsa-let-7g-5p	100.0	100.0
hsa-let-7i-5p	100.0	100.0
hsa-miR-103a-3p	100.0	100.0
hsa-miR-106b-5p	100.0	100.0
hsa-miR-107	100.0	100.0
hsa-miR-1202	100.0	100.0
hsa-miR-1207-5p	100.0	100.0
hsa-miR-1225-5p	100.0	100.0
hsa-miR-1234-5p	100.0	100.0
hsa-miR-1246	100.0	100.0
hsa-miR-125b-5p	100.0	100.0
hsa-miR-126-3p	100.0	100.0
hsa-miR-1260a	100.0	100.0
hsa-miR-1260b	100.0	100.0
hsa-miR-1268a	100.0	100.0
hsa-miR-1273g-3p	100.0	100.0
hsa-miR-1275	100.0	100.0
hsa-miR-128	100.0	100.0
hsa-miR-130a-3p	100.0	100.0
hsa-miR-130b-3p	100.0	100.0
hsa-miR-140-3p	100.0	100.0
hsa-miR-142-3p	100.0	100.0
hsa-miR-145-5p	100.0	100.0
hsa-miR-148a-3p	100.0	100.0
hsa-miR-148b-3p	100.0	100.0
hsa-miR-150-5p	100.0	100.0
hsa-miR-151a-3p	100.0	100.0
hsa-miR-151a-5p	100.0	100.0
hsa-miR-151b	100.0	100.0
hsa-miR-1587	100.0	100.0
hsa-miR-15a-5p	100.0	100.0
hsa-miR-15b-5p	100.0	100.0
hsa-miR-16-5p	100.0	100.0
hsa-miR-17-5p	100.0	100.0
hsa-miR-181a-5p	100.0	100.0
hsa-miR-182-5p	100.0	100.0
hsa-miR-183-5p	100.0	100.0
hsa-miR-185-5p	100.0	100.0
hsa-miR-186-5p	100.0	100.0
hsa-miR-191-5p	100.0	100.0
hsa-miR-1914-3p	100.0	100.0
hsa-miR-1915-3p	100.0	100.0
hsa-miR-192-5p	100.0	100.0
hsa-miR-194-5p	100.0	100.0
hsa-miR-197-3p	100.0	100.0
hsa-miR-197-5p	100.0	100.0
hsa-miR-19a-3p	100.0	100.0
hsa-miR-19b-3p	100.0	100.0
hsa-miR-20a-5p	100.0	100.0
hsa-miR-20b-5p	100.0	100.0
hsa-miR-21-5p	100.0	100.0
hsa-miR-210	100.0	100.0
hsa-miR-215	100.0	100.0
hsa-miR-22-3p	100.0	100.0
hsa-miR-222-3p	100.0	100.0
hsa-miR-223-3p	100.0	100.0
hsa-miR-23a-3p	100.0	100.0
hsa-miR-23b-3p	100.0	100.0
hsa-miR-24-3p	100.0	100.0
hsa-miR-25-3p	100.0	100.0
hsa-miR-26a-5p	100.0	100.0
hsa-miR-26b-5p	100.0	100.0
hsa-miR-2861	100.0	100.0
hsa-miR-29a-3p	100.0	100.0
hsa-miR-29b-3p	100.0	100.0
hsa-miR-29c-3p	100.0	100.0
hsa-miR-29c-5p	100.0	100.0
hsa-miR-30b-5p	100.0	100.0
hsa-miR-30c-5p	100.0	100.0
hsa-miR-30d-5p	100.0	100.0
hsa-miR-30e-5p	100.0	100.0
hsa-miR-3135b	100.0	100.0
hsa-miR-3162-5p	100.0	100.0
hsa-miR-3180-3p	100.0	100.0
hsa-miR-3195	100.0	100.0
hsa-miR-320a	100.0	100.0
hsa-miR-320b	100.0	100.0
hsa-miR-320c	100.0	100.0
hsa-miR-320d	100.0	100.0
hsa-miR-320e	100.0	100.0
hsa-miR-324-3p	100.0	100.0
hsa-miR-324-5p	100.0	100.0
hsa-miR-331-3p	100.0	100.0
hsa-miR-339-5p	100.0	100.0
hsa-miR-342-3p	100.0	100.0
hsa-miR-361-3p	100.0	100.0
hsa-miR-361-5p	100.0	100.0
hsa-miR-362-5p	100.0	100.0
hsa-miR-363-3p	100.0	100.0
hsa-miR-3651	100.0	100.0
hsa-miR-3656	100.0	100.0
hsa-miR-365a-3p	100.0	100.0
hsa-miR-3665	100.0	100.0
hsa-miR-3676-5p	100.0	100.0
hsa-miR-374b-5p	100.0	100.0
hsa-miR-378a-3p	100.0	100.0
hsa-miR-378i	100.0	100.0
hsa-miR-3940-5p	100.0	100.0
hsa-miR-3960	100.0	100.0
hsa-miR-423-3p	100.0	100.0
hsa-miR-425-5p	100.0	100.0
hsa-miR-4281	100.0	100.0
hsa-miR-4284	100.0	100.0
hsa-miR-4286	100.0	100.0
hsa-miR-4299	100.0	100.0
hsa-miR-4306	100.0	100.0
hsa-miR-4318	100.0	100.0
hsa-miR-4323	100.0	100.0
hsa-miR-4428	100.0	100.0
hsa-miR-4442	100.0	100.0
hsa-miR-4443	100.0	100.0
hsa-miR-4454	100.0	100.0
hsa-miR-4459	100.0	100.0
hsa-miR-4466	100.0	100.0
hsa-miR-4497	100.0	100.0
hsa-miR-4505	100.0	100.0
hsa-miR-4507	100.0	100.0
hsa-miR-4516	100.0	100.0
hsa-miR-451a	100.0	100.0
hsa-miR-4530	100.0	100.0
hsa-miR-4687-3p	100.0	100.0
hsa-miR-4713-3p	100.0	100.0
hsa-miR-4721	100.0	100.0
hsa-miR-4728-5p	100.0	100.0
hsa-miR-4732-3p	100.0	100.0
hsa-miR-4739	100.0	100.0
hsa-miR-4763-3p	100.0	100.0
hsa-miR-4787-5p	100.0	100.0
hsa-miR-4788	100.0	100.0
hsa-miR-484	100.0	100.0
hsa-miR-486-5p	100.0	100.0
hsa-miR-494	100.0	100.0
hsa-miR-5001-5p	100.0	100.0
hsa-miR-500a-3p	100.0	100.0
hsa-miR-500a-5p	100.0	100.0
hsa-miR-501-3p	100.0	100.0
hsa-miR-501-5p	100.0	100.0
hsa-miR-502-3p	100.0	100.0
hsa-miR-505-5p	100.0	100.0
hsa-miR-5100	100.0	100.0
hsa-miR-532-3p	100.0	100.0
hsa-miR-532-5p	100.0	100.0
hsa-miR-550a-3-5p	100.0	100.0
hsa-miR-550a-3p	100.0	100.0
hsa-miR-5739	100.0	100.0
hsa-miR-574-3p	100.0	100.0
hsa-miR-574-5p	100.0	100.0
hsa-miR-5787	100.0	100.0
hsa-miR-584-5p	100.0	100.0
hsa-miR-6085	100.0	100.0
hsa-miR-6087	100.0	100.0
hsa-miR-6088	100.0	100.0
hsa-miR-6089	100.0	100.0
hsa-miR-6090	100.0	100.0
hsa-miR-6125	100.0	100.0
hsa-miR-6127	100.0	100.0
hsa-miR-625-5p	100.0	100.0
hsa-miR-638	100.0	100.0
hsa-miR-642a-3p	100.0	100.0
hsa-miR-642b-3p	100.0	100.0
hsa-miR-652-3p	100.0	100.0
hsa-miR-660-5p	100.0	100.0
hsa-miR-664a-3p	100.0	100.0
hsa-miR-664b-3p	100.0	100.0
hsa-miR-6717-5p	100.0	100.0
hsa-miR-6724-5p	100.0	100.0
hsa-miR-7-5p	100.0	100.0
hsa-miR-762	100.0	100.0
hsa-miR-766-3p	100.0	100.0
hsa-miR-92a-3p	100.0	100.0
hsa-miR-93-3p	100.0	100.0
hsa-miR-93-5p	100.0	100.0
hsa-miR-937-5p	100.0	100.0
hsa-miR-940	100.0	100.0
hsa-miR-1228-3p	99.1	100.0
hsa-miR-1268b	99.1	100.0
hsa-miR-142-5p	100.0	98.3
hsa-miR-27a-3p	99.1	100.0
hsa-miR-296-5p	99.1	100.0
hsa-miR-3196	99.1	100.0
hsa-miR-3198	99.1	100.0
hsa-miR-342-5p	100.0	98.3
hsa-miR-3653	100.0	98.3
hsa-miR-4465	99.1	100.0
hsa-miR-4515	99.1	100.0
hsa-miR-4653-3p	99.1	100.0
hsa-miR-4665-3p	99.1	100.0
hsa-miR-4746-3p	99.1	100.0
hsa-miR-505-3p	100.0	98.3
hsa-miR-6073	99.1	100.0
hsa-miR-6126	99.1	100.0
hsa-miR-6132	99.1	100.0
hsa-miR-6165	99.1	100.0
hsa-miR-744-5p	100.0	98.3
hsa-miR-874	99.1	100.0
hsa-miR-942	100.0	98.3
hsa-miR-96-5p	99.1	100.0
hsa-miR-1238-3p	98.2	100.0
hsa-miR-1285-3p	99.1	98.3
hsa-miR-1305	98.2	100.0
hsa-miR-146a-5p	98.2	100.0
hsa-miR-15b-3p	99.1	98.3
hsa-miR-17-3p	98.2	100.0
hsa-miR-195-5p	99.1	98.3
hsa-miR-199a-5p	99.1	98.3
hsa-miR-28-5p	99.1	98.3
hsa-miR-30a-5p	99.1	98.3
hsa-miR-340-3p	99.1	98.3
hsa-miR-3679-5p	99.1	98.3
hsa-miR-374a-5p	99.1	98.3
hsa-miR-378a-5p	99.1	98.3
hsa-miR-4433-5p	98.2	100.0
hsa-miR-454-3p	99.1	98.3
hsa-miR-4685-5p	99.1	98.3
hsa-miR-575	98.2	100.0
hsa-miR-6068	98.2	100.0
hsa-miR-6124	98.2	100.0
hsa-miR-6131	98.2	100.0
hsa-miR-939-5p	98.2	100.0
hsa-miR-1234-3p	99.1	96.6
hsa-miR-1249	98.2	98.3
hsa-miR-132-3p	99.1	96.6
hsa-miR-30e-3p	98.2	98.3
hsa-miR-326	99.1	96.6
hsa-miR-374c-5p	98.2	98.3
hsa-miR-4270	97.3	100.0
hsa-miR-4672	97.3	100.0
hsa-miR-4741	98.2	98.3
hsa-miR-6515-3p	97.3	100.0
hsa-miR-371b-5p	97.3	98.3
hsa-miR-4485	96.4	100.0
hsa-miR-4513	98.2	96.6
hsa-miR-454-5p	98.2	96.6
hsa-miR-4716-3p	96.4	100.0
hsa-miR-5006-5p	97.3	98.3
hsa-miR-6069	98.2	96.6
hsa-miR-101-3p	97.3	96.6
hsa-miR-155-5p	97.3	96.6
hsa-miR-16-2-3p	98.2	94.9
hsa-miR-27b-3p	98.2	94.9
hsa-miR-328	98.2	94.9
hsa-miR-4486	96.4	98.3
hsa-miR-513a-5p	96.4	98.3
hsa-miR-92b-3p	98.2	94.9
hsa-miR-98-5p	98.2	94.9
hsa-miR-18b-5p	96.4	96.6
hsa-miR-191-3p	97.3	94.9
hsa-miR-3200-5p	97.3	94.9
hsa-miR-4313	97.3	94.9
hsa-miR-4532	96.4	96.6
hsa-miR-4787-3p	97.3	94.9
hsa-miR-513b	95.5	98.3
hsa-miR-550a-5p	97.3	94.9
hsa-miR-5581-5p	94.6	100.0
hsa-miR-629-3p	97.3	94.9
hsa-miR-629-5p	94.6	100.0
hsa-miR-7-1-3p	98.2	93.2
hsa-miR-125a-3p	94.6	98.3
hsa-miR-1281	97.3	93.2
hsa-miR-140-5p	95.5	96.6
hsa-miR-144-5p	96.4	94.9
hsa-let-7b-3p	96.4	93.2
hsa-let-7f-1-3p	95.5	94.9
hsa-miR-125a-5p	96.4	93.2
hsa-miR-183-3p	96.4	93.2
hsa-miR-3162-3p	97.3	91.5
hsa-miR-33b-3p	97.3	91.5
hsa-miR-4669	94.6	96.6
hsa-miR-502-5p	96.4	93.2
hsa-miR-1304-3p	97.3	89.8
hsa-miR-1306-5p	95.5	93.2
hsa-miR-221-3p	93.7	96.6
hsa-miR-4649-3p	96.4	91.5
hsa-miR-4690-5p	94.6	94.9
hsa-miR-627	95.5	93.2
hsa-miR-99a-5p	96.4	91.5
hsa-miR-18a-5p	94.6	93.2
hsa-miR-211-3p	94.6	93.2
hsa-miR-4430	95.5	91.5
hsa-miR-6508-5p	95.5	91.5
hsa-miR-933	95.5	91.5
hsa-miR-339-3p	94.6	91.5
hsa-miR-624-5p	95.5	89.8
hsa-miR-425-3p	95.5	88.1
hsa-miR-5194	91.9	93.2
hsa-miR-6511b-3p	92.8	91.5
hsa-let-7d-3p	92.8	89.8
hsa-miR-129-2-3p	92.8	89.8
hsa-miR-1825	92.8	89.8
hsa-miR-362-3p	93.7	88.1
hsa-miR-665	91.0	93.2
hsa-miR-149-5p	92.8	88.1
hsa-miR-3620-5p	91.0	91.5
hsa-miR-4478	90.1	91.5
hsa-miR-4484	92.8	86.4
hsa-miR-4656	90.1	91.5
hsa-miR-602	91.9	88.1
hsa-miR-1233-1-5p	89.2	91.5
hsa-miR-3125	89.2	91.5
hsa-miR-4725-5p	91.0	88.1
hsa-miR-4732-5p	91.0	88.1
hsa-miR-146b-5p	92.8	83.1
hsa-miR-4659a-3p	91.0	86.4
hsa-miR-6510-5p	88.3	91.5
hsa-miR-1225-3p	91.0	84.7
hsa-miR-1539	90.1	86.4
hsa-miR-188-5p	88.3	89.8
hsa-miR-4758-3p	91.0	84.7
hsa-miR-550b-2-5p	91.9	83.1
hsa-miR-144-3p	89.2	86.4
hsa-miR-4310	89.2	84.7
hsa-miR-4749-3p	89.2	84.7
hsa-miR-1229-5p	87.4	86.4
hsa-miR-1288	86.5	88.1
hsa-miR-3156-5p	84.7	91.5
hsa-miR-2116-3p	89.2	81.4
hsa-miR-4664-3p	87.4	84.7
hsa-miR-23c	87.4	83.1
hsa-miR-3652	85.6	86.4
hsa-miR-424-5p	88.3	81.4
hsa-miR-4745-5p	85.6	86.4
hsa-miR-1973	83.8	88.1
hsa-miR-4291	84.7	86.4
hsa-miR-3200-3p	86.5	81.4
hsa-miR-4436b-5p	84.7	84.7
hsa-miR-6512-5p	82.9	88.1
hsa-miR-3613-3p	86.5	78.0
hsa-miR-4793-5p	81.1	88.1
hsa-miR-628-3p	83.8	83.1
hsa-miR-1181	82.9	83.1
hsa-miR-3646	82.0	84.7
hsa-miR-4317	82.9	83.1
hsa-miR-5684	83.8	81.4
hsa-miR-1227-5p	81.1	84.7
hsa-miR-3180-5p	84.7	78.0
hsa-miR-4665-5p	82.9	81.4
hsa-miR-129-1-3p	82.0	81.4
hsa-miR-4652-3p	82.9	79.7
hsa-miR-500b	82.0	79.7
hsa-miR-181b-5p	83.8	74.6
hsa-miR-3676-3p	82.9	76.3
hsa-miR-671-5p	77.5	86.4
hsa-miR-1185-1-3p	78.4	83.1
hsa-miR-378d	78.4	83.1
hsa-miR-1271-5p	81.1	76.3
hsa-miR-4433-3p	78.4	81.4
hsa-miR-564	81.1	76.3
hsa-miR-6723-5p	81.1	76.3
hsa-miR-100-5p	82.9	71.2
hsa-miR-135a-3p	77.5	81.4
hsa-miR-181a-2-3p	80.2	76.3
hsa-miR-4666b	78.4	79.7
hsa-miR-98-3p	79.3	76.3
hsa-miR-3940-3p	77.5	74.6
hsa-miR-513c-5p	74.8	79.7
hsa-miR-634	79.3	71.2
hsa-miR-4769-3p	77.5	72.9
hsa-miR-6507-3p	76.6	72.9
hsa-miR-3907	72.1	79.7
hsa-miR-4634	73.0	78.0
hsa-miR-563	73.9	74.6
hsa-miR-892b	73.9	74.6
hsa-miR-103a-2-5p	74.8	71.2
hsa-miR-2392	73.9	72.9
hsa-miR-3127-5p	72.1	76.3
hsa-miR-338-5p	73.0	74.6
hsa-miR-3614-5p	73.9	72.9
hsa-miR-4499	70.3	79.7
hsa-miR-3667-5p	74.8	69.5
hsa-miR-1290	68.5	78.0
hsa-miR-130b-5p	75.7	62.7
hsa-miR-4449	73.0	67.8
hsa-miR-4695-5p	70.3	67.8
hsa-miR-4271	67.6	71.2
hsa-miR-4651	69.4	67.8
hsa-miR-340-5p	63.1	74.6
hsa-miR-133b	67.6	61.0
hsa-miR-199b-5p	70.3	55.9
hsa-miR-200c-3p	67.6	61.0
hsa-miR-4257	63.1	69.5
hsa-miR-150-3p	62.2	69.5
hsa-miR-30c-1-3p	68.5	57.6
hsa-miR-139-3p	64.9	62.7
hsa-miR-625-3p	62.2	67.8
hsa-miR-106b-3p	67.6	54.2
hsa-miR-409-3p	63.1	62.7
hsa-miR-1237-3p	63.1	61.0
hsa-miR-5571-5p	66.7	54.2
hsa-miR-652-5p	63.1	61.0
hsa-miR-196b-5p	61.3	62.7
hsa-miR-22-5p	64.9	55.9
hsa-miR-338-3p	64.0	55.9
hsa-miR-26b-3p	62.2	55.9
hsa-miR-4261	55.9	67.8
hsa-miR-345-5p	60.4	57.6
hsa-miR-10a-5p	58.6	59.3
hsa-miR-3176	56.8	62.7
hsa-miR-1224-5p	56.8	61.0
hsa-miR-4462	55.9	62.7
hsa-miR-4728-3p	58.6	57.6
hsa-miR-193a-5p	59.5	54.2
hsa-miR-664b-5p	55.9	61.0
hsa-miR-3141	53.2	64.4
hsa-miR-6075	55.9	59.3
hsa-miR-6086	55.0	61.0
hsa-miR-99b-5p	55.9	59.3
hsa-miR-1307-3p	58.6	52.5
hsa-miR-148b-5p	56.8	55.9
hsa-miR-15a-3p	59.5	50.8
hsa-miR-6513-3p	61.3	47.5
hsa-miR-590-5p	54.1	57.6
hsa-miR-199a-3p	52.3	59.3
hsa-miR-301a-3p	55.0	52.5
hsa-miR-4698	51.4	59.3
hsa-miR-491-5p	56.8	49.2
hsa-miR-4701-5p	53.2	54.2
hsa-miR-572	53.2	54.2
hsa-let-7e-5p	52.3	54.2
hsa-miR-134	52.3	54.2
hsa-miR-335-5p	51.4	54.2
hsa-miR-4646-3p	54.1	49.2
hsa-miR-4463	51.4	52.5
hsa-miR-5690	56.8	39.0
hsa-miR-1972	46.8	50.8
hsa-miR-769-5p	48.6	47.5
hsa-miR-126-5p	43.2	55.9
hsa-miR-192-3p	52.3	39.0
hsa-miR-4800-5p	42.3	52.5
hsa-miR-212-3p	42.3	50.8
hsa-miR-5010-3p	43.2	49.2
hsa-miR-641	48.6	39.0
hsa-miR-3648	40.5	50.8
hsa-miR-548ai	45.9	40.7
hsa-miR-3663-3p	42.3	44.1
hsa-miR-4298	38.7	49.2
hsa-miR-4707-3p	41.4	44.1
hsa-miR-1273e	38.7	47.5
hsa-miR-487b	36.9	49.2
hsa-miR-1227-3p	40.5	40.7
hsa-miR-18a-3p	43.2	35.6
hsa-miR-769-3p	40.5	39.0
hsa-miR-598	39.6	39.0
hsa-miR-1273f	38.7	37.3
hsa-miR-663a	38.7	37.3
hsa-miR-2110	36.9	39.0
hsa-miR-371a-5p	34.2	42.4
hsa-miR-483-3p	36.0	39.0
hsa-miR-5195-3p	37.8	35.6
hsa-miR-654-3p	35.1	35.6
hsa-miR-877-3p	34.2	37.3
hsa-miR-3190-5p	34.2	35.6
hsa-miR-4697-5p	34.2	35.6
hsa-miR-617	36.0	32.2
hsa-miR-4324	35.1	30.5
hsa-miR-4534	31.5	35.6
hsa-miR-4633-5p	28.8	39.0
hsa-miR-4538	27.9	39.0
hsa-miR-664a-5p	29.7	35.6
hsa-miR-4312	26.1	37.3
hsa-miR-6076	25.2	35.6
hsa-miR-5585-3p	28.8	27.1
hsa-miR-125b-1-3p	25.2	32.2
hsa-miR-4632-5p	27.0	28.8
hsa-miR-139-5p	27.9	25.4
hsa-miR-4767	33.3	15.3
hsa-miR-34a-5p	27.9	22.0
hsa-miR-4455	25.2	27.1
hsa-miR-330-3p	28.8	18.6
hsa-miR-1180	25.2	23.7
hsa-miR-193b-3p	28.8	16.9
hsa-miR-4784	20.7	30.5
hsa-miR-4667-5p	23.4	23.7
hsa-miR-660-3p	23.4	23.7
hsa-miR-4731-3p	22.5	23.7
hsa-miR-503-5p	24.3	20.3
hsa-miR-378g	18.0	27.1
hsa-miR-4481	19.8	23.7
hsa-miR-138-2-3p	18.9	23.7
hsa-miR-1469	20.7	20.3
hsa-miR-4327	21.6	18.6
hsa-miR-1236-5p	17.1	23.7
hsa-miR-152	18.0	22.0
hsa-miR-21-3p	18.9	20.3
hsa-miR-4697-3p	16.2	25.4
hsa-miR-548aa	17.1	23.7
hsa-miR-636	19.8	18.6
hsa-miR-767-3p	18.0	22.0
hsa-miR-4689	23.4	8.5
hsa-miR-3679-3p	19.8	13.6
hsa-miR-4326	15.3	22.0
hsa-miR-2276	17.1	16.9
hsa-miR-3137	17.1	16.9
hsa-miR-4734	16.2	18.6
hsa-miR-181c-5p	18.0	13.6
hsa-miR-921	17.1	15.3
hsa-miR-3688-3p	15.3	16.9
hsa-miR-4274	15.3	16.9
hsa-miR-4758-5p	16.2	13.6
hsa-miR-5010-5p	15.3	15.3
hsa-miR-4488	13.5	16.9
hsa-miR-483-5p	14.4	15.3
hsa-miR-542-5p	15.3	13.6
hsa-miR-623	11.7	20.3
hsa-miR-650	9.9	23.7
hsa-miR-3188	11.7	18.6
hsa-miR-378b	10.8	20.3
hsa-miR-576-5p	12.6	16.9
hsa-miR-20a-3p	15.3	10.2
hsa-miR-4487	15.3	10.2
hsa-miR-1976	12.6	13.6
hsa-miR-3605-3p	12.6	13.6
hsa-miR-4647	9.9	18.6
hsa-miR-4700-3p	11.7	15.3
hsa-miR-6503-3p	12.6	13.6
hsa-miR-3615	10.8	13.6
hsa-miR-424-3p	10.8	13.6
hsa-miR-4636	11.7	11.9
hsa-miR-4646-5p	9.0	16.9
hsa-miR-3610	12.6	8.5
hsa-miR-557	9.9	13.6
hsa-miR-718	14.4	5.1
hsa-miR-193b-5p	9.0	13.6
hsa-miR-3692-5p	12.6	6.8
hsa-miR-509-3-5p	11.7	8.5
hsa-miR-1470	10.8	8.5
hsa-miR-28-3p	8.1	13.6
hsa-miR-378f	10.8	8.5
hsa-miR-4252	6.3	16.9
hsa-miR-4417	11.7	6.8
hsa-miR-4498	10.8	8.5
hsa-miR-491-3p	8.1	13.6
hsa-miR-495-3p	7.2	15.3
hsa-miR-5096	12.6	5.1
hsa-miR-1229-3p	6.3	15.3
hsa-miR-299-5p	6.3	15.3
hsa-miR-3138	6.3	15.3
hsa-miR-335-3p	8.1	11.9
hsa-miR-3682-3p	8.1	11.9
hsa-miR-485-3p	8.1	11.9
hsa-miR-630	7.2	13.6
hsa-miR-936	9.0	10.2
hsa-miR-101-5p	10.8	5.1
hsa-miR-122-5p	9.9	6.8
hsa-miR-4446-3p	5.4	15.3
hsa-miR-4518	8.1	10.2
hsa-miR-4640-3p	6.3	13.6
hsa-miR-5189	8.1	10.2
hsa-miR-6129	8.1	10.2
hsa-miR-1471	8.1	8.5
hsa-miR-29b-2-5p	8.1	8.5
hsa-miR-5003-5p	5.4	13.6
hsa-miR-1273c	6.3	10.2
hsa-miR-190a	9.0	5.1
hsa-miR-3675-3p	8.1	6.8
hsa-miR-6511b-5p	5.4	11.9
hsa-miR-1291	4.5	11.9
hsa-miR-3934-5p	4.5	11.9
hsa-miR-4737	7.2	6.8
hsa-miR-486-3p	6.3	8.5
hsa-miR-5580-3p	2.7	15.3
hsa-miR-671-3p	7.2	6.8
hsa-miR-154-5p	6.3	6.8
hsa-miR-3158-5p	7.2	5.1
hsa-miR-337-3p	3.6	11.9
hsa-miR-363-5p	4.5	10.2
hsa-miR-376a-3p	3.6	11.9
hsa-miR-5190	3.6	11.9
hsa-miR-5701	6.3	6.8
hsa-miR-770-5p	3.6	11.9
hsa-miR-1226-5p	3.6	10.2
hsa-miR-1267	6.3	5.1
hsa-miR-1306-3p	6.3	5.1
hsa-miR-3154	4.5	8.5
hsa-miR-329	3.6	10.2
hsa-miR-4659b-3p	7.2	3.4
hsa-miR-6134	3.6	10.2
hsa-miR-181a-3p	4.5	6.8
hsa-miR-1827	5.4	5.1
hsa-miR-3926	2.7	10.2
hsa-miR-662	4.5	6.8
hsa-miR-127-3p	4.5	5.1
hsa-miR-148a-5p	3.6	6.8
hsa-miR-18b-3p	3.6	6.8
hsa-miR-202-3p	2.7	8.5
hsa-miR-4325	2.7	8.5
hsa-miR-4673	5.4	3.4
hsa-miR-4730	6.3	1.7
hsa-miR-489	4.5	5.1
hsa-miR-584-3p	4.5	5.1
hsa-miR-6720-3p	1.8	10.2
hsa-let-7i-3p	5.4	1.7
hsa-miR-1307-5p	3.6	5.1
hsa-miR-204-5p	4.5	3.4
hsa-miR-218-5p	4.5	3.4
hsa-miR-378e	3.6	5.1
hsa-miR-3911	2.7	6.8
hsa-miR-543	3.6	5.1
hsa-miR-5703	3.6	5.1
hsa-miR-589-3p	3.6	5.1
hsa-miR-885-5p	1.8	8.5
hsa-let-7g-3p	3.6	3.4
hsa-miR-1185-2-3p	4.5	1.7
hsa-miR-1238-5p	3.6	3.4
hsa-miR-19b-1-5p	3.6	3.4
hsa-miR-3130-5p	2.7	5.1
hsa-miR-3163	3.6	3.4
hsa-miR-377-3p	2.7	5.1
hsa-miR-421	2.7	5.1
hsa-miR-4419a	2.7	5.1
hsa-miR-4425	3.6	3.4
hsa-miR-4470	3.6	3.4
hsa-miR-4539	2.7	5.1
hsa-miR-516a-5p	3.6	3.4
hsa-miR-610	4.5	1.7
hsa-miR-628-5p	3.6	3.4
hsa-miR-99b-3p	2.7	5.1
hsa-let-7f-2-3p	2.7	3.4
hsa-miR-193a-3p	0.9	6.8
hsa-miR-195-3p	2.7	3.4
hsa-miR-221-5p	3.6	1.7
hsa-miR-223-5p	4.5	0.0
hsa-miR-23a-5p	1.8	5.1
hsa-miR-25-5p	1.8	5.1
hsa-miR-3616-3p	0.9	6.8
hsa-miR-376c-3p	1.8	5.1
hsa-miR-4701-3p	2.7	3.4
hsa-miR-4743-5p	1.8	5.1
hsa-miR-5008-5p	1.8	5.1
hsa-miR-570-3p	2.7	3.4
hsa-miR-595	1.8	5.1
hsa-miR-6716-3p	3.6	1.7
hsa-miR-887	2.7	3.4
hsa-miR-1299	0.9	5.1
hsa-miR-133a	2.7	1.7
hsa-miR-198	1.8	3.4
hsa-miR-3622b-5p	0.9	5.1
hsa-miR-373-5p	3.6	0.0
hsa-miR-3917	0.9	5.1
hsa-miR-409-5p	1.8	3.4
hsa-miR-4440	2.7	1.7
hsa-miR-4514	0.9	5.1
hsa-miR-4535	0.9	5.1
hsa-miR-4668-5p	0.9	5.1
hsa-miR-4776-5p	0.9	5.1
hsa-miR-4793-3p	2.7	1.7
hsa-miR-542-3p	0.9	5.1
hsa-miR-548am-5p	1.8	3.4
hsa-miR-548q	1.8	3.4
hsa-miR-582-5p	2.7	1.7
hsa-miR-654-5p	1.8	3.4
hsa-miR-758-3p	2.7	1.7
hsa-miR-760	0.0	6.8
hsa-miR-765	1.8	3.4
hsa-miR-875-5p	1.8	3.4
hsa-miR-106a-3p	2.7	0.0
hsa-miR-1236-3p	0.0	5.1
hsa-miR-1255b-5p	1.8	1.7
hsa-miR-181c-3p	2.7	0.0
hsa-miR-26a-2-3p	0.9	3.4
hsa-miR-298	0.9	3.4
hsa-miR-3194-5p	0.9	3.4
hsa-miR-3620-3p	1.8	1.7
hsa-miR-374a-3p	1.8	1.7
hsa-miR-411-3p	1.8	1.7
hsa-miR-4475	0.9	3.4
hsa-miR-4476	0.9	3.4
hsa-miR-4716-5p	1.8	1.7
hsa-miR-4762-3p	1.8	1.7
hsa-miR-544a	1.8	1.7
hsa-miR-548d-5p	1.8	1.7
hsa-miR-561-3p	1.8	1.7
hsa-miR-5695	2.7	0.0
hsa-miR-580	1.8	1.7
hsa-miR-612	1.8	1.7
hsa-miR-622	0.9	3.4
hsa-miR-670	1.8	1.7
hsa-miR-744-3p	1.8	1.7
hsa-let-7a-3p	0.9	1.7
hsa-miR-1255a	0.9	1.7
hsa-miR-1270	0.9	1.7
hsa-miR-185-3p	0.0	3.4
hsa-miR-186-3p	0.0	3.4
hsa-miR-187-5p	0.9	1.7
hsa-miR-194-3p	1.8	0.0
hsa-miR-200b-5p	0.9	1.7
hsa-miR-2052	0.0	3.4
hsa-miR-224-5p	0.9	1.7
hsa-miR-2964a-5p	0.9	1.7
hsa-miR-29b-1-5p	0.9	1.7
hsa-miR-30d-3p	0.0	3.4
hsa-miR-3150b-5p	1.8	0.0
hsa-miR-3184-3p	0.9	1.7
hsa-miR-32-3p	0.9	1.7
hsa-miR-323a-3p	1.8	0.0
hsa-miR-3663-5p	1.8	0.0
hsa-miR-370	0.9	1.7
hsa-miR-376a-5p	0.9	1.7
hsa-miR-381-3p	0.9	1.7
hsa-miR-3924	0.0	3.4
hsa-miR-3945	0.9	1.7
hsa-miR-422a	1.8	0.0
hsa-miR-4289	0.9	1.7
hsa-miR-432-3p	0.0	3.4
hsa-miR-4468	0.9	1.7
hsa-miR-452-3p	0.9	1.7
hsa-miR-452-5p	0.0	3.4
hsa-miR-4714-5p	0.9	1.7
hsa-miR-504	1.8	0.0
hsa-miR-5088	0.0	3.4
hsa-miR-518b	0.9	1.7
hsa-miR-545-3p	0.9	1.7
hsa-miR-545-5p	0.9	1.7
hsa-miR-548at-5p	0.9	1.7
hsa-miR-556-3p	0.9	1.7
hsa-miR-559	0.0	3.4
hsa-miR-5686	0.9	1.7
hsa-miR-5692a	0.0	3.4
hsa-miR-586	0.9	1.7
hsa-miR-590-3p	1.8	0.0
hsa-miR-601	0.9	1.7
hsa-miR-607	0.9	1.7
hsa-miR-619	0.0	3.4
hsa-miR-624-3p	1.8	0.0
hsa-miR-642a-5p	0.9	1.7
hsa-miR-645	0.9	1.7
hsa-miR-668	0.9	1.7
hsa-miR-6722-3p	1.8	0.0
hsa-miR-675-5p	0.9	1.7
hsa-miR-888-3p	0.9	1.7
hsa-miR-937-3p	0.9	1.7
hsa-miR-939-3p	0.9	1.7
hsa-miR-10b-3p	0.0	1.7
hsa-miR-10b-5p	0.0	1.7
hsa-miR-1183	0.0	1.7
hsa-miR-1208	0.0	1.7
hsa-miR-1226-3p	0.0	1.7
hsa-miR-1228-5p	0.0	1.7
hsa-miR-124-3p	0.9	0.0
hsa-miR-124-5p	0.0	1.7
hsa-miR-1247-3p	0.9	0.0
hsa-miR-1261	0.0	1.7
hsa-miR-1269a	0.0	1.7
hsa-miR-1273d	0.9	0.0
hsa-miR-1285-5p	0.0	1.7
hsa-miR-1287	0.0	1.7
hsa-miR-1296	0.0	1.7
hsa-miR-143-3p	0.9	0.0
hsa-miR-1538	0.0	1.7
hsa-miR-16-1-3p	0.9	0.0
hsa-miR-184	0.9	0.0
hsa-miR-188-3p	0.9	0.0
hsa-miR-1909-5p	0.0	1.7
hsa-miR-1910	0.0	1.7
hsa-miR-196a-3p	0.9	0.0
hsa-miR-19a-5p	0.0	1.7
hsa-miR-19b-2-5p	0.9	0.0
hsa-miR-205-5p	0.9	0.0
hsa-miR-206	0.0	1.7
hsa-miR-20b-3p	0.9	0.0
hsa-miR-2115-5p	0.9	0.0
hsa-miR-218-1-3p	0.0	1.7
hsa-miR-218-2-3p	0.9	0.0
hsa-miR-2277-3p	0.0	1.7
hsa-miR-2681-3p	0.9	0.0
hsa-miR-26a-1-3p	0.9	0.0
hsa-miR-27b-5p	0.0	1.7
hsa-miR-297	0.0	1.7
hsa-miR-29a-5p	0.0	1.7
hsa-miR-300	0.9	0.0
hsa-miR-301b	0.9	0.0
hsa-miR-302b-3p	0.0	1.7
hsa-miR-30a-3p	0.9	0.0
hsa-miR-3132	0.0	1.7
hsa-miR-3149	0.0	1.7
hsa-miR-3157-5p	0.0	1.7
hsa-miR-3161	0.0	1.7
hsa-miR-32-5p	0.9	0.0
hsa-miR-330-5p	0.9	0.0
hsa-miR-33a-3p	0.9	0.0
hsa-miR-33b-5p	0.0	1.7
hsa-miR-34c-3p	0.0	1.7
hsa-miR-3591-3p	0.0	1.7
hsa-miR-3607-3p	0.9	0.0
hsa-miR-3654	0.0	1.7
hsa-miR-3666	0.0	1.7
hsa-miR-367-5p	0.9	0.0
hsa-miR-374b-3p	0.9	0.0
hsa-miR-379-3p	0.9	0.0
hsa-miR-380-5p	0.9	0.0
hsa-miR-3935	0.0	1.7
hsa-miR-3937	0.0	1.7
hsa-miR-3942-3p	0.9	0.0
hsa-miR-3976	0.0	1.7
hsa-miR-410	0.0	1.7
hsa-miR-4259	0.0	1.7
hsa-miR-4272	0.0	1.7
hsa-miR-4290	0.0	1.7
hsa-miR-4294	0.0	1.7
hsa-miR-431-5p	0.0	1.7
hsa-miR-4420	0.9	0.0
hsa-miR-4422	0.0	1.7
hsa-miR-4489	0.0	1.7
hsa-miR-4500	0.9	0.0
hsa-miR-450a-5p	0.9	0.0
hsa-miR-450b-3p	0.0	1.7
hsa-miR-451b	0.9	0.0
hsa-miR-4520b-3p	0.0	1.7
hsa-miR-4639-3p	0.9	0.0
hsa-miR-4648	0.0	1.7
hsa-miR-4657	0.0	1.7
hsa-miR-4677-3p	0.9	0.0
hsa-miR-4677-5p	0.9	0.0
hsa-miR-4685-3p	0.9	0.0
hsa-miR-4694-3p	0.0	1.7
hsa-miR-4695-3p	0.0	1.7
hsa-miR-4707-5p	0.0	1.7
hsa-miR-4710	0.0	1.7
hsa-miR-4723-3p	0.9	0.0
hsa-miR-4726-5p	0.0	1.7
hsa-miR-4733-3p	0.0	1.7
hsa-miR-4733-5p	0.9	0.0
hsa-miR-4736	0.0	1.7
hsa-miR-4740-5p	0.0	1.7
hsa-miR-4755-3p	0.0	1.7
hsa-miR-4762-5p	0.0	1.7
hsa-miR-4763-5p	0.0	1.7
hsa-miR-4785	0.0	1.7
hsa-miR-4792	0.9	0.0
hsa-miR-4800-3p	0.9	0.0
hsa-miR-493-5p	0.0	1.7
hsa-miR-5007-3p	0.9	0.0
hsa-miR-5011-5p	0.9	0.0
hsa-miR-5087	0.0	1.7
hsa-miR-5093	0.0	1.7
hsa-miR-513a-3p	0.0	1.7
hsa-miR-513c-3p	0.0	1.7
hsa-miR-517c-3p	0.0	1.7
hsa-miR-518a-5p	0.0	1.7
hsa-miR-5196-3p	0.9	0.0
hsa-miR-520c-3p	0.9	0.0
hsa-miR-541-3p	0.0	1.7
hsa-miR-548a-3p	0.9	0.0
hsa-miR-548ap-3p	0.9	0.0
hsa-miR-548d-3p	0.9	0.0
hsa-miR-548e	0.9	0.0
hsa-miR-552	0.9	0.0
hsa-miR-558	0.0	1.7
hsa-miR-5591-3p	0.0	1.7
hsa-miR-5681b	0.9	0.0
hsa-miR-5692b	0.9	0.0
hsa-miR-5692c	0.9	0.0
hsa-miR-571	0.0	1.7
hsa-miR-588	0.9	0.0
hsa-miR-589-5p	0.9	0.0
hsa-miR-593-3p	0.9	0.0
hsa-miR-597	0.0	1.7
hsa-miR-609	0.9	0.0
hsa-miR-615-3p	0.0	1.7
hsa-miR-615-5p	0.0	1.7
hsa-miR-616-5p	0.9	0.0
hsa-miR-618	0.0	1.7
hsa-miR-621	0.9	0.0
hsa-miR-631	0.0	1.7
hsa-miR-633	0.0	1.7
hsa-miR-637	0.0	1.7
hsa-miR-639	0.9	0.0
hsa-miR-642b-5p	0.9	0.0
hsa-miR-646	0.9	0.0
hsa-miR-6509-3p	0.9	0.0
hsa-miR-651	0.9	0.0
hsa-miR-6511a-3p	0.0	1.7
hsa-miR-657	0.9	0.0
hsa-miR-6722-5p	0.0	1.7
hsa-miR-708-5p	0.9	0.0
hsa-miR-767-5p	0.9	0.0
hsa-miR-875-3p	0.0	1.7
hsa-miR-876-5p	0.9	0.0
hsa-miR-877-5p	0.9	0.0
hsa-miR-891a	0.9	0.0
hsa-miR-920	0.9	0.0
hsa-miR-922	0.9	0.0
hsa-miR-924	0.0	1.7
hsa-miR-92a-2-5p	0.9	0.0
hsa-miR-935	0.9	0.0
hsa-miR-938	0.0	1.7
hsa-miR-943	0.9	0.0
hsa-miR-423-5p	100.0	100.0

15. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - Hepatobiliary Questionnaire (FACT-Hep) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model
Description	FACT-Hep consists of 27-item FACT-G, and 18-item Hepatobiliary Subscale. FACT-Hep questionnaire uses 5-point Likert rating scale, range '0'-not at all to '4'. FACT-Hep total score ranges from 0 to 180, where highest score represents maximum achievable quality of life. Domains of FACT-G include Physical Well-Being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB). Hepatobiliary disease specific items include: swelling or cramps, losing weight, gastrointestinal (GI)-related questions, lack of energy, side effects, pain, fatigue, usual activities, jaundice, fevers, itching, taste of food and chills. Eight of the items (pain, back pain, stomach pain/discomfort, lack of energy, fatigue, nausea, weight loss and jaundice) make up FACT-Hepatobiliary Symptom Index (FHSI-8), and are considered to be symptoms specific to hepatobiliary cancer. Table below included mixed effect model estimated average based on all observed values/time points.
Time Frame	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	123.33; (120.17 to 126.50)	135.22; (129.17 to 141.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0006
	Comments	No adjustment made for multiple comparisons.
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.89
	Confidence Interval	(2-Sided) 95%; -18.70 to -5.08
	Estimation Comments	[Not Specified]

16. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - General (FACT-G) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model
Description	FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate QoL in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): PWB, SWB, EWB and FWB; each ranging from 0 (not at all) to 4 (very much). FACT-G ranged between 0 and 108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.
Time Frame	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	71.20; (69.00 to 73.41)	78.81; (74.68 to 82.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0014
	Comments	No adjustment made for multiple comparisons.
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.60
	Confidence Interval	(2-Sided) 95%; -12.27 to -2.94
	Estimation Comments	[Not Specified]

17. Secondary Outcome

Title	Functional Assessment of Cancer Therapy (FACT)-Hepatobiliary Symptom Index-8 (FHSI-8) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model
Description	The FACT-Hep includes the FACT-G and a hepatobiliary module. The hepatobiliary disease specific items include: swelling or cramps, losing weight, GI related questions, lack of energy, side effects, pain, fatigue, usual activities, jaundice, fevers, itching, taste of food and chills. Eight of the items (pain, back pain, stomach pain/discomfort, lack of energy, fatigue, nausea, weight loss, and jaundice) make up the FHSI-8, and are considered to be symptoms specific to hepatobiliary cancer. FHSI-8 total score ranges from 0 to 32 where "0" is a severely symptomatic participant and the highest score indicates an asymptomatic participant. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.
Time Frame	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	23.42; (22.77 to 24.07)	26.69; (25.35 to 28.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	No adjustment made for multiple comparisons.
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.27
	Confidence Interval	(2-Sided) 95%; -4.76 to -1.78
	Estimation Comments	[Not Specified]

18. Secondary Outcome

Title	Functional Assessment of Cancer Therapy-G (FACT-G) Subscales in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model
Description	FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate QoL in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general HRQoL: PWB, SWB, EWB and FWB. Each of the individual subscale, except EWB has 7 items and each integer scored 0 to 4 making a maximum possible score of 28 (range 0 to 28). EWB has 6 items and each integer scored 0 to 4 making a maximum possible score of 24 (range 0 to 24). For all the 4 scales, higher values correspond to better health. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.
Time Frame	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
PWB	19.39; (18.72 to 20.07)	23.13; (21.76 to 24.50)
SWB	18.94; (18.05 to 19.83)	20.21; (18.66 to 21.77)
EWB	17.23; (16.63 to 17.84)	17.71; (16.54 to 18.89)
FWB	15.76; (14.88 to 16.65)	17.83; (16.19 to 19.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis presented above is for FACT-G PWB. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	No adjustment made for multiple comparisons.
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.74
	Confidence Interval	(2-Sided) 95%; -5.26 to -2.21
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis presented above is for FACT-G SWB. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1642
	Comments	No adjustment made for multiple comparisons.
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.27
	Confidence Interval	(2-Sided) 95%; -3.07 to 0.52
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis presented above is for FACT-G EWB. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4759
	Comments	No adjustment made for multiple comparisons.
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -1.80 to 0.84
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis presented above is for FACT-G FWB. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0288
	Comments	No adjustment made for multiple comparisons.
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.07
	Confidence Interval	(2-Sided) 95%; -3.92 to -0.21
	Estimation Comments	[Not Specified]

19. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - Hepatobiliary Cancer Subscale (FACT Hep-CS18) Questionnaire in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model
Description	This subscale consists of 18 items rated on a scale from '0' - not at all to '4' - very much regarding how much each item was present in the last 7 days. FACT-Hep-CS18 total score ranges from 0 to 72. The higher score reflects better QoL or fewer symptoms. The 18 items of this scale are associated with hepatocellular carcinoma. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.
Time Frame	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	51.78; (50.46 to 53.10)	56.74; (54.08 to 59.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0011
	Comments	No adjustment made for multiple comparisons.
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.96
	Confidence Interval	(2-Sided) 95%; -7.93 to -1.99
	Estimation Comments	[Not Specified]

20. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - Hepatobiliary Cancer Trial Outcome Index (FACT Hep-TOI) Questionnaire in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model
Description	The trial outcome index is defined to be the sum (PWB+FWB+HepCS), making it 32 items altogether. Each ranges from '0' - not at all to '4' - very much regarding how much each item was present in the last 7 days. FACT Hep -TOI total score ranges from 0 to 128, where the highest score represents a maximum achievable quality of life. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.
Time Frame	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	87.28; (84.98 to 89.58)	97.73; (93.24 to 102.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	No adjustment made for multiple comparisons.
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.45
	Confidence Interval	(2-Sided) 95%; -15.49 to -5.42
	Estimation Comments	[Not Specified]

21. Secondary Outcome

Title	Time to Deterioration (TTD) Based on the Composite Endpoint in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model
Description	TTD analysis was performed for FHSI-8. Time to deterioration was defined as the time between date of randomization and date of the event.
Time Frame	From randomization to death or tumor progression or FHSI-8 mean score decrease >=3 points, whichever comes first

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Median (95% Confidence Interval); Unit of Measure: months
	1.9; (1.8 to 1.9)	1.9; (1.8 to 2.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9182
	Comments	The p-value is from a 1-sided log-rank test.
	Method	1-sided, unstratified log-rank test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.252
	Confidence Interval	(2-Sided) 95%; 0.923 to 1.698
	Estimation Comments	Assuming proportional hazards, a hazard ratio <1 indicates reduction in hazard rate to favor Axitinib, hazard ratio >1 indicates reduction to favor Placebo.

22. Secondary Outcome

Title	EuroQoL (EQ-5D)- Health State Profile Utility Score in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model
Description	EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state. Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.
Time Frame	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	0.67; (0.63 to 0.70)	0.79; (0.72 to 0.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0024
	Comments	[Not Specified]
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.20 to -0.04
	Estimation Comments	[Not Specified]

23. Secondary Outcome

Title	EuroQoL Visual Analogue Scale (EQ-VAS) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model
Description	EQ-5D VAS in rates the participant's overall health status using values from 0 (worst imaginable) to 100 (best imaginable). The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used.
Time Frame	Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants, and participants were classified according to the randomized treatment arm regardless of what treatment, if any, was received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	134	68
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	68.67; (66.11 to 71.23)	75.70; (70.40 to 81.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib, Placebo
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0193
	Comments	[Not Specified]
	Method	Longitudinal mixed effect analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.03
	Confidence Interval	(2-Sided) 95%; -12.91 to -1.15
	Estimation Comments	[Not Specified]

24. Secondary Outcome

Title	Number of Participants With Dose-Limiting Toxicities (DLTs) in Non-Randomized Portion
Description	Number of Child-Pugh Class B (score 7) participants with DLT was evaluated during Cycle 1 of treatment in the non-randomized portion of the study.
Time Frame	Cycle 1 (4 weeks)

Outcome Measure Data

Analysis Population Description

Participants with Child-Pugh Class B, score 7 are only included in this analysis.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B
Arm/Group Description:	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
Overall Number of Participants Analyzed	0	7
Measure Type: Number; Unit of Measure: participants
		2

25. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) in Non-Randomized Portion
Description	An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. The grade of an AE was determined according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.
Time Frame	Up to 28 days after last dose of study drug (up to 6 years)

Outcome Measure Data

Analysis Population Description

The safety analysis population included participants who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B
Arm/Group Description:	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
Overall Number of Participants Analyzed	15	7
Measure Type: Number; Unit of Measure: participants
Participants with AEs	15	7
Participants with SAEs	10	3
Participants >=Grade 3 AEs	13	5
Participants Grade 5 AEs	4	1

26. Secondary Outcome

Title	Number of Participants With Treatment-Related Adverse Events (AEs) in Non-Randomized Portion
Description	Treatment-related AE was any untoward medical occurrence in a participant with causal relationship to the study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The grade of an AE was determined according to CTCAE Version 3.0.
Time Frame	Up to 28 days after last dose of study drug (up to 6 years)

Outcome Measure Data

Analysis Population Description

The safety analysis population included participants who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B
Arm/Group Description:	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
Overall Number of Participants Analyzed	15	7
Measure Type: Number; Unit of Measure: participants
Participants with AEs	14	6
Participants with SAEs	2	2
Participants ≥Grade 3 AEs	9	4
Participants Grade 5 AEs	0	0

27. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) in Randomized Portion
Description	An AE was an untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. The grade of an AE was determined according to CTCAE Version 3.0.
Time Frame	Up to 28 days after last dose of study drug (up to 6 years)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all randomized participants who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	133	68
Measure Type: Number; Unit of Measure: participants
Participants with AEs	131	63
Participants with SAEs	62	16
Participants with Grade >=3 AEs	109	26
Participants with Grade 5 AEs	16	8

28. Secondary Outcome

Title	Number of Participants With Treatment-Related Adverse Events (AEs) in Randomized Portion
Description	Treatment-related AE was any untoward medical occurrence in a participant with causal relationship to the study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The grade of an AE was determined according to CTCAE Version 3.0.
Time Frame	Up to 28 days after last dose of study drug (up to 6 years)

Outcome Measure Data

Analysis Population Description

The safety analysis population included all randomized participants who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Axitinib	Placebo
Arm/Group Description:	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
Overall Number of Participants Analyzed	133	68
Measure Type: Number; Unit of Measure: participants
Participants with AEs	128	40
Participants with SAEs	24	1
Participants with Grade >=3 AEs	90	12
Participants with Grade 5 AEs	1	0

Adverse Events

Time Frame	Baseline up to follow-up visit (up to 6 years)
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Child-Pugh Class A	Child-Pugh Class B	Axitinib	Placebo
Arm/Group Description	Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.	Participants with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non randomized portion of this study to determine the recommended starting dose of axitinib for this population.	Participants in this group received axitinib + best supportive care. Participants with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Participants with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non randomized portion. Study treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles).	Participants in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration (up to a maximum of 55 cycles). The starting dose of placebo for participants with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Participants with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, participants with Child Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
All-Cause Mortality
	Child-Pugh Class A	Child-Pugh Class B	Axitinib	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--
Serious Adverse Events
	Child-Pugh Class A	Child-Pugh Class B	Axitinib	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	10/15 (66.67%)	3/7 (42.86%)	62/133 (46.62%)	16/68 (23.53%)
Blood and lymphatic system disorders
Anaemia * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Febrile neutropenia * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Cardiac disorders
Acute myocardial infarction * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Bradycardia * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Ventricular tachycardia * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Eye disorders
Cataract * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Retinal vein occlusion * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Gastrointestinal disorders
Abdominal pain * 1	1/15 (6.67%)	0/7 (0.00%)	3/133 (2.26%)	2/68 (2.94%)
Ascites * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	2/68 (2.94%)
Colitis * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Diarrhoea * 1	0/15 (0.00%)	0/7 (0.00%)	7/133 (5.26%)	0/68 (0.00%)
Enterocolitis haemorrhagic * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Gastric ulcer * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Gastrointestinal disorder * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Gastrointestinal haemorrhage * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Haematochezia * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Rectal haemorrhage * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Varices oesophageal * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Upper gastrointestinal haemorrhage * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	1/68 (1.47%)
General disorders
Asthenia * 1	0/15 (0.00%)	0/7 (0.00%)	4/133 (3.01%)	0/68 (0.00%)
Disease progression * 1	3/15 (20.00%)	0/7 (0.00%)	8/133 (6.02%)	4/68 (5.88%)
General physical health deterioration * 1	0/15 (0.00%)	0/7 (0.00%)	3/133 (2.26%)	0/68 (0.00%)
Inflammation * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Oedema peripheral * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Pyrexia * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	1/68 (1.47%)
Fatigue * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Hepatobiliary disorders
Bile duct stenosis * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Cholangitis * 1	0/15 (0.00%)	0/7 (0.00%)	4/133 (3.01%)	0/68 (0.00%)
Cholecystitis acute * 1	2/15 (13.33%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Hepatic failure * 1	0/15 (0.00%)	0/7 (0.00%)	2/133 (1.50%)	0/68 (0.00%)
Hepatic function abnormal * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Hepatorenal syndrome * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Jaundice cholestatic * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Bile duct stone * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Infections and infestations
Abscess rupture * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Appendicitis * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Gastroenteritis * 1	0/15 (0.00%)	0/7 (0.00%)	2/133 (1.50%)	0/68 (0.00%)
Otitis media * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Ovarian abscess * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Peritonitis bacterial * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Pneumonia * 1	1/15 (6.67%)	0/7 (0.00%)	1/133 (0.75%)	1/68 (1.47%)
Sepsis * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Upper respiratory tract infection * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	1/68 (1.47%)
Urinary tract infection * 1	0/15 (0.00%)	0/7 (0.00%)	3/133 (2.26%)	0/68 (0.00%)
Injury, poisoning and procedural complications
Femur fracture * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Humerus fracture * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Road traffic accident * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Investigations
Alanine aminotransferase increased * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Aspartate aminotransferase increased * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Metabolism and nutrition disorders
Cachexia * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Decreased appetite * 1	1/15 (6.67%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Dehydration * 1	0/15 (0.00%)	0/7 (0.00%)	3/133 (2.26%)	0/68 (0.00%)
Electrolyte imbalance * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Hyperkalaemia * 1	0/15 (0.00%)	0/7 (0.00%)	2/133 (1.50%)	0/68 (0.00%)
Hyponatraemia * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Hypovolaemia * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Musculoskeletal and connective tissue disorders
Muscular weakness * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Necrotising myositis * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Osteoporotic fracture * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma * 1	0/15 (0.00%)	1/7 (14.29%)	1/133 (0.75%)	0/68 (0.00%)
Malignant neoplasm progression * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Tumour rupture * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Nervous system disorders
Brain stem infarction * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Cerebral infarction * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Coma hepatic * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Dizziness * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Encephalopathy * 1	0/15 (0.00%)	1/7 (14.29%)	2/133 (1.50%)	0/68 (0.00%)
Epilepsy * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Hepatic encephalopathy * 1	0/15 (0.00%)	0/7 (0.00%)	4/133 (3.01%)	1/68 (1.47%)
Ischaemic stroke * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Quadriparesis * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Psychiatric disorders
Completed suicide * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Dysthymic disorder * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Renal and urinary disorders
Renal failure * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	1/68 (1.47%)
Renal impairment * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Ureteric obstruction * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Dyspnoea * 1	1/15 (6.67%)	0/7 (0.00%)	3/133 (2.26%)	0/68 (0.00%)
Epistaxis * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Lung disorder * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Obstructive airways disorder * 1	0/15 (0.00%)	0/7 (0.00%)	0/133 (0.00%)	1/68 (1.47%)
Pulmonary alveolar haemorrhage * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Respiratory failure * 1	0/15 (0.00%)	0/7 (0.00%)	2/133 (1.50%)	0/68 (0.00%)
Skin and subcutaneous tissue disorders
Drug eruption * 1	0/15 (0.00%)	0/7 (0.00%)	1/133 (0.75%)	0/68 (0.00%)
Vascular disorders
Hypertension * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Hypotension * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (v17.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Child-Pugh Class A	Child-Pugh Class B	Axitinib	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	15/15 (100.00%)	7/7 (100.00%)	130/133 (97.74%)	55/68 (80.88%)
Blood and lymphatic system disorders
Anaemia * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Thrombocytopenia * 1	0/15 (0.00%)	0/7 (0.00%)	8/133 (6.02%)	0/68 (0.00%)
Cardiac disorders
Atrial fibrillation * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Congenital, familial and genetic disorders
Hydrocele * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Ear and labyrinth disorders
Ear disorder * 1	1/15 (6.67%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Endocrine disorders
Hypothyroidism * 1	4/15 (26.67%)	0/7 (0.00%)	33/133 (24.81%)	0/68 (0.00%)
Eye disorders
Ocular surface disease * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Gastrointestinal disorders
Abdominal distension * 1	2/15 (13.33%)	0/7 (0.00%)	5/133 (3.76%)	7/68 (10.29%)
Abdominal pain * 1	6/15 (40.00%)	1/7 (14.29%)	45/133 (33.83%)	12/68 (17.65%)
Abdominal pain upper * 1	2/15 (13.33%)	1/7 (14.29%)	17/133 (12.78%)	3/68 (4.41%)
Anal inflammation * 1	2/15 (13.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Ascites * 1	1/15 (6.67%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Constipation * 1	5/15 (33.33%)	2/7 (28.57%)	21/133 (15.79%)	8/68 (11.76%)
Diarrhoea * 1	9/15 (60.00%)	1/7 (14.29%)	71/133 (53.38%)	8/68 (11.76%)
Dry mouth * 1	1/15 (6.67%)	0/7 (0.00%)	7/133 (5.26%)	2/68 (2.94%)
Dyspepsia * 1	5/15 (33.33%)	2/7 (28.57%)	10/133 (7.52%)	6/68 (8.82%)
Enterocolitis * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Gastritis erosive * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Glossitis * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Nausea * 1	5/15 (33.33%)	3/7 (42.86%)	35/133 (26.32%)	7/68 (10.29%)
Stomatitis * 1	3/15 (20.00%)	0/7 (0.00%)	19/133 (14.29%)	0/68 (0.00%)
Varices oesophageal * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Vomiting * 1	3/15 (20.00%)	0/7 (0.00%)	26/133 (19.55%)	7/68 (10.29%)
General disorders
Asthenia * 1	0/15 (0.00%)	2/7 (28.57%)	27/133 (20.30%)	3/68 (4.41%)
Chest discomfort * 1	2/15 (13.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Chest pain * 1	2/15 (13.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Chills * 1	1/15 (6.67%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Face oedema * 1	2/15 (13.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Fatigue * 1	12/15 (80.00%)	2/7 (28.57%)	46/133 (34.59%)	18/68 (26.47%)
Influenza like illness * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Malaise * 1	0/15 (0.00%)	2/7 (28.57%)	13/133 (9.77%)	1/68 (1.47%)
Mucosal inflammation * 1	1/15 (6.67%)	0/7 (0.00%)	8/133 (6.02%)	0/68 (0.00%)
Oedema * 1	1/15 (6.67%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Oedema peripheral * 1	4/15 (26.67%)	1/7 (14.29%)	14/133 (10.53%)	10/68 (14.71%)
Pain * 1	5/15 (33.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Pyrexia * 1	3/15 (20.00%)	1/7 (14.29%)	16/133 (12.03%)	3/68 (4.41%)
Catheter site pain * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Hepatobiliary disorders
Hyperbilirubinaemia * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Infections and infestations
Bronchitis * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Cystitis * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Nasopharyngitis * 1	0/15 (0.00%)	1/7 (14.29%)	9/133 (6.77%)	8/68 (11.76%)
Pneumonia * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Injury, poisoning and procedural complications
Contusion * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Fall * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Laceration * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Procedural pain * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Investigations
Alanine aminotransferase increased * 1	2/15 (13.33%)	0/7 (0.00%)	8/133 (6.02%)	2/68 (2.94%)
Alpha 1 foetoprotein increased * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Ammonia increased * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Aspartate aminotransferase increased * 1	4/15 (26.67%)	0/7 (0.00%)	10/133 (7.52%)	4/68 (5.88%)
Blood alkaline phosphatase increased * 1	2/15 (13.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Blood bilirubin increased * 1	1/15 (6.67%)	0/7 (0.00%)	7/133 (5.26%)	0/68 (0.00%)
Blood creatinine increased * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Blood thyroid stimulating hormone increased * 1	1/15 (6.67%)	0/7 (0.00%)	9/133 (6.77%)	0/68 (0.00%)
Gamma-glutamyltransferase increased * 1	3/15 (20.00%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Neutrophil count decreased * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Platelet count decreased * 1	2/15 (13.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Weight decreased * 1	5/15 (33.33%)	3/7 (42.86%)	36/133 (27.07%)	2/68 (2.94%)
Metabolism and nutrition disorders
Decreased appetite * 1	6/15 (40.00%)	5/7 (71.43%)	62/133 (46.62%)	14/68 (20.59%)
Dehydration * 1	0/15 (0.00%)	0/7 (0.00%)	9/133 (6.77%)	0/68 (0.00%)
Hypercalcaemia * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Hyperkalaemia * 1	0/15 (0.00%)	1/7 (14.29%)	9/133 (6.77%)	2/68 (2.94%)
Hypoalbuminaemia * 1	4/15 (26.67%)	2/7 (28.57%)	8/133 (6.02%)	1/68 (1.47%)
Hypocalcaemia * 1	1/15 (6.67%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Hypokalaemia * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Hyponatraemia * 1	1/15 (6.67%)	3/7 (42.86%)	8/133 (6.02%)	3/68 (4.41%)
Hypophosphataemia * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	2/15 (13.33%)	0/7 (0.00%)	7/133 (5.26%)	1/68 (1.47%)
Arthropathy * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Back pain * 1	4/15 (26.67%)	1/7 (14.29%)	11/133 (8.27%)	11/68 (16.18%)
Bone pain * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Flank pain * 1	4/15 (26.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Muscle spasms * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Muscular weakness * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Musculoskeletal pain * 1	2/15 (13.33%)	0/7 (0.00%)	8/133 (6.02%)	4/68 (5.88%)
Musculoskeletal chest pain * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Musculoskeletal discomfort * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Musculoskeletal stiffness * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Myalgia * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Neck pain * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Pain in extremity * 1	2/15 (13.33%)	0/7 (0.00%)	7/133 (5.26%)	1/68 (1.47%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Nervous system disorders
Dysgeusia * 1	0/15 (0.00%)	0/7 (0.00%)	9/133 (6.77%)	0/68 (0.00%)
Dizziness * 1	6/15 (40.00%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Headache * 1	5/15 (33.33%)	2/7 (28.57%)	21/133 (15.79%)	3/68 (4.41%)
Hepatic encephalopathy * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Neuropathy peripheral * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Peripheral sensory neuropathy * 1	2/15 (13.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Tremor * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Psychiatric disorders
Agitation * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Confusional state * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Depression * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Insomnia * 1	2/15 (13.33%)	1/7 (14.29%)	12/133 (9.02%)	3/68 (4.41%)
Irritability * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Renal and urinary disorders
Chromaturia * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Dysuria * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Pollakiuria * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Proteinuria * 1	4/15 (26.67%)	1/7 (14.29%)	27/133 (20.30%)	1/68 (1.47%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	3/15 (20.00%)	0/7 (0.00%)	16/133 (12.03%)	6/68 (8.82%)
Dysphonia * 1	6/15 (40.00%)	3/7 (42.86%)	33/133 (24.81%)	0/68 (0.00%)
Dyspnoea * 1	3/15 (20.00%)	1/7 (14.29%)	13/133 (9.77%)	6/68 (8.82%)
Epistaxis * 1	1/15 (6.67%)	0/7 (0.00%)	10/133 (7.52%)	2/68 (2.94%)
Haemoptysis * 1	1/15 (6.67%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Interstitial lung disease * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Nasal congestion * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Nasal inflammation * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Oropharyngeal pain * 1	2/15 (13.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Productive cough * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Upper respiratory tract inflammation * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Skin and subcutaneous tissue disorders
Alopecia * 1	0/15 (0.00%)	0/7 (0.00%)	6/133 (4.51%)	7/68 (10.29%)
Blister * 1	2/15 (13.33%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Dry skin * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Facial wasting * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Nail disorder * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Night sweats * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Palmar-plantar erythrodysaesthesia syndrome * 1	8/15 (53.33%)	2/7 (28.57%)	45/133 (33.83%)	4/68 (5.88%)
Petechiae * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
Pruritus * 1	0/15 (0.00%)	1/7 (14.29%)	11/133 (8.27%)	8/68 (11.76%)
Rash * 1	2/15 (13.33%)	2/7 (28.57%)	23/133 (17.29%)	2/68 (2.94%)
Skin ulcer * 1	0/15 (0.00%)	1/7 (14.29%)	0/133 (0.00%)	0/68 (0.00%)
Vascular disorders
Hypertension * 1	7/15 (46.67%)	3/7 (42.86%)	72/133 (54.14%)	9/68 (13.24%)
Hypotension * 1	1/15 (6.67%)	0/7 (0.00%)	0/133 (0.00%)	0/68 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (v17.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kang YK, Yau T, Park JW, Lim HY, Lee TY, Obi S, Chan SL, Qin S, Kim RD, Casey M, Chen C, Bhattacharyya H, Williams JA, Valota O, Chakrabarti D, Kudo M. Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma. Ann Oncol. 2015 Dec;26(12):2457-63. doi: 10.1093/annonc/mdv388. Epub 2015 Sep 18.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01210495
• Other Study ID Numbers: A4061058; 2010-021590-37 ( EudraCT Number )
• First Submitted: September 22, 2010
• First Posted: September 28, 2010
• Results First Submitted: March 3, 2015
• Results First Posted: May 27, 2015
• Last Update Posted: January 9, 2019