Trial Outcomes & Findings for Study of TAC-101 as Second Line Treatment in Patients With Advanced Hepatocellular Carcinoma Who Received Sorafenib as First Line Therapy (NCT NCT00687596)

Last Updated: 2024-09-19

Results Overview

OS was defined as the time from the date of randomization to the date of death. Participants who were still alive were censored at the date last known to be alive (last contact date or last follow-up visit).

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

52 participants

Primary outcome timeframe

From the date of randomization to date of death or up to 1 year post last participant was randomized, whichever was earlier (maximum duration: up to 21.3 months)

Results posted on

2024-09-19

Participant Flow

The study was conducted at 17 study centers worldwide between 01-August-2008 to 10-May-2010.

The study was stopped after only 52 of the required 220 participants (26 of 110 participants in each treatment group) were randomized. Sponsor terminated the study due to safety concerns and thus, stopped enrollment and study treatment on 06-May-2009, but continued follow-up of all the treated participants for survival till 10 May 2010 and thus, the same was considered as study completion date.

Participant milestones

Participant milestones
Measure	TAC-101 Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 milligram per day (mg/day) of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Overall Study STARTED	26	26
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	26	26

Reasons for withdrawal

Reasons for withdrawal
Measure	TAC-101 Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 milligram per day (mg/day) of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Overall Study Adverse Event (AE)	10	3
Overall Study Radiological Disease Progression	6	2
Overall Study Clinical Disease Progression	1	3
Overall Study Investigator Discretion	3	1
Overall Study Sponsor Terminated Study	6	17

Baseline Characteristics

Study of TAC-101 as Second Line Treatment in Patients With Advanced Hepatocellular Carcinoma Who Received Sorafenib as First Line Therapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	TAC-101 n=26 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=26 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Total n=52 Participants Total of all reporting groups
Age, Continuous	71.1 years STANDARD_DEVIATION 6.93 • n=5 Participants	68.2 years STANDARD_DEVIATION 6.38 • n=7 Participants	69.7 years STANDARD_DEVIATION 6.75 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	22 Participants n=7 Participants	45 Participants n=5 Participants
Race/Ethnicity, Customized White	23 Participants n=5 Participants	24 Participants n=7 Participants	47 Participants n=5 Participants
Race/Ethnicity, Customized Black, of African Heritage	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Other: Unspecified	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: From the date of randomization to date of death or up to 1 year post last participant was randomized, whichever was earlier (maximum duration: up to 21.3 months)

Outcome measures

Outcome measures
Measure	TAC-101 n=26 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=26 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Overall Survival (OS)	8.23 months Standard Deviation 5.406	8.35 months Standard Deviation 5.351

SECONDARY outcome

Timeframe: From the date of randomization to date of tumor disease progression or death or up to 1 year post last participant was randomized, whichever was earlier (maximum duration: up to 21.3 months)

Population: Analysis was performed on safety population that included all randomized participants who received at least one dose of double-blind study medication and was summarized by the treatment received. Here, 'Overall number of participants analyzed' signifies participants with valid assessment at specified timepoint.

PFS was defined as the time from date of randomization to the date of tumor disease progression (ie, radiological only) or death due to any cause. Participants who were alive at the time of analysis and had no signs of tumor progression had their time of PFS censored at the date of the last tumor assessment, unless they received new antitumor therapy.

Outcome measures

Outcome measures
Measure	TAC-101 n=21 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=22 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Radiologic Progression-free Survival (PFS)	4.95 months Standard Deviation 4.904	4.82 months Standard Deviation 3.647

SECONDARY outcome

Timeframe: From the date of randomization to date of tumor disease progression or up to 1 year post last participant was randomized, whichever was earlier (maximum duration: up to 21.3 months)

TTP was defined as time from randomization to the date of tumor progression (radiological only). Participants who were alive with no tumor progression or who died prior to tumor progression had their TTP censored at the date of their last tumor assessment, unless they received new antitumor therapy.

Outcome measures

Outcome measures
Measure	TAC-101 n=21 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=22 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Time To Progression (TTP)	4.14 months Standard Deviation 4.430	4.09 months Standard Deviation 3.146

SECONDARY outcome

Timeframe: From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101)

Any untoward medical condition that occurs in a participants while participating in a clinical study and does not necessarily have a causal relationship with the use of the study treatment was considered an AE. A serious AE (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were defined as AEs (both serious/non-serious) that occur from the initiation of any study medication administration, and do not necessarily have a causal relationship to the use of the study medication.

Outcome measures

Outcome measures
Measure	TAC-101 n=26 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=26 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) TEAE	26 Participants	25 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) TESAE	12 Participants	11 Participants

SECONDARY outcome

Timeframe: From the date of randomization to date of tumor disease progression or up to 1 year post last participant was randomized, whichever was earlier (maximum duration: up to 21.3 months)

Population: Analysis was performed on safety population that included all randomized participants who received at least 1 dose of double-blind study medication and was summarized by the treatment received. Here, 'Overall number of participants analyzed' signifies participants with valid assessment at specified timepoint.

AFP is a tumor marker for hepatocellular carcinoma and elevations in AFP values could precede clinical deterioration and tumor recurrence in participants. Baseline was defined as the last value obtained within 72 hours prior to study treatment administration on Cycle 1 Day 1.

Outcome measures

Outcome measures
Measure	TAC-101 n=21 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=23 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Change From Baseline in Plasma Levels of the Tumor Marker Alpha-fetoprotein (AFP)	2779.3 nanogram per milliliter (ng/mL) Standard Deviation 16314.87	571.7 nanogram per milliliter (ng/mL) Standard Deviation 14301.08

SECONDARY outcome

Timeframe: From the date of randomization to date of tumor disease progression or up to 1 year post last participant was randomized, whichever was earlier (maximum duration: up to 21.3 months)

AFP-L3 is a tumor marker for hepatocellular carcinoma and elevations in AFP-L3 values could precede clinical deterioration and tumor recurrence in participants. Baseline was defined as the last value obtained within 72 hours prior to study treatment administration on Cycle 1 Day 1.

Outcome measures

Outcome measures
Measure	TAC-101 n=20 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=22 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Percent Change From Baseline in Plasma Levels of the Tumor Marker Alpha Fetoprotein-L3 (AFP-L3)	2.27 percent change Standard Deviation 12.107	3.20 percent change Standard Deviation 8.129

SECONDARY outcome

Timeframe: Cycle 1-day 1: 4, 8, and 24 hours after the first dose of study drug

Population: PK population included all participants in safety population participating in this sub-study and treated with active study treatment. Due to limited number of participants with evaluable PK data, no data was collected and analyzed for the conclusion of maximum exposure. Here, 'Overall number of participants analyzed' signifies participants with valid assessment at specified timepoint.

Cmax: maximum plasma concentration; Pharmacokinetic (PK) blood samples were collected at 4 hours (± 1 hour), 8 hours (± 1 hour), and 24 hours (± 1 hour) post-dose on Day 1 of treatment Cycle 1. The 24-hour sample was collected prior to dosing on Day 2.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1-day 1: 4, 8, and 24 hours after the first dose of study drug

Population: PK population included all participants in safety population participating in this sub-study and treated with active study treatment. Due to limited number of participants with evaluable PK data, no data was collected and analyzed for conclusion of maximum exposure. Here, 'Overall number of participants analyzed' signifies participants with valid assessment at specified timepoint.

AUC(0-inf): Area under the curve from time zero extrapolated to infinity. PK blood samples were collected at 4 hours (± 1 hour), 8 hours (± 1 hour), and 24 hours (± 1 hour) post-dose on Day 1 of treatment Cycle 1. The 24-hour sample was collected prior to dosing on Day 2.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Baseline up to end of study treatment or up to tumor disease progression or up to death or up to 1 year post last participant was randomized, whichever was earlier (maximum duration: up to 21.3 months)

RAR related factors are markers for disease progression in hepatocellular carcinoma participants. In hepatocellular carcinoma participants, IGF-2 is a characteristic biomarkers and its levels are higher in responder cells. The detection of IGF-2 levels showed the efficacy of TAC-101 in IGF-2 influenced malignancy.

Outcome measures

Outcome measures
Measure	TAC-101 n=3 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=7 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Changes From Baseline in Plasma Insulin-like Growth Factor-2 (IGF-2)	330.8 ng/mL Standard Deviation 87.82	115.6 ng/mL Standard Deviation 181.59

SECONDARY outcome

TGF-β is responsible for tissue regeneration, cell differentiation, embryonic development, and regulation of the immune system. TGF-β2 levels are higher in non-responder cells hence helps in detection of such cells.

Outcome measures

Outcome measures
Measure	TAC-101 n=2 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=7 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Changes From Baseline in Plasma Transforming Growth Factor-beta (TGFβ2)	-3.51 picograms per milliliter (pg/mL) Standard Deviation 4.957	0.92 picograms per milliliter (pg/mL) Standard Deviation 2.427

SECONDARY outcome

IGFBP-3 acts as a mediator of antiproliferative signals in hepatocellular carcinoma cells. The inhibition of hepatocellular carcinoma cell proliferation is associated with upregulation of IGFBP-3. Retinoic acid response element (RARE) exists on the promoter region of the IGFBP-3.

Outcome measures

Outcome measures
Measure	TAC-101 n=3 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=7 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Changes From Baseline in Plasma Insulin-like Growth Factor Binding Protein-3 (IGFBP-3)	370.6 ng/mL Standard Deviation 242.97	-112.4 ng/mL Standard Deviation 179.64

SECONDARY outcome

IGFBP-6 has an IGF-2 binding specificity and inhibits growth of a number of IGF-2-dependent cancers. RARE exists on the promoter region of the IGFBP-6.

Outcome measures

Outcome measures
Measure	TAC-101 n=3 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=7 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Changes From Baseline in Plasma Insulin-like Growth Factor Binding Protein-6 (IGFBP-6)	-40.7 ng/mL Standard Deviation 82.08	-86.9 ng/mL Standard Deviation 72.82

SECONDARY outcome

RARE exists on the promoter region of the lactoferrin gene.

Outcome measures

Outcome measures
Measure	TAC-101 n=3 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=6 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Changes From Baseline in Plasma Lactoferrin	-133.3 ng/mL Standard Deviation 177.20	-25.5 ng/mL Standard Deviation 25.83

SECONDARY outcome

End of Treatment was defined as "as soon as possible following the last dose of study medication".

Outcome measures

Outcome measures
Measure	TAC-101 n=3 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=7 Participants Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Changes From Baseline in Plasma Vascular Endothelial Growth Factor-A (VEGF-A)	-29.50 pg/mL Standard Deviation 51.859	11.40 pg/mL Standard Deviation 83.141

SECONDARY outcome

Timeframe: From the date of treatment discontinuation to date of tumor disease progression or death or up to 1 year post last participant was randomized, whichever was earlier (maximum duration: up to 21.3 months)

Population: The data were not collected and analyzed for this outcome measure due to low enrollment of participants.

Antitumor activity after treatment discontinuation in participant was determined by images, computed tomography (CT), and magnetic resonance imaging (MRI). Tumor imaging was done at Baseline any time within 4 weeks prior to the first dose of study treatment on Cycle 1, Day 1 and every 6 weeks (±1 week) during treatment, regardless of a dose delay. If participant discontinued study treatment for a reason other than disease progression (PD), data collected every 6 weeks until PD and following PD, data collected optionally every 6 weeks until death or up to 1 year after the last participant was randomized.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At Baseline (prior to treatment after consenting informed consent form [ICF]) up to last dose of study treatment, assessed every 6 weeks (maximum duration: up to 21.3 months)

Population: The data were not collected and analyzed for this outcome measure due to low enrollment of participants.

The assessment of correlative factors was to be conducted on tissue removed prior to the study, if available. Tumor tissue assessments included investigation of the relationship between tumor gene mRNA expression of co-activators and co-repressors and efficacy parameters.

Outcome measures

Outcome data not reported

Adverse Events

TAC-101

Serious events: 12 serious events

Other events: 25 other events

Deaths: 2 deaths

Placebo

Serious events: 11 serious events

Other events: 24 other events

Deaths: 6 deaths

Serious adverse events

Other adverse events

Additional Information

Taiho Central

Taiho Oncology, Inc.

Phone: +1 844-878-2446

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER

Measure	TAC-101 n=26 participants at risk Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=26 participants at risk Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Cardiac disorders Atrial thrombosis	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Cardiac disorders Cardiac arrest	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Cardiac disorders Left ventricular failure	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Abdominal pain	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Oesophageal varices haemorrhage	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
General disorders Disease progression	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
General disorders Fatigue	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
General disorders General physical health deterioration	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
General disorders Oedema due to hepatic disease	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Hepatobiliary disorders Cytolytic hepatitis	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Hepatobiliary disorders Hepatic failure	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Infections and infestations Pneumonia	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Investigations Weight decreased	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Nervous system disorders Epilepsy	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Nervous system disorders Hepatic encephalopathy	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.8% 1/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Vascular disorders Deep vein thrombosis	15.4% 4/26 • Number of events 4 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.

Measure	TAC-101 n=26 participants at risk Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a dose of 20 mg/day of TAC-101 (as second line treatment) oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period on Days 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.	Placebo n=26 participants at risk Participants with advanced hepatocellular carcinoma who had previously received Sorafenib (as first line therapy) were administered a matching placebo for TAC-101 oral tablets within 1 hour post morning meals on Days 1 to 14 followed by a recovery period from on 15 to 21 in 21-day cycle until disease progression or participant met a treatment discontinuation criterion.
Blood and lymphatic system disorders Anaemia	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Abdominal pain	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	15.4% 4/26 • Number of events 4 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Abdominal pain upper	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Ascites	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	15.4% 4/26 • Number of events 4 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Constipation	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Diarrhoea	15.4% 4/26 • Number of events 4 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	19.2% 5/26 • Number of events 5 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Dry mouth	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Nausea	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Gastrointestinal disorders Vomiting	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
General disorders Asthenia	26.9% 7/26 • Number of events 7 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
General disorders Fatigue	23.1% 6/26 • Number of events 8 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	19.2% 5/26 • Number of events 7 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
General disorders General physical health deterioration	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
General disorders Oedema peripheral	23.1% 6/26 • Number of events 6 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	19.2% 5/26 • Number of events 5 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
General disorders Performance status decreased	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Hepatobiliary disorders Hyperbilirubinaemia	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Infections and infestations Bronchitis	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Injury, poisoning and procedural complications Fall	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Investigations Blood bilirubin increased	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Metabolism and nutrition disorders Anorexia	19.2% 5/26 • Number of events 7 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Arthralgia	19.2% 5/26 • Number of events 5 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Back pain	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	15.4% 4/26 • Number of events 4 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Myalgia	7.7% 2/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Nervous system disorders Dizziness	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Nervous system disorders Headache	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Psychiatric disorders Insomnia	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Cough	3.8% 1/26 • Number of events 1 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Epistaxis	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Dry skin	7.7% 2/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	11.5% 3/26 • Number of events 4 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Pruritus	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	15.4% 4/26 • Number of events 4 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Skin and subcutaneous tissue disorders Rash	11.5% 3/26 • Number of events 3 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Vascular disorders Hypertension	7.7% 2/26 • Number of events 4 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.
Vascular disorders Hypotension	0.00% 0/26 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.	7.7% 2/26 • Number of events 2 • From Baseline up to 30 days after the last dose (maximum duration: up to 7.2 months for Placebo and up to 7.9 months for TAC-101) Analysis was performed on safety population.