E7050 in Combination With Sorafenib Versus Sorafenib Alone as First Line Therapy in Participants With Hepatocellular Carcinoma

An Open-Label, Multicenter, Randomized, Phase Ib/II Study of E7050 in Combination With Sorafenib Versus Sorafenib Alone as First Line Therapy in Patients With Hepatocellular Carcinoma

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01271504

Enrollment

102

Registered

2011-01-06

Start date

2011-07-19

Completion date

2015-06-23

Last updated

2021-05-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hepatocellular Carcinoma

Keywords

Cancer, liver, hepatocellular carcinoma, phase I, phase II

Brief summary

The purpose of this study is to determine whether patients with hepatocellular carcinoma who receive either E7050 administered with Sorafenib or Sorafenib alone experience greater benefit (cancer responds to treatment) when E7050 is administered with Sorafenib.

Detailed description

This open-label, multicenter, randomized study will consist of a Phase Ib: a safety run-in period with 3 ascending doses of E7050 in combination with sorafenib; and a Phase II portion: a randomized 2-arm period. Approximately 95 patients with hepatocellular carcinoma will be enrolled in the study (10-15 patients in the Phase Ib portion and 80 patients in the Phase II portion). Patients will only participate in either the Phase Ib or the Phase II portion of the study. In both Phase Ib and phase II, Patients will receive study treatment (E7050 plus sorafenib or sorafenib alone) until the occurrence of progressive disease (PD)for approximately six 28-day cycles (24 weeks). After 6 cycles. ath the discretion of the Investigator and in consultation with the Medical Monitor, patients who are experiencing clinical benefit may continue E7050, with or without sorafenib (Arm 1), or may continue sorafenib alone (Arm 2), depending on the original randomization treatment arm, for as long as clinical benefit is sustained and the treatment is well tolerated. Patients will be followed until death following completion of therapy.

Interventions

DRUGSorafenib

Phase Ib: Cohort 1; 200 mg E7050 + 400 mg Sorafenib Cohort 2; 300 mg E7050 + 400 mg Sorafenib Cohort 3; 400 mg E7050 + Sorafenib

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Unresectable locally advanced or metastatic HCC; * Histologic confirmation not required if other diagnostic criteria are met; * No previous systemic anti-cancer therapy permitted (2 prior systemic anti-cancer regimen are allowed in Phase Ib). Previous chemoembolization, radioembolization, radiofrequency ablation, or other local ablative therapies are permitted if greater than 6 weeks of first day of study-defined treatment; * ECOG PS 0 or 1; Child-Pugh Cirrhotic Status A or B with a score of 7; * Blood pressure must be well-controlled (less than or equal to 140/90 mmHg at screening) with or without antihypertensive medication. Patients must have no history of hypertensive crisis or hypertensive encephalopathy;

Exclusion criteria

* Previously received E7050 anti-cmet, or anti-angiogenic therapy (prior anti-angiogenic therapy is permitted in Phase Ib only); * Presence of brain metastases, unless the patient has received adequate treatment at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 4 weeks prior to randomization; * Palliative radiotherapy is not permitted throughout the study period; * Active hemoptysis * Serious non-healing wound, ulcer, or active bone fracture; * Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to commencing study treatment, or anticipation of need for a major surgical procedure during the course of the study; * Clinically significant gastrointestinal bleeding (bleeding requiring procedural intervention, eg. variceal banding, transjugular intrahepatic portosystemic shunt (TIPS) procedure, arterial embolization, topical coagulation therapy) within 6 months prior to first dose.

Design outcomes

Primary

Measure	Time frame	Description
Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)	Cycle 1 (Cycle length is 28 days)	DLTs were defined as clinically significant adverse events (AEs) (non-hematological, hematological and other events) occurring less than or equal to (\<=) 28 days after commencing study treatment and considered to be at least possibly or probably related to study drug by the Investigator. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v.4.0).
Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7	Day -7: 0-72 hours post-dose	—
Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)	—
Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	Cycle 1 Day 28: 0-24 hours post-dose	—
Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7	Day -7: 0-72 hours post-dose	—
Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)	—
Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	Cycle 1 Day 28: 0-24 hours post-dose	—
Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day -7	Day -7: 0-72 hours post-dose	—
Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)	—
Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	Cycle 1 Day 28: 0-24 hours post-dose (Cycle length is 28 days)	—
Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7	Day -7: 0-72 hours post-dose	—
Phase 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	—
Phase 2: Number of Participants With AEs by Severity Grades	From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	AE severity was graded using CTCAE version 4.0, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death related to the AE. All AEs graded as 4 or 5 were considered to be serious. Higher grade indicates more severe condition.
Phase 2: Number of Participants With Adverse Events Related to Vital Signs	From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	Number of participants are reported with AEs related to Vital signs including body temperature, respiratory rate, heart rate, height, and weight.
Phase 2: Number of Participants With Clinically Significant Change From Baseline in Blood Pressure Including Systolic and Diastolic Blood Pressures	From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	—
Phase 2: Number of Participants With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)	From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	Number of participants with worst shifts post baseline in ECOG-PS levels were reported. ECOG has 6 levels (0-5). Level 0 is the best status (fully active, able to carry on all pre-disease performance without restriction); Level 1 is mildly restricted (Restricted in physically strenuous activity but ambulatory ad able to carry out work of a light or sedentary nature, e.g. light house work, office work); Level 2 is more restricted (Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours); Level 3 is restricted (Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours); Level 4 is highly restricted (completely disabled; cannot carry on any selfcare; totally confined to bed or chair); and Level 5 is death (dead).
Phase 2: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values	From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	—
Phase 2: Number of Participants With Markedly Abnormal Change From Baseline in Electrocardiograms (ECGs) Parameters	From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	—

Secondary

Measure	Time frame	Description
Phase 2: Time to Progression (TTP)	From the date of randomization until the date of PD (up to approximately 3 years 11 months)	TTP was defined as the time from the date of randomization until the date of PD of such participants disease based on independent assessments according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. PD was defined as at least a 20% increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. TTP was estimated and analyzed using Kaplan-Meier (K-M) method.
Phase 2: Progression Free Survival (PFS)	From the date of randomization until the earlier of the following two events: the date of PD or the date of death (Up to approximately 3 years 11 months)	PFS was defined as the time from the date of randomization of a participant until (1) the date of first documented progression (2) the date of such participant's death due to any cause based on independent assessments according to RECIST v. 1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using KM method.
Phase 2: Percentage of Participants With PFS at Week 12	At 12 weeks	The PFS rate at week 12 was defined as the percentage of participants who were still alive without disease progression at 12 weeks from the date of randomization. PFS was defined as the time from the date of randomization of a participant until (1) the date of first documented progression (2) the date of such participant's death due to any cause based on independent assessments according to RECIST v. 1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions.
Phase 2: Overall Survival (OS)	From the date of randomization until the date of death (Up to approximately 3 years 11 months)	OS was defined as the time from the date of randomization until the date of death. Participants were censored at the date of last known alive. OS was analyzed using K-M method.
Phase 2: Percentage of Participants With Overall Response	From the date of randomization until disease progression or death (Up to approximately 3 years 11 months)	Overall response rate was defined as percentage of participants with best confirmed response (CR) or partial response (PR) assessed by investigator per RECIST v1.1. A confirmatory scan was required after no less than 4 weeks and no later than 8 weeks, starting on the date that the response was first recorded. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (\<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Countries

Belgium, Italy, Spain, Ukraine, United Kingdom, United States

Participant flow

Recruitment details

Participants took part in the study at 23 investigative sites in Belgium, Italy, Spain, the Ukraine, the United Kingdom and the United States from 19 July 2011 to 23 June 2015.

Pre-assignment details

A total of 102 participants were enrolled and randomized in this study, out of which, 15 participants were enrolled in Phase 1b of study, of which 14 received study drug, and 87 participants were enrolled in Phase 2 of study, of which 84 participants received the study drug.

Participants by arm

Arm	Count
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	7
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	7
Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).	42
Phase 2: Sorafenib 400 mg Participants received sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).	42
Total	98

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Administrative Reasons	0	0	6	5
Overall Study	Death	7	6	32	32
Overall Study	Lost to Follow-up	0	1	3	1
Overall Study	Other	0	1	2	0
Overall Study	Protocol Violation	0	0	0	2
Overall Study	Withdrawal by Subject	0	0	1	3

Baseline characteristics

Characteristic	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg	Total
Age, Continuous	52.9 years STANDARD_DEVIATION 15.68	68.1 years STANDARD_DEVIATION 9.56	63.2 years STANDARD_DEVIATION 9.31	65.8 years STANDARD_DEVIATION 8.02	63.9 years STANDARD_DEVIATION 9.82
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	2 Participants	1 Participants	5 Participants	8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants	5 Participants	36 Participants	36 Participants	84 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	5 Participants	1 Participants	6 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	2 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	4 Participants	1 Participants	5 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	1 Participants	3 Participants	4 Participants
Race (NIH/OMB) White	7 Participants	5 Participants	37 Participants	37 Participants	86 Participants
Sex: Female, Male Female	1 Participants	2 Participants	10 Participants	12 Participants	25 Participants
Sex: Female, Male Male	6 Participants	5 Participants	32 Participants	30 Participants	73 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	7 / 7	6 / 7	32 / 42	32 / 42
other Total, other adverse events	7 / 7	6 / 7	40 / 42	40 / 42
serious Total, serious adverse events	4 / 7	3 / 7	20 / 42	17 / 42

Outcome results

Primary

Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

Time frame: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Arm	Measure	Value (MEAN)	Dispersion
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	24000 ng*h/mL	Standard Deviation 14300
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	36800 ng*h/mL	Standard Deviation 38000

Primary

Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

Time frame: Cycle 1 Day 28: 0-24 hours post-dose (Cycle length is 28 days)

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters. Here, overall number analyzed N were the participants who were evaluable for the outcome measure.

Arm	Measure	Value (MEAN)	Dispersion
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	35300 ng*h/mL	Standard Deviation 16700
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	68700 ng*h/mL	Standard Deviation 72500

Primary

Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day -7

Time frame: Day -7: 0-72 hours post-dose

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Arm	Measure	Value (MEAN)	Dispersion
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day -7	30400 nanogramhour per milliliter(ngh/mL)	Standard Deviation 18900
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day -7	47200 nanogramhour per milliliter(ngh/mL)	Standard Deviation 37500

Primary

Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

Time frame: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Arm	Measure	Value (MEAN)	Dispersion
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	1820 ng/mL	Standard Deviation 750
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	2820 ng/mL	Standard Deviation 3170

Primary

Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

Time frame: Cycle 1 Day 28: 0-24 hours post-dose

Arm	Measure	Value (MEAN)	Dispersion
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	2140 ng/mL	Standard Deviation 757
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	4570 ng/mL	Standard Deviation 3610

Primary

Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7

Time frame: Day -7: 0-72 hours post-dose

Population: Pharmacokinetic (PK) analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Arm	Measure	Value (MEAN)	Dispersion
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7	1330 nanograms per milliliter (ng/mL)	Standard Deviation 858
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7	2320 nanograms per milliliter (ng/mL)	Standard Deviation 2720

Primary

Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)

DLTs were defined as clinically significant adverse events (AEs) (non-hematological, hematological and other events) occurring less than or equal to (\<=) 28 days after commencing study treatment and considered to be at least possibly or probably related to study drug by the Investigator. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v.4.0).

Time frame: Cycle 1 (Cycle length is 28 days)

Population: Safety analysis set included all participants enrolled and randomized into the Phase 1b of this study, except those who dropped out of the study prior to receiving any study drug, or were without any safety assessment after first dose of study drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)	1 Participants
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)	2 Participants

Primary

Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7

Time frame: Day -7: 0-72 hours post-dose

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Arm	Measure	Value (MEAN)	Dispersion
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7	38.1 hour	Standard Deviation 6.82
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7	35.9 hour	Standard Deviation 11.7

Primary

Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

Time frame: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Arm	Measure	Value (MEDIAN)
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	3 hour
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	3.53 hour

Primary

Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

Time frame: Cycle 1 Day 28: 0-24 hours post-dose

Arm	Measure	Value (MEDIAN)
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	2.98 hour
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	5.01 hour

Primary

Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7

Time frame: Day -7: 0-72 hours post-dose

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Arm	Measure	Value (MEDIAN)
Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7	2 hour
Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7	2.38 hour

Primary

Phase 2: Number of Participants With Adverse Events Related to Vital Signs

Number of participants are reported with AEs related to Vital signs including body temperature, respiratory rate, heart rate, height, and weight.