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

Sponsor
Eisai Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01271504
Collaborator
PharmaBio Development Inc. (Industry)
102
24
2
47.1
4.3
0.1

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
102 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Jul 19, 2011
Actual Primary Completion Date :
Jun 23, 2015
Actual Study Completion Date :
Jun 23, 2015

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Phase Ib: Cohort 1,2, and 3

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

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

Active Comparator: Phase II: Arm 1; E7050 + Sorafenib

Phase II: Arm 1; E7050 + 400 mg Sorafenib Arm 2; 400 mg Sorafenib

Drug: Sorafenib
E7050 given orally at 200, 300 or 400 mg once daily. Sorafenib given orally, 400 mg twice daily.

Outcome Measures

Primary Outcome Measures

  1. 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).

  2. 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]

  3. 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)]

  4. 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]

  5. 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]

  6. 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)]

  7. 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]

  8. 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]

  9. 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)]

  10. 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)]

  11. 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]

  12. 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)]

  13. 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.

  14. 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.

  15. 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)]

  16. 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).

  17. 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)]

  18. 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 Outcome Measures

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

Eligibility Criteria

Criteria

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

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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Tucson Arizona United States 85715
2 Fort Myers Florida United States 33905
3 Saint Petersburg Florida United States 33705
4 Chapel Hill North Carolina United States 27599
5 Cincinnati Ohio United States 45267
6 Toledo Ohio United States 43623
7 Nashville Tennessee United States 37203
8 Brussels Belgium 1070
9 Bruxelles Belgium 1200
10 Leuven Belgium 3000
11 Rozzano Milano Italy 20089
12 Modena Italy 40124
13 Pavia Italy 27100
14 Madrid Spain 28007
15 Madrid Spain 28034
16 Madrid Spain 28046
17 Madrid Spain 28050
18 Dnipropetrovsk Ukraine 49102
19 Donetsk Ukraine 83092
20 Kharkiv Ukraine 61037
21 Lviv Ukraine 79031
22 London Greater London United Kingdom WC1E 6BT
23 Manchester Greater Manchester United Kingdom M20 4BX
24 Glasgow Strathclyde United Kingdom G12 OYN

Sponsors and Collaborators

  • Eisai Inc.
  • PharmaBio Development Inc.

Investigators

  • Study Director: Melissa J Versola, RN, Quintiles, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01271504
Other Study ID Numbers:
  • E7050-701
  • 2011-000752-41
First Posted:
Jan 6, 2011
Last Update Posted:
May 12, 2021
Last Verified:
Aug 1, 2017
Keywords provided by Eisai Inc.
Additional relevant MeSH terms:

Study Results

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 Detail 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.
Arm/Group Title 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
Arm/Group Description Participants received golvatinib 200 milligram (mg), tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of progressive disease (PD), unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days). 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). 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). 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).
Period Title: Overall Study
STARTED 7 8 44 43
Treated 7 7 42 42
COMPLETED 0 0 0 0
NOT COMPLETED 7 8 44 43

Baseline Characteristics

Arm/Group Title 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
Arm/Group Description 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). 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). 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). 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). Total of all reporting groups
Overall Participants 7 7 42 42 98
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
52.9
(15.68)
68.1
(9.56)
63.2
(9.31)
65.8
(8.02)
63.9
(9.82)
Sex: Female, Male (Count of Participants)
Female
1
14.3%
2
28.6%
10
23.8%
12
28.6%
25
25.5%
Male
6
85.7%
5
71.4%
32
76.2%
30
71.4%
73
74.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
0
0%
2
28.6%
1
2.4%
5
11.9%
8
8.2%
Not Hispanic or Latino
7
100%
5
71.4%
36
85.7%
36
85.7%
84
85.7%
Unknown or Not Reported
0
0%
0
0%
5
11.9%
1
2.4%
6
6.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
2
28.6%
0
0%
0
0%
2
2%
Asian
0
0%
0
0%
0
0%
1
2.4%
1
1%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
0
0%
0
0%
Black or African American
0
0%
0
0%
4
9.5%
1
2.4%
5
5.1%
White
7
100%
5
71.4%
37
88.1%
37
88.1%
86
87.8%
More than one race
0
0%
0
0%
0
0%
0
0%
0
0%
Unknown or Not Reported
0
0%
0
0%
1
2.4%
3
7.1%
4
4.1%

Outcome Measures

1. Primary Outcome
Title Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)
Description 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)

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 7 7
Count of Participants [Participants]
1
14.3%
2
28.6%
2. Primary Outcome
Title Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7
Description
Time Frame Day -7: 0-72 hours post-dose

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once in combination with sorafenib 400 mg, tablet, orally twice on Day-7. Participants received golvatinib 300 mg, tablet, orally, once in combination with sorafenib 400 mg, tablet, orally twice on Day-7.
Measure Participants 7 6
Mean (Standard Deviation) [nanograms per milliliter (ng/mL)]
1330
(858)
2320
(2720)
3. Primary Outcome
Title Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1
Description
Time Frame Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice on Day 1 of Cycle 1. Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice on Day 1 of Cycle 1.
Measure Participants 7 6
Mean (Standard Deviation) [ng/mL]
1820
(750)
2820
(3170)
4. Primary Outcome
Title Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1
Description
Time Frame Cycle 1 Day 28: 0-24 hours post-dose

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily from Day 1 to 28 of Cycle 1. Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily from Day 1 to 28 of Cycle 1.
Measure Participants 7 4
Mean (Standard Deviation) [ng/mL]
2140
(757)
4570
(3610)
5. Primary Outcome
Title Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7
Description
Time Frame Day -7: 0-72 hours post-dose

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once in combination with sorafenib 400 mg, tablet, orally twice on Day-7. Participants received golvatinib 300 mg, tablet, orally, once in combination with sorafenib 400 mg, tablet, orally twice on Day-7.
Measure Participants 7 6
Median (Full Range) [hour]
2
2.38
6. Primary Outcome
Title Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1
Description
Time Frame Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice on Day 1 of Cycle 1. Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice on Day 1 of Cycle 1.
Measure Participants 7 6
Median (Full Range) [hour]
3
3.53
7. Primary Outcome
Title Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1
Description
Time Frame Cycle 1 Day 28: 0-24 hours post-dose

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily from Day 1 to 28 of Cycle 1. Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily from Day 1 to 28 of Cycle 1.
Measure Participants 7 4
Median (Full Range) [hour]
2.98
5.01
8. Primary Outcome
Title 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
Description
Time Frame Day -7: 0-72 hours post-dose

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once in combination with sorafenib 400 mg, tablet, orally twice on Day-7. Participants received golvatinib 300 mg, tablet, orally, once in combination with sorafenib 400 mg, tablet, orally twice on Day-7.
Measure Participants 7 6
Mean (Standard Deviation) [nanogram*hour per milliliter(ng*h/mL)]
30400
(18900)
47200
(37500)
9. Primary Outcome
Title 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
Description
Time Frame Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice on Day 1 of Cycle 1. Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice on Day 1 of Cycle 1.
Measure Participants 7 6
Mean (Standard Deviation) [ng*h/mL]
24000
(14300)
36800
(38000)
10. Primary Outcome
Title 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
Description
Time Frame Cycle 1 Day 28: 0-24 hours post-dose (Cycle length is 28 days)

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily from Day 1 to 28 of Cycle 1. Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily from Day 1 to 28 of Cycle 1.
Measure Participants 7 4
Mean (Standard Deviation) [ng*h/mL]
35300
(16700)
68700
(72500)
11. Primary Outcome
Title Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7
Description
Time Frame Day -7: 0-72 hours post-dose

Outcome Measure Data

Analysis Population Description
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/Group Title Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Arm/Group Description Participants received golvatinib 200 mg, tablet, orally, once in combination with sorafenib 400 mg, tablet, orally twice on Day-7. Participants received golvatinib 300 mg, tablet, orally, once in combination with sorafenib 400 mg, tablet, orally twice on Day-7.
Measure Participants 7 6
Mean (Standard Deviation) [hour]
38.1
(6.82)
35.9
(11.7)
12. Primary Outcome
Title Phase 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description
Time Frame From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 42 42
TEAEs
42
600%
40
571.4%
SAEs
20
285.7%
17
242.9%
13. Primary Outcome
Title Phase 2: Number of Participants With AEs by Severity Grades
Description 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.
Time Frame From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug. Here, overall number analyzed included are those participants who were evaluable for this outcome measure.
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 42 40
Any AE: Grade 1
0
0%
2
28.6%
Any AE: Grade 2
4
57.1%
6
85.7%
Any AE: Grade 3
24
342.9%
25
357.1%
Any AE: Grade 4
6
85.7%
5
71.4%
Any AE: Grade 5
8
114.3%
2
28.6%
14. Primary Outcome
Title Phase 2: Number of Participants With Adverse Events Related to Vital Signs
Description Number of participants are reported with AEs related to Vital signs including body temperature, respiratory rate, heart rate, height, and weight.
Time Frame From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 42 42
Count of Participants [Participants]
2
28.6%
0
0%
15. Primary Outcome
Title Phase 2: Number of Participants With Clinically Significant Change From Baseline in Blood Pressure Including Systolic and Diastolic Blood Pressures
Description
Time Frame From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 42 42
Count of Participants [Participants]
0
0%
0
0%
16. Primary Outcome
Title Phase 2: Number of Participants With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)
Description 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).
Time Frame From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 42 42
ECOG PS Level change from 0 to 1
7
100%
4
57.1%
ECOG PS Level change from 0 to 2
3
42.9%
7
100%
ECOG PS Level change from 0 to 3
3
42.9%
0
0%
ECOG PS Level change from 1 to 2
4
57.1%
6
85.7%
ECOG PS Level change from 0 to 4
0
0%
1
14.3%
ECOG PS Level change from 1 to 3
0
0%
5
71.4%
17. Primary Outcome
Title Phase 2: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values
Description
Time Frame From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 42 42
Count of Participants [Participants]
0
0%
0
0%
18. Primary Outcome
Title Phase 2: Number of Participants With Markedly Abnormal Change From Baseline in Electrocardiograms (ECGs) Parameters
Description
Time Frame From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 42 42
Count of Participants [Participants]
0
0%
0
0%
19. Secondary Outcome
Title Phase 2: Time to Progression (TTP)
Description 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.
Time Frame From the date of randomization until the date of PD (up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
Modified Intent-to-Treat (MITT) set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug. Here 'N' (Overall number of participants analyzed) signifies participants with events (PD).
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 31 36
Median (99% Confidence Interval) [weeks]
10.29
16.00
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg, Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.56 to 1.50
Parameter Dispersion Type:
Value:
Estimation Comments
20. Secondary Outcome
Title Phase 2: Progression Free Survival (PFS)
Description 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.
Time Frame 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)

Outcome Measure Data

Analysis Population Description
MITT analysis set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug. Here 'N' (Overall number of participants analyzed) signifies participants with events (PD or/and death).
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 32 37
Median (95% Confidence Interval) [weeks]
10.29
15.57
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg, Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.57 to 1.50
Parameter Dispersion Type:
Value:
Estimation Comments
21. Secondary Outcome
Title Phase 2: Percentage of Participants With PFS at Week 12
Description 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.
Time Frame At 12 weeks

Outcome Measure Data

Analysis Population Description
MITT analysis set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug. Here 'N' (Overall number of participants analyzed) signifies participants with events (PD or/and death).
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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. 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.
Measure Participants 32 37
Number [percentage of participants]
47.4
677.1%
57.5
821.4%
22. Secondary Outcome
Title Phase 2: Overall Survival (OS)
Description 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.
Time Frame From the date of randomization until the date of death (Up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
MITT analysis set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug.
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 42 42
Median (95% Confidence Interval) [weeks]
27.86
37.71
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg, Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.60 to 1.62
Parameter Dispersion Type:
Value:
Estimation Comments
23. Secondary Outcome
Title Phase 2: Percentage of Participants With Overall Response
Description 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.
Time Frame From the date of randomization until disease progression or death (Up to approximately 3 years 11 months)

Outcome Measure Data

Analysis Population Description
MITT analysis set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug.
Arm/Group Title Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Phase 2: Sorafenib 400 mg
Arm/Group Description 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). 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).
Measure Participants 42 42
Number (95% Confidence Interval) [percentage of participant]
4.8
4.8

Adverse Events

Time Frame From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Adverse Event Reporting Description
Arm/Group Title 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
Arm/Group Description 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). 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). 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). 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).
All Cause Mortality
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
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 7/7 (100%) 6/7 (85.7%) 32/42 (76.2%) 32/42 (76.2%)
Serious Adverse Events
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
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 4/7 (57.1%) 3/7 (42.9%) 20/42 (47.6%) 17/42 (40.5%)
Blood and lymphatic system disorders
Anaemia 0/7 (0%) 0/7 (0%) 0/42 (0%) 2/42 (4.8%)
Febrile Neutropenia 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Cardiac disorders
Cardiac Arrest 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Gastrointestinal disorders
Abdominal Pain 1/7 (14.3%) 1/7 (14.3%) 3/42 (7.1%) 0/42 (0%)
Nausea 1/7 (14.3%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Vomiting 1/7 (14.3%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Abdominal Distension 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Constipation 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Diverticular Perforation 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Dysphagia 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Gastric Ulcer 0/7 (0%) 0/7 (0%) 0/42 (0%) 2/42 (4.8%)
Haematemesis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Haematochezia 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Oesophageal Varices Haemorrhage 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Pancreatitis Acute 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Upper Gastrointestinal Haemorrhage 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
General disorders
General Physical Health Deterioration 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Non-Cardiac Chest Pain 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Oedema Peripheral 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hepatobiliary disorders
Hepatic Failure 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 0/42 (0%)
Hyperbilirubinaemia 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Liver Disorder 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Infections and infestations
Gastroenteritis 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Cellulitis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Escherichia Urinary Tract Infection 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Infected Skin Ulcer 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Infective Exacerbation Of Chronic Obstructive Airways Disease 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Klebsiella Infection 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Liver Abscess 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Pneumonia 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 1/42 (2.4%)
Scrotal Abscess 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Sepsis 0/7 (0%) 0/7 (0%) 3/42 (7.1%) 0/42 (0%)
Septic Shock 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Urinary Tract Infection 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Injury, poisoning and procedural complications
Spinal Compression Fracture 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Investigations
Transaminases Increased 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Metabolism and nutrition disorders
Hyperkalaemia 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hypoalbuminaemia 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hyponatraemia 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Gastric 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Malignant Neoplasm Progression 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Nervous system disorders
Metabolic Encephalopathy 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Ataxia 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hepatic Encephalopathy 0/7 (0%) 0/7 (0%) 0/42 (0%) 2/42 (4.8%)
Ischaemic Stroke 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Psychiatric disorders
Confusional State 1/7 (14.3%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Renal and urinary disorders
Nephropathy Toxic 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Renal Impairment 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Renal Failure 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Pleural Effusion 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Skin and subcutaneous tissue disorders
Dermatitis Acneiform 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Dermatitis Psoriasiform 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Palmar-Plantar Erythrodysaesthesia Syndrome 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Vascular disorders
Aneurysm Ruptured 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Hypertensive Crisis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Hypotension 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Other (Not Including Serious) Adverse Events
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
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 7/7 (100%) 6/7 (85.7%) 40/42 (95.2%) 40/42 (95.2%)
Blood and lymphatic system disorders
Anaemia 1/7 (14.3%) 3/7 (42.9%) 6/42 (14.3%) 3/42 (7.1%)
Thrombocytopenia 1/7 (14.3%) 3/7 (42.9%) 4/42 (9.5%) 4/42 (9.5%)
Neutropenia 1/7 (14.3%) 2/7 (28.6%) 1/42 (2.4%) 1/42 (2.4%)
Anaemia Macrocytic 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Lymphadenopathy 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Lymphopenia 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 1/42 (2.4%)
Leukopenia 0/7 (0%) 2/7 (28.6%) 0/42 (0%) 0/42 (0%)
Cardiac disorders
Angina pectoris 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Cardiac failure 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Sinus tachycardia 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Ear and labyrinth disorders
Ear pruritus 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
External ear inflammation 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Endocrine disorders
Hyperthyroidism 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hypothyroidism 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Eye disorders
Dry Eye 0/7 (0%) 1/7 (14.3%) 2/42 (4.8%) 0/42 (0%)
Vision Blurred 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Eye pain 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Gastrointestinal disorders
Diarrhoea 2/7 (28.6%) 6/7 (85.7%) 26/42 (61.9%) 22/42 (52.4%)
Nausea 6/7 (85.7%) 5/7 (71.4%) 15/42 (35.7%) 12/42 (28.6%)
Vomiting 2/7 (28.6%) 5/7 (71.4%) 14/42 (33.3%) 7/42 (16.7%)
Abdominal Pain 2/7 (28.6%) 5/7 (71.4%) 8/42 (19%) 7/42 (16.7%)
Abdominal Pain Upper 0/7 (0%) 1/7 (14.3%) 8/42 (19%) 5/42 (11.9%)
Ascites 0/7 (0%) 0/7 (0%) 8/42 (19%) 5/42 (11.9%)
Constipation 3/7 (42.9%) 1/7 (14.3%) 7/42 (16.7%) 5/42 (11.9%)
Dry Mouth 1/7 (14.3%) 1/7 (14.3%) 3/42 (7.1%) 3/42 (7.1%)
Gastrooesophageal Reflux Disease 0/7 (0%) 2/7 (28.6%) 1/42 (2.4%) 0/42 (0%)
Abdominal Discomfort 0/7 (0%) 1/7 (14.3%) 1/42 (2.4%) 3/42 (7.1%)
Anal Fissure 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Anorectal Discomfort 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Dyspepsia 1/7 (14.3%) 0/7 (0%) 5/42 (11.9%) 2/42 (4.8%)
Dysphagia 0/7 (0%) 1/7 (14.3%) 1/42 (2.4%) 2/42 (4.8%)
Flatulence 1/7 (14.3%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Hypoaesthesia Oral 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Stomatitis 1/7 (14.3%) 0/7 (0%) 6/42 (14.3%) 4/42 (9.5%)
Leukopenia 0/7 (0%) 2/7 (28.6%) 0/42 (0%) 0/42 (0%)
Abdominal distension 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 1/42 (2.4%)
Haemorrhoids 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 1/42 (2.4%)
Gastric ulcer 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Abdominal hernia 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Enterocolitis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Faecal incontinence 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Faeces soft 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Food poisoning 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Gastric hypomotility 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Gastritis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Gastrointestinal pain 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Glossitis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Lip blister 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Malabsorption 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Melaena 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Rectal haemorrhage 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Retching 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Toothache 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Varices oesophageal 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Abdominal Pain Lower 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
General disorders
Fatigue 1/7 (14.3%) 4/7 (57.1%) 13/42 (31%) 12/42 (28.6%)
Asthenia 0/7 (0%) 1/7 (14.3%) 12/42 (28.6%) 12/42 (28.6%)
Oedema Peripheral 2/7 (28.6%) 3/7 (42.9%) 5/42 (11.9%) 3/42 (7.1%)
Mucosal Inflammation 1/7 (14.3%) 1/7 (14.3%) 3/42 (7.1%) 3/42 (7.1%)
Pain 2/7 (28.6%) 0/7 (0%) 0/42 (0%) 2/42 (4.8%)
Chills 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Oedema 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 2/42 (4.8%)
Vessel Puncture Site Bruise 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Malaise 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 2/42 (4.8%)
Early satiety 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Face oedema 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Facial pain 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hypothermia 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Inflammation 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Influenza like illness 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Injection site haematoma 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Localised oedema 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Thirst 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Xerosis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Pyrexia 2/7 (28.6%) 1/7 (14.3%) 3/42 (7.1%) 6/42 (14.3%)
Chest Pain 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Generalised Oedema 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hepatobiliary disorders
Hyperbilirubinaemia 1/7 (14.3%) 4/7 (57.1%) 5/42 (11.9%) 6/42 (14.3%)
Liver disorder 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Cholangitis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Hepatic cirrhosis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hepatic function abnormal 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hepatic pain 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Hepatotoxicity 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Jaundice 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Liver tenderness 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Portal vein thrombosis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Immune system disorders
Drug Hypersensitivity 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Infections and infestations
Urinary Tract Infection 2/7 (28.6%) 1/7 (14.3%) 2/42 (4.8%) 6/42 (14.3%)
Bronchitis 1/7 (14.3%) 0/7 (0%) 2/42 (4.8%) 0/42 (0%)
Nasopharyngitis 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Oesophageal Candidiasis 1/7 (14.3%) 0/7 (0%) 2/42 (4.8%) 1/42 (2.4%)
Pneumonia 0/7 (0%) 1/7 (14.3%) 1/42 (2.4%) 0/42 (0%)
Upper Respiratory Tract Infection 0/7 (0%) 1/7 (14.3%) 1/42 (2.4%) 1/42 (2.4%)
Acid fast bacilli infection 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Cellulitis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Cystitis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Influenza 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Localised infection 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Sinusitis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Tooth abscess 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Viral diarrhoea 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Vulvovaginal candidiasis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Fungal Skin Infection 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Gastroenteritis Viral 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Oral candidiasis 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 1/42 (2.4%)
Injury, poisoning and procedural complications
Fall 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Contusion 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Spinal compression fracture 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Subcutaneous haematoma 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Wound 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Eye Contusion 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Investigations
Aspartate Aminotransferase Increased 2/7 (28.6%) 5/7 (71.4%) 11/42 (26.2%) 13/42 (31%)
Blood Alkaline Phosphatase Increased 3/7 (42.9%) 4/7 (57.1%) 6/42 (14.3%) 11/42 (26.2%)
Alanine Aminotransferase Increased 1/7 (14.3%) 4/7 (57.1%) 7/42 (16.7%) 8/42 (19%)
Blood Creatinine Increased 3/7 (42.9%) 2/7 (28.6%) 1/42 (2.4%) 2/42 (4.8%)
Blood Bilirubin Increased 3/7 (42.9%) 1/7 (14.3%) 3/42 (7.1%) 5/42 (11.9%)
Lipase Increased 1/7 (14.3%) 3/7 (42.9%) 1/42 (2.4%) 7/42 (16.7%)
Ammonia Increased 0/7 (0%) 1/7 (14.3%) 1/42 (2.4%) 1/42 (2.4%)
Amylase Increased 1/7 (14.3%) 0/7 (0%) 1/42 (2.4%) 4/42 (9.5%)
Blood Lactate Dehydrogenase Increased 0/7 (0%) 1/7 (14.3%) 1/42 (2.4%) 2/42 (4.8%)
Blood Thyroid Stimulating Hormone Increased 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Heart Rate Increased 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Platelet Count Decreased 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Weight Decreased 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Transaminases increased 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 2/42 (4.8%)
Protein urine present 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 1/42 (2.4%)
Bacterial test positive 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Blood albumin decreased 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Blood potassium increased 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Blood urine present 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Body temperature increased 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Breath sounds abnormal 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Globulins increased 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Oxygen saturation decreased 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Serum ferritin increased 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Thyroxine increased 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Urine analysis abnormal 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Weight Decreased 0/7 (0%) 0/7 (0%) 6/42 (14.3%) 3/42 (7.1%)
Hepatitis C Virus Test Positive 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Liver Palpable Subcostal 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Metabolism and nutrition disorders
Hypoalbuminaemia 3/7 (42.9%) 4/7 (57.1%) 1/42 (2.4%) 3/42 (7.1%)
Hypocalcaemia 3/7 (42.9%) 4/7 (57.1%) 3/42 (7.1%) 2/42 (4.8%)
Hypokalaemia 1/7 (14.3%) 4/7 (57.1%) 3/42 (7.1%) 2/42 (4.8%)
Decreased Appetite 1/7 (14.3%) 3/7 (42.9%) 13/42 (31%) 15/42 (35.7%)
Hypomagnesaemia 2/7 (28.6%) 2/7 (28.6%) 2/42 (4.8%) 0/42 (0%)
Hyponatraemia 2/7 (28.6%) 2/7 (28.6%) 2/42 (4.8%) 2/42 (4.8%)
Hyperglycaemia 1/7 (14.3%) 2/7 (28.6%) 2/42 (4.8%) 1/42 (2.4%)
Hypophosphataemia 0/7 (0%) 3/7 (42.9%) 4/42 (9.5%) 0/42 (0%)
Dehydration 0/7 (0%) 2/7 (28.6%) 0/42 (0%) 1/42 (2.4%)
Fluid Overload 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Hypermagnesaemia 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hypervolaemia 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
hypoproteinaemia 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Hyperlipasaemia 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 0/42 (0%)
Acidosis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Gout 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hyperuricaemia 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Malnutrition 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Metabolic acidosis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hyperkalaemia 1/7 (14.3%) 4/7 (57.1%) 1/42 (2.4%) 3/42 (7.1%)
Musculoskeletal and connective tissue disorders
Back Pain 2/7 (28.6%) 1/7 (14.3%) 3/42 (7.1%) 7/42 (16.7%)
Neck Pain 1/7 (14.3%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Muscular Weakness 0/7 (0%) 2/7 (28.6%) 0/42 (0%) 2/42 (4.8%)
Muscle Spasms 1/7 (14.3%) 1/7 (14.3%) 3/42 (7.1%) 1/42 (2.4%)
Pain In Extremity 2/7 (28.6%) 0/7 (0%) 2/42 (4.8%) 5/42 (11.9%)
Bone Pain 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Bursitis 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Musculoskeletal Pain 1/7 (14.3%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Arthralgia 0/7 (0%) 0/7 (0%) 0/42 (0%) 2/42 (4.8%)
Arthropathy 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Axillary mass 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Groin pain 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Joint swelling 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Musculoskeletal discomfort 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Myalgia 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Myositis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Spinal pain 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Tenosynovitis stenosans 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Musculoskeletal Chest Pain 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 5/42 (11.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Paraneoplastic syndrome 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Keratoacanthoma 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Nervous system disorders
Headache 0/7 (0%) 3/7 (42.9%) 8/42 (19%) 4/42 (9.5%)
Paraesthesia 1/7 (14.3%) 1/7 (14.3%) 2/42 (4.8%) 0/42 (0%)
Dizziness 1/7 (14.3%) 1/7 (14.3%) 0/42 (0%) 2/42 (4.8%)
Dementia 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Dysgeusia 1/7 (14.3%) 0/7 (0%) 4/42 (9.5%) 3/42 (7.1%)
Hepatic Encephalopathy 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 3/42 (7.1%)
Memory Impairment 1/7 (14.3%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Neuropathy Peripheral 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Restless Legs Syndrome 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Lethargy 0/7 (0%) 0/7 (0%) 3/42 (7.1%) 2/42 (4.8%)
Aphonia 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Balance disorder 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Mental impairment 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Monoparesis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Somnolence 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Syncope 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Psychiatric disorders
Anxiety 0/7 (0%) 3/7 (42.9%) 1/42 (2.4%) 2/42 (4.8%)
Agitation 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Insomnia 1/7 (14.3%) 0/7 (0%) 5/42 (11.9%) 2/42 (4.8%)
Depression 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 1/42 (2.4%)
Confusional state 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Depressed mood 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Renal and urinary disorders
Proteinuria 2/7 (28.6%) 2/7 (28.6%) 1/42 (2.4%) 2/42 (4.8%)
Nocturia 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Renal Failure Chronic 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 1/42 (2.4%)
Urinary Incontinence 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 1/42 (2.4%)
Dysuria 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 1/42 (2.4%)
Pollakiuria 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 2/42 (4.8%)
Renal failure acute 0/7 (0%) 0/7 (0%) 0/42 (0%) 2/42 (4.8%)
Haematuria 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Nephrolithiasis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Polyuria 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Renal failure 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Reproductive system and breast disorders
Vaginal Haemorrhage 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Vaginal Polyp 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Vulvovaginal Discomfort 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Erectile dysfunction 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Genital lesion 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Nipple pain 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Prostatic obstruction 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Testicular pain 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Testicular swelling 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Dysphonia 1/7 (14.3%) 1/7 (14.3%) 1/42 (2.4%) 5/42 (11.9%)
Dyspnoea 1/7 (14.3%) 0/7 (0%) 1/42 (2.4%) 7/42 (16.7%)
Epistaxis 0/7 (0%) 1/7 (14.3%) 2/42 (4.8%) 4/42 (9.5%)
Hiccups 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Oropharyngeal pain 0/7 (0%) 1/7 (14.3%) 1/42 (2.4%) 1/42 (2.4%)
Paranasal sinus hypersecretion 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Pulmonary oedema 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Throat tightness 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Cough 0/7 (0%) 0/7 (0%) 3/42 (7.1%) 4/42 (9.5%)
Haemoptysis 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 1/42 (2.4%)
Asthma 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Nasal dryness 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Pneumonitis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Productive cough 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Sleep apnoea syndrome 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Dyspnoea Exertional 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 0/42 (0%)
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysaesthesia Syndrome 2/7 (28.6%) 3/7 (42.9%) 15/42 (35.7%) 9/42 (21.4%)
Rash 0/7 (0%) 1/7 (14.3%) 13/42 (31%) 9/42 (21.4%)
Pruritus 1/7 (14.3%) 1/7 (14.3%) 9/42 (21.4%) 3/42 (7.1%)
Alopecia 1/7 (14.3%) 0/7 (0%) 8/42 (19%) 2/42 (4.8%)
Rash maculo-papular 1/7 (14.3%) 1/7 (14.3%) 2/42 (4.8%) 0/42 (0%)
Dermatitis acneiform 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Dermatitis psoriasiform 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Dry skin 1/7 (14.3%) 0/7 (0%) 2/42 (4.8%) 2/42 (4.8%)
Night sweats 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Rash generalised 0/7 (0%) 1/7 (14.3%) 1/42 (2.4%) 0/42 (0%)
Skin irritation 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Urticaria 1/7 (14.3%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Blister 0/7 (0%) 0/7 (0%) 0/42 (0%) 4/42 (9.5%)
Pain of skin 0/7 (0%) 0/7 (0%) 0/42 (0%) 4/42 (9.5%)
Hyperkeratosis 0/7 (0%) 0/7 (0%) 0/42 (0%) 3/42 (7.1%)
Plantar erythema 0/7 (0%) 0/7 (0%) 0/42 (0%) 2/42 (4.8%)
Skin exfoliation 0/7 (0%) 0/7 (0%) 0/42 (0%) 2/42 (4.8%)
Skin ulcer 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 1/42 (2.4%)
Decubitus ulcer 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Dermatitis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Diabetic ulcer 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Hyperhidrosis 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Rash erythematous 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Skin fissures 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Skin toxicity 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Erythema 0/7 (0%) 0/7 (0%) 3/42 (7.1%) 1/42 (2.4%)
Vascular disorders
Hypertension 0/7 (0%) 1/7 (14.3%) 8/42 (19%) 9/42 (21.4%)
Deep vein thrombosis 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 0/42 (0%)
Hot flush 1/7 (14.3%) 0/7 (0%) 0/42 (0%) 0/42 (0%)
Orthostatic hypotension 0/7 (0%) 1/7 (14.3%) 0/42 (0%) 1/42 (2.4%)
Haematoma 0/7 (0%) 0/7 (0%) 0/42 (0%) 2/42 (4.8%)
Arteriosclerosis 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Flushing 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Pallor 0/7 (0%) 0/7 (0%) 0/42 (0%) 1/42 (2.4%)
Vascular insufficiency 0/7 (0%) 0/7 (0%) 1/42 (2.4%) 0/42 (0%)
Hypotension 0/7 (0%) 0/7 (0%) 2/42 (4.8%) 1/42 (2.4%)

Limitations/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.

Results Point of Contact

Name/Title Eisai Medical Information
Organization Eisai Inc.
Phone 1-888-274-2378
Email esi_oncmedinfo@eisai.com
Responsible Party:
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01271504
Other Study ID Numbers:
  • E7050-701
  • 2011-000752-41
First Posted:
Jan 6, 2011
Last Update Posted:
May 12, 2021
Last Verified:
Aug 1, 2017