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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Sorafenib
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Phase Ib: Cohort 1,2, and 3<br>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<br>* Phase Ib: Cohort 1; 200 mg E7050 + 400 mg Sorafenib Cohort 2; 300 mg E7050 + 400 mg Sorafenib Cohort 3; 400 mg E7050 + Sorafenib<br>|
| Active Comparator: Phase II: Arm 1; E7050 + Sorafenib<br>Phase II: Arm 1; E7050 + 400 mg Sorafenib Arm 2; 400 mg Sorafenib | Drug: Sorafenib<br>* E7050 given orally at 200, 300 or 400 mg once daily. Sorafenib given orally, 400 mg twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Cycle 1 (Cycle length is 28 days) | 
| 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 | 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. | 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 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. | 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 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) | 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). | 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 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Time to Progression (TTP) | 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. | From the date of randomization until the date of PD (up to approximately 3 years 11 months) | 
| Phase 2: Progression Free Survival (PFS) | 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. | 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) | 
| Phase 2: Percentage of Participants With PFS at Week 12 | 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. | At 12 weeks | 
| Phase 2: Overall Survival (OS) | 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. | From the date of randomization until the date of death (Up to approximately 3 years 11 months) | 
| Phase 2: Percentage of Participants With Overall Response | 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. | From the date of randomization until disease progression or death (Up to approximately 3 years 11 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, liver, hepatocellular carcinoma, phase I, phase II