An International Phase 2 Study Of SU011248 In Patients With Inoperable Liver Cancer

Study Overview
=================
Brief Summary
-----------------
The study will consist of two parts. In Part 1 the study will start enrolling 38 patients and then further 25 patients up to a total of 63 eligible patients. If the study gives good results it can be expanded to a total of 160 patients. SU011248 will be administered orally daily for 4 weeks followed by a 2-week rest at a starting dose of 50 mg [milligrams] with provision for dose reduction based on tolerability. All patients will receive repeated cycles of SU011248 until disease progression, occurrence of unacceptable toxicity, or other withdrawal criteria are met. After discontinuation of treatment, patients will be followed up in order to collect information on further antineoplastic therapy and survival

Official Title
-----------------
An Open Label International Multi-Center Phase 2 Activity And Safety Study Of SU011248 In Patients With Unresectable Hepatocellular Carcinoma

Conditions
-----------------
Liver Neoplasms, Unresectable Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Drug: Sunitinib (SU011248)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed diagnosis of hepatocellular carcinoma Patients must present with disease not amenable to curative surgery (i.e. either hepatectomy, or liver transplant). Evidence of measurable disease by radiographic technique Adequate organ function. Exclusion Criteria: Prior treatment with any systemic treatment for liver cancer Presence of clinically relevant ascites Severe hemorrhage <4 weeks of starting study treatment. Diagnosis of second malignancy within last 3 years History of or known brain metastases, spinal cord compression, or carcinomatous meningitis Known human immunodeficiency virus (HIV) Serious acute or chronic illness Current treatment on another clinical trial Pregnant or breastfeeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: Sunitinib (SU011248)<br>* Sunitinib 50 mg by oral capsule, daily for 4 weeks in every 6 week cycle until progression or unacceptable toxicity.<br>* Other names: SU011248, Sutent;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | Number of subjects with best overall response. Complete response (CR)=disappearance of all target lesions. Partial Response (PR)= ≥30% decrease in sum of longest dimensions of lesions taking as reference baseline sum longest dimensions. Progressive disease (PD)= ≥ 20% increase in sum of longest dimensions of lesions taking as a reference smallest sum of the longest dimensions since treatment start, or the appearance of ≥ 1 new lesion. Stable disease (SD)=neither shrinkage for PR or increase for PD taking as reference smallest sum of longest dimensions since treatment start. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter | 
| Objective Response (CR or PR) | Number of patients with objective response: confirmed CR or confirmed PR according to RECIST. CR was defined as the disappearance of all target lesions. A PR was defined as a ≥30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. To be assigned a status of PR or CR, changes in tumor measurements in patients with responding tumors had to have been confirmed by repeat studies that were performed ≥ 4 weeks after the criteria for response were first met. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Objective Response (CR or PR) | Time from the first documentation of objective tumor response (CR or PR) that was subsequently confirmed to the first documentation of disease progression or to death due to any cause. CR=disappearance of all target lesions. PR= ≥30% decrease in sum of longest dimensions of lesions taking as reference baseline sum longest dimensions. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter or death due to cancer | 
| Clinical Benefit Response (CR, PR, or SD With Duration ≥12 Weeks) | Number of patients with Clinical Benefit Response: confirmed CR, confirmed PR, or SD for at least 12 weeks on study according to RECIST. CR=disappearance of all target lesions. PR= ≥30% decrease in sum of longest dimensions of lesions taking as reference baseline sum longest dimensions. SD=neither shrinkage for PR or increase for PD taking as reference smallest sum of longest dimensions since treatment start. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter or SD with duration of at least 12 weeks on study | 
| Best Overall Response of PR or SD With Duration ≥12 Weeks | Number of patients with best overall response of PR or SD with duration ≥ 12 weeks. Best overall response was defined as the time from the first documentation of tumor response that was subsequently confirmed to the first documentation of disease progression or to death due to any cause. CR=disappearance of all target lesions. PR= ≥30% decrease in sum of longest dimensions of lesions taking as reference baseline sum longest dimensions. SD=neither shrinkage for PR or increase for PD taking as reference smallest sum of longest dimensions since treatment start. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter or SD with duration of at least 12 weeks or death due to cancer | 
| Progression-Free Survival (Overall ITT) | Time from start of study treatment to first documentation of objective tumor progression, or to death due to any cause. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter or death | 
| Progression-Free Survival (ITT Child Pugh Class A Subject Population) | Time from start of study treatment to first documentation of objective tumor progression, or to death due to any cause. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter or death | 
| Time to Tumor Progression (Overall ITT) | Time from the start of study treatment to the first documentation of objective tumor progression. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter | 
| Time to Tumor Progression (ITT Child Pugh Class A Subject Population) | Time from the start of study treatment to the first documentation of objective tumor progression. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter | 
| Overall Survival (Overall ITT) | Time from the date of first dose of study medication to the date of death due to any cause. | From start of study treatment until death. | 
| Overall Survival (ITT Child Pugh Class A Subject Population) | Time from the date of first dose of study medication to the date of death due to any cause. | From start of study treatment until death. | 
| 1-Year Survival Probability | Probability of survival 1 year after the first dose of study treatment. | From start of treatment until Day 28 of Cycle 1, Day 28 of Cycles thereafter up until 1 year. | 
| Trough Plasma Concentrations (Ctrough) of Sunitinib | Ctrough = the concentration prior to study drug administration. | Cycle 1 (Days 1, 14, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) | 
| Ctrough of SU-012662 (Metabolite of Sunitinib) | Ctrough = the concentration prior to study drug administration. | Cycle 1 (Days 1, 14, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) | 
| Ctrough of Total Drug (Sunitinib + SU-012662) | Ctrough = the concentration prior to study drug administration. | Cycle 1 (Days 14, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) | 
| Dose-Corrected Ctrough of Sunitinib | Data was dose-corrected to the starting dose (dose-corrected Ctrough = observed Ctrough x [starting dose/actual dose]). | Cycle 1 (Days 1, 14, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) | 
| Dose-Corrected Ctrough of SU-012662 (Metabolite of Sunitinib) | Data was dose-corrected to the starting dose (dose-corrected Ctrough = observed Ctrough x [starting dose/actual dose]). | Cycle 1 (Days 1, 14, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) | 
| Dose-Corrected Ctrough of Total Drug (Sunitinib + SU-012662) | Data was dose-corrected to the starting dose (dose-corrected Ctrough = observed Ctrough x [starting dose/actual dose]). | Cycle 1 (Days 14, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) | 
| Circulating Endothelial Cells (CECs) and Circulating Endothelial Progenitor Cells (CEPs) | Blood samples for the assessment of CECs and circulating CEPs were planned to be obtained for subjects in Part 1 of the study, and for a subset of subjects in Part 2 of the study to complete the angiogenic profile of unresectable hepatocellular carcinoma, in addition to the soluble protein evaluation. | Cycle 1 (Days 1, 14), Cycle 2 (Days 1, 28), Cycle 5 (Day 1) | 
| Tissue Tumor Markers Assessed by Tumor Biopsy | Provision of previously collected tumor paraffin blocks (or at least 5-10 4-micron slides prepared from the paraffin block) for correlative laboratory analysis was optional. For all subjects showing OR on study, it was highly recommended to provide previously collected paraffin blocks (or at least 5-10 4-micron slides prepared from the paraffin block). These samples were to be analyzed for markers that may be associated with tumor proliferation or angiogenesis. | Day 28 of Cycle 1 (optional) | 
| Plasma Concentration of Vascular Endothelial Growth Factor (VEGF) | Plasma concentrations of VEGF that may be associated with tumor proliferation or angiogenesis were collected from a subset of subjects and analyzed by e nzyme-linked immunosorbent assay (ELISA). Soluble protein values: Baseline concentration (pM) and ratio to Baseline at each timepoint; ratio to Baseline = plasma concentration of soluble protein at timepoint / concentration of soluble protein at baseline. Samples below the limit of quantitation and samples with insufficient volume available were excluded. | Cycle 1 (Days 1, 14, 28), Cycle 2 (Days 1, 28), Cycle 5 (Day 28) | 
| Plasma Concentration of VEGF-C | Plasma concentrations of VEGF-C that may be associated with tumor proliferation or angiogenesis were collected from a subset of subjects and analyzed by ELISA. Soluble protein values: Baseline concentration (pM) and ratio to Baseline at each timepoint; ratio to Baseline = plasma concentration of soluble protein at timepoint / concentration of soluble protein at baseline. Samples below the limit of quantitation and samples with insufficient volume available were excluded. | Cycle 1 (Days 1, 14, 28), Cycle 2 (Days 1, 28), Cycle 5 (Day 28) | 
| Plasma Concentration of Soluble VEGF Receptor-2 (sVEGFR-2) | Plasma concentrations of sVEGFR-2 that may be associated with tumor proliferation or angiogenesis were collected from a subset of subjects and analyzed by ELISA. Soluble protein values: Baseline concentration (pM) and ratio to Baseline at each timepoint; ratio to Baseline = plasma concentration of soluble protein at timepoint / concentration of soluble protein at baseline). Samples below the limit of quantitation and samples with insufficient volume available were excluded. | Cycle 1 (Days 1, 14, 28), Cycle 2 (Days 1, 28), Cycle 5 (Day 28) | 
| Plasma Concentration of Soluble VEGF Receptor-3 (sVEGFR-3) | Plasma concentrations of sVEGFR-3 that may be associated with tumor proliferation or angiogenesis were collected from a subset of subjects and analyzed by ELISA. Soluble protein values: Baseline concentration (pM) and ratio to Baseline at each timepoint; ratio to Baseline = plasma concentration of soluble protein at timepoint / concentration of soluble protein at baseline. Samples below the limit of quantitation and samples with insufficient volume available were excluded. | Cycle 1 (Days 1, 14, 28), Cycle 2 (Days 1, 28), Cycle 5 (Day 28) | 
| Plasma Concentration of Soluble KIT (sKIT) | Plasma concentrations of sKIT that may be associated with tumor proliferation or angiogenesis were collected from a subset of subjects and analyzed by ELISA analysis. Soluble protein values: Baseline concentration (pM) and ratio to Baseline at each timepoint; ratio to Baseline = plasma concentration of soluble protein at timepoint / concentration of soluble protein at baseline. Samples below the limit of quantitation and samples with insufficient volume available were excluded. | Cycle 1 (Days 1, 14, 28), Cycle 2 (Days 1, 28), Cycle 5 (Day 28) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Liver neoplasms, sunitinib, Phase 2