Sorafenib Dose Escalation in Renal Cell Carcinoma

Study Overview
=================
Brief Summary
-----------------
Sorafenib is a new drug, which is approved under the brand name Nexavar for the treatment of advanced kidney cancer. It is also currently being tested in various other cancers. Sorafenib works by stopping the development of new cancer cells and new blood vessels. By stopping the growth of new blood vessels around a tumor, it is believed that sorafenib prevents the growth of kidney cancer tumors. This is an open-label study which means that the patient, the doctor and Bayer Healthcare will know what tablets the patient is taking. All patients in this study will receive sorafenib tablets. Sorafenib is taken orally as a tablet (two tablets are taken twice a day). Treatment with sorafenib will continue until the patient's tumor grows larger or spreads further or if the patient has intolerable side effects. The dose of sorafenib that the patient will receive in the study will increase at certain points during the patient's treatment, as long as the patient is not experiencing side effects and the patient's tumor has not grown.

Detailed Description
-----------------
Issues on Outcome Measure Safety and tolerability will be addressed in the Adverse Events section.

Official Title
-----------------
A Phase II, Multi-centre, Open-label Study to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of Intrapatient Dose Escalation of Sorafenib as First Line Treatment for Metastatic Renal Cell Carcinoma.

Conditions
-----------------
Carcinoma, Renal Cell

Intervention / Treatment
-----------------
* Drug: Sorafenib (Nexavar, BAY43-9006)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age > 18 years. Metastatic clear cell RCC (renal cell carcinoma) Subjects with at least one uni-dimensional measurable lesion. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Memorial Sloan Kettering Cancer Center (MSKCC) good or intermediate category Life expectancy of at least 12 weeks. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to treatment Signed informed consent must be obtained prior to any study specific procedures. Subjects must have received no prior systemic anticancer therapy for the treatment of their renal cell carcinoma Prior total nephrectomy Exclusion Criteria: History of cardiac disease History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C Active clinically serious infections (> grade 2 National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 3.0) Symptomatic metastatic brain or meningeal tumors unless the subject is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Subjects with evidence or history of bleeding diathesis Deep vein thrombosis and/or pulmonary embolus within 12 months of the start of treatment. Delayed healing of wounds, ulcers or bone fractures Subjects with pre-existing thyroid abnormality whose thyroid function cannot be maintained within the normal range by medication Subjects undergoing renal dialysis Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and three months after the completion of trial. Prior adjuvant sorafenib is excluded. Radiotherapy during study or within 3 weeks of start of study drug Major surgery within 4 weeks of start of study Investigational drug therapy outside of this trial during or within 4 weeks of study entry

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib (Nexavar, BAY43-9006)<br>Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed. | Drug: Sorafenib (Nexavar, BAY43-9006)<br>* The initial dose of sorafenib will be 400 mg bid administered orally, on a continuous basis. A treatment cycle is considered to be 28 days. Intrapatient dose escalation will occur according to the following schedule, providing no grade 3 or 4 toxicities are observed (except for alopecia, nausea and vomiting); Day 1-28 400 mg bid, Day 29-56 600 mg bid, Day 57 onwards 800 mg bid. Subjects will continue on treatment until progression, unacceptable toxicity, subject withdraws consent or the decision is taken to stop the study following the analysis of response rates.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response - mITT (Modified Intent-to-treat) Population | Best Response (Response Rate) of a subject was defined as the proportion of patients with confirmed Complete Response (CR) or Partial Response (PR) as their best response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed CR was defined as disappearance of tumor and PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes. | Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months. | 
| Tumor Response - ITT (Intent to Treat) Population | Tumor Response of a subject was defined as the best tumor response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed Complete Response (CR) was defined as disappearance of tumor, Partial Response (PR) was defined as a decrease of at least 30% in the sum of target lesions, Stable Disease (SD) was defined as steady state of disease, and Progressive Disease (PD) was defined as at least a 20% increase in the sum of measured lesions or appearance of new lesions. | Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) Analysis - Area Under the Drug Concentration-time Curve From Time Zero to 10 Hours Postdose (AUC(0-10),ss) | AUC(0-10),ss was defined as an area under the plasma concentration versus time curve from time zero to 10 hours post-dose. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib. | Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8 and 10 hours post-dose. | 
| Pharmacokinetics (PK) Analysis - Area Under the Drug Concentration-time Curve From Time Zero to 12 Hours Postdose (AUC(0-12),ss) | AUC(0-12),ss was defined as an area under the plasma concentration versus time curve from time zero to 12 hours post-dose. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib. | Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose. | 
| Pharmacokinetics (PK) Analysis - Maximum Observed Concentration in Plasma (Cmax) | Cmax was defined as a maximum plasma concentration at steady-state. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib. | Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose. | 
| Pharmacokinetics (PK) Analysis - Time to Maximum Concentration (Tmax) | Tmax was defined as a time to maximum concentration at steady-state. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib. | Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose. | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) was defined as the time from start of study medication to the first documented disease progression per RECIST (by independent radiological assessment) or clinical progression as per investigator assessment or death due to any cause whichever occurred first. For patients who had not recurred or died at the time of analysis, PFS was censored at their last date of evaluable scan. | Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months. | 
| Time to Progression (TTP) | Time to progression (TTP) was defined as the time from start of study medication to the first documented disease progression per RECIST (by independent radiological assessment) or clinical progression as per investigator assessment whichever occurred first. For patients who had not progressed at the time of analysis or died before progression, TTP was censored at their last date of evaluable scan. | Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Kidney cancer,, Sorafenib,, Dose escalation,, No previous treatment