Velcade and Sorafenib in Unresected or Metastatic Renal Cell Carcinoma

Velcade (Bortezomib) and Sorafenib in Unresected or Metastatic Renal Cell Carcinoma

This is an open label, non-randomized, single arm phase II study. The primary objective of this study is to investigate the efficacy of combination of sorafenib and VELCADE® (bortezomib). The primary efficacy endpoint is Progression-Free Survival (PFS). The secondary objectives of this study are to:

Assess the response rate of this combination in this patient population and Assess the toxicity of this combination in this patient population

• Pretreatment, a complete history and physical examination to include performance status, weight and concurrent non-malignant disease and therapy will be done before starting treatment. Prior surgery, chemotherapy, and radiotherapy details will be noted.
• Prior to the initiation of treatment, laboratory studies should include a CBC with differential cell count, platelet count, urinalysis, complete metabolic profile, magnesium and electrocardiogram. A baseline imaging study of the tumor will be performed. Other X-rays will be done as clinically indicated.
• Physical examination, performance status and toxicity recording will be done before each course of therapy.
• During the study, patients will be followed with complete blood count (CBC), differential and platelet counts on days 1, 4, 8, and 11. Chemistries will also be performed before each course within a 3 day leeway prior to treatment. Clinical schedules will be considered when scheduling patients for treatment, specimen collection and processing, and specimen shipment.
• Measureable and evaluable disease will be evaluated by the same imaging studies done at baseline and every 2 courses thereafter to determine tumor response.
• For patients on warfarin, International Normalized Ration (INR) testing will be performed prior to the first cycle, weekly during the first cycle, and then prior to day one for subsequent cycles if the INR is in an acceptable range during the first cycle. If the INR has not been in an acceptable range during the first cycle, the INR will be monitored weekly until the value is stable on three consecutive measurements one week apart.
• Since Sorafenib is a competitive inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4) patients will be assessed each cycle for medications or changes in diet that would affect CYP3A4 metabolism.

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
• Male subject agrees to use an acceptable method for contraception for the duration of the study.
• All patients, 18 years or older with cytologically confirmed clear cell renal with no prior chemotherapy are eligible.
• Patients must have a life expectancy of at least 12 weeks
• Patients must have a Zebroid performance of 0-2
• Patients should have adequate bone marrow function defined by an absolute peripheral granulocyte count of > 1500 cells/mm3 and platelet count > 100,000/mm3 and absence of a regular red blood cell transfusion requirement.
• Patients should have adequate hepatic function with a total bilirubin < 2 mg/dl and Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic-pyruvic transaminase (SGPT) < two times the upper limit of normal, and adequate renal function as defined by a Serum creatinine < 1.5 x the upper limit of normal.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

• Patients with non-measurable disease.
• Patients who are unable to take medications orally.
• Patients with resectable renal cell carcinoma
• Patients with a history of Hepatitis B, or Hepatitis C
• Patients known to be Human Immunodeficiency Virus (HIV) positive
• Patients with poorly controlled diabetes mellitus
• Patients with poorly controlled hypertension or hypotension
• Chronic pulmonary disease and a diffusion capacity < 50 %, or a forced vital capacity (FVC) or forced expiratory volume in 1 second (FEV1) of <50%
• Severe renal impairment (Creatinine clearance [CrCL]< 13 ml/min)
• Patients with known malabsorption syndromes.
• Patient has Grade 2 peripheral neuropathy within 14 days before enrollment.
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
• Patient has hypersensitivity to bortezomib, boron or mannitol or sorafenib.
• Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
• Patient has received other investigational drugs with 28 days before enrollment.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
• Patients may receive no other concurrent chemotherapy or radiation therapy (XRT) during this trial.
• Patients may not have received XRT within 4 weeks prior to the first treatment.