Randomized Study of Sorafenib Dose Escalation in Patients With Previously Untreated Metastatic Renal Cell Carcinoma
Condition: Renal Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Sorafenib Escalated Dose; Sorafenib Standard Dose
Intervention description: Patients randomized to Group A will receive sorafenib 600 mg bid for Weeks 5 through 8 (Dose Level 2). Patients who tolerate this dose through Week 8 will be further escalated to Dose Level 3 (800 mg po bid) for Weeks 9 through 12.; Patients randomized to Group B will receive Dose Level 1 (sorafenib 400 mg po bid) until progression of disease, intolerable toxicity, patient refusal to continue with the study, or investigator decision to remove the patient from the study.
Intervention MeSH terms: Sorafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Renal Cell Carcinoma; Kidney Cancer

Summary:

      The primary objective of this study is to compare the effectiveness of a dose-escalation
      regimen (400 to 800mg bid) relative to the standard dosing regimen (400mg bid) of sorafenib
      given in patients with metastatic RCC.

      The secondary objectives are to evaluate the effects of the dose-escalation regimen on the
      quality of life (QoL) of patients with metastatic RCC and to characterize the safety and
      tolerability profile of a dose-escalation regimen of sorafenib in patients with metastatic
      RCC.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age ≥18 years old.

          -  Diagnosis of unresectable/metastatic renal cell carcinoma (RCC). Nonclear cell
             histology is permitted (except for medullary, collecting duct, or sarcomatoid >50% of
             specimen). Prior metastasectomy is permitted as long as there is measurable disease at
             time of consent.

          -  Karnofsky Performance Status of 50% or greater at study entry.

          -  Adequate bone marrow, liver and renal function as assessed by the following: o
             Hemoglobin ≥ 9.0 g/dL. o ANC ≥ 1500/mm3. o Platelet count ≥ 100,000/mm3. o Total
             bilirubin ≤ 1.5 ULN. o ALT and AST ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver
             involvement). o Creatinine ≤ 1.5 × ULN.

          -  Women of childbearing potential must have a negative serum or urine pregnancy test
             performed within 7 days prior to the start of treatment.

          -  Women of childbearing potential and sexually active men must agree to use adequate
             barrier contraception prior to study entry, for the duration of study participation,
             and for at least three months after the last administration of sorafenib.

          -  INR < 1.5 or a PT/ PTT within normal limits. Patients receiving anti-coagulation
             treatment with an agent such as warfarin or heparin may be allowed to participate. For
             patients on warfarin, the INR should be measured prior to initiation of sorafenib and
             monitored at least weekly, or as defined by the local standard of care, until INR is
             stable.

          -  Ability to understand and the willingness to sign a written informed consent. A signed
             informed consent must be obtained prior to any study specific procedures.

        Exclusion Criteria:

          -  Prior systemic anticancer treatment for metastatic disease, including investigational
             therapy.

          -  Prior treatment with bevacizumab, sunitinib, or sorafenib even in the adjuvant
             setting.

          -  Prior cytokine therapy with interleukin (IL)-2 or interferon (IFN) for metastatic
             disease.

          -  Active malignancy other than RCC (except non-melanoma skin cancer) within 5 years of
             enrollment.

          -  Hemodialysis or peritoneal dialysis.

          -  Treatment with radiotherapy within 2 weeks of enrollment.

          -  Cardiac disease: Congestive heart failure Class II or higher per NYHA. Patients must
             not have unstable angina (anginal symptoms at rest) or new onset angina (began within
             the last 3 months) or myocardial infarction within the past 6 months.

          -  Uncontrolled CNS metastases. All patients must undergo a CT) scan/MRI of the brain to
             exclude brain metastasis. Patients with adequately treated CNS disease may be
             considered for participation as long as the first dose of sorafenib is 4 weeks after
             completion of CNS therapy.

          -  Uncontrolled hypertension defined as SBP > 150 mmHg or DBP > 90 mmHg, despite optimal
             medical management.

          -  Active clinically serious infection > Grade 2 per the CTCAE v3.

          -  Thrombolic or embolic events such as a cerebrovascular accident including transient
             ischemic attacks within the past 6 months.

          -  Pulmonary hemorrhage/bleeding event ≥ Grade 2 per CTCAE v3.0 within 4 weeks of
             administration of the first dose of study drug.

          -  Any other hemorrhage/bleeding event ≥ Grade 3 per CTCAE v3.0 within 4 weeks of
             administration of the first dose of study drug.

          -  Serious non-healing wound, ulcer, or bone fracture.

          -  Evidence or history of bleeding diathesis or coagulopathy.

          -  Major surgery, open biopsy or significant traumatic injury within 4 weeks of
             administration of the first study drug dose.

          -  Use of St. John's Wort, rifampin (rifampicin), phenytoin, Phenobarbital,
             carbamazepine, dexamethasone.

          -  Known or suspected allergy to sorafenib or any agent given in the course of this
             trial.

          -  Any condition that impairs patient's ability to swallow whole pills.

          -  Any malabsorption problem.

          -  Pregnancy or lactation.