A Dose Escalation Study of Sorafenib (BAY 43-9006, NSC 724772) in Nomotensive Patients With Advanced Malignancies
I. Determine whether increasing the dose of sorafenib tosylate increases the plasma
steady-state concentration in patients with advanced solid tumors.
II. Determine whether increasing the dose of this drug affects blood pressure in these
I. Determine whether the variability in blood pressure elevation is due to pharmacokinetic
or pharmacodynamic variability.
II. Compare the toxicity and differences in pharmacokinetics of delivering a higher dose of
this drug per day (using two different schedules) vs delivering the currently recommended
dose of this drug.
III. Investigate mechanisms of sorafenib tosylate-induced hypophosphatemia with serial
measurements of phosphate metabolism (no longer assessed as of 4/29/2009) in these patients,
detailed baseline measurements in all patients, and detailed evaluations of patients
developing grade 3 or greater hypophosphatemia.
IV. Detect subclinical effects of this drug on measures of thyroid function. V. Identify
biomarkers predicting the categorization of patient response.
OUTLINE: This is a randomized, dose-escalation study.
Patients receive oral sorafenib tosylate twice daily on days 1-7 and once on day 8. Patients
not experiencing at least one grade 2 or higher toxicity during the initial sorafenib
treatment are randomized to 1 of 3 dose-escalated treatment arms.
ARM I: Patients receive higher-dose oral sorafenib tosylate twice daily on days 15-36.
ARM II: Patients receive standard-dose oral sorafenib tosylate three times daily on days
ARM III: (closed to accrual as of 4/29/2009) Patients receive standard-dose oral sorafenib
tosylate twice daily on days 15-36.
In all arms, treatment repeats every 3 weeks in the absence of disease progression or
Patients undergo ambulatory blood pressure monitoring at baseline, on days 7, 14, and 21,
and at 6 and 12 months. Blood samples are collected periodically throughout study and
evaluated for pharmacokinetic studies, thyroid function, serum markers, and phosphate
metabolism*. CT perfusion imaging is performed at baseline, week 6, week 12, and then every
8-12 weeks thereafter.
NOTE: * Phosphate metabolism no longer assessed as of 4/29/2009.
After completion of study treatment, patients are followed every 4 weeks for 1 year and then
every 3 months thereafter.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Changes in BP
BP will first be calculated for each subject as BP after 1 week of treatment minus BP before that treatment dose. Then, for each randomized group separately, the BP changes in the two study phases will be compared using paired t-tests.
From baseline to day 21
University of Chicago Comprehensive Cancer Center
United States: Food and Drug Administration
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