A Phase I Study of the Raf Kinase/VEGFR Inhibitor BAY 43-9006 in Combination With the Proteasome Inhibitor PS-341 in Patients With Advanced Malignancies
I. To determine the maximum tolerated dose (MTD) of sorafenib and bortezomib in patients
with advanced malignancies.
II. To describe the toxicities associated with the combination of sorafenib and bortezomib.
III. To evaluate the therapeutic antitumor activity of the combination of sorafenib and
IV. To evaluate the effects of sorafenib on the disposition of bortezomib.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 groups according
to disease type.
GROUP I (solid tumors-dose-escalation group): Patients receive oral sorafenib twice daily
on days 1-21 and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6
patients receive escalating doses of sorafenib and bortezomib until the MTD is determined.
The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience
GROUP II (multiple myeloma or chronic lymphocytic leukemia-maximum tolerated dose [MTD]
group): Patients receive oral sorafenib at the MTD twice daily on days 3-21 of course 1 and
on days 1-21 of each subsequent course. Patients also receive bortezomib IV over 3-5 seconds
at the MTD on days 1, 4, 8, and 11.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed for 3 months.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD as assessed by the number of patients with dose-limiting toxicity (DLT) using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0)
DLTs include: Hematologic: Grade 4 ANC for ≥5 days, Grade 4 anemia of any duration, or PLT <25,000 of any duration; Renal: Serum creatinine ≥2 times baseline or > 2x upper limit of normal if baseline levels normal; All other non-hematologic toxicities ≥grade 3 as per CTCAE v3.0 except fatigue; Any toxicities that caused dose delay of > 2 weeks of the intended next dose. MTD is the dose level below the lowest dose that induces DLT in at least one-third of patients (2 of 6 patients).
Observed for at least 3 weeks at a given dose level combination
United States: Food and Drug Administration
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