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
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
This phase I trial is studying the side effects and best dose of sorafenib and bortezomib in treating patients with advanced cancer. Sorafenib and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of cancer cells by blocking blood flow to the cancer
OBJECTIVES:
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 bortezomib.
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 dose-limiting toxicity.
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.
Inclusion Criteria:
Diagnosis of 1 of the following:
Cytologically or histologically proven unresectable solid tumor for which no curative treatment options exist (group I - dose-escalation phase)
Multiple myeloma or chronic lymphocytic leukemia requiring treatment (group II - maximum tolerated dose phase)
No known standard therapy that is potentially curative or definitely capable of extending life expectancy exists
Tumor amenable to serial sampling (group II)
ECOG performance status 0-2
Absolute neutrophil count ≥ 1,500/mm^3
Hemoglobin ≥ 9 g/dL
Platelet count ≥ 100,000/mm^3 (75,000/mm^3 for patients with multiple myeloma [group II])
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST ≤ 3 times ULN (5 times ULN if liver involvement)
Creatinine ≤ 1.5 times ULN (2.5 times ULN for patients with multiple myeloma [group II])
Life expectancy ≥ 12 weeks
No uncontrolled infection
No New York Heart Association class III or IV heart disease
No uncontrolled hypertension, labile hypertension, or history of poor compliance with antihypertensive medication
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No sensory peripheral neuropathy of any etiology > grade 1 or neuropathic pain of any etiology
No active HIV infection requiring therapy
No inability to swallow that would preclude use of oral medications
No evidence of bleeding diathesis
Medically capable and willing to provide biologic specimens as required (mandatory for patients in group II)
Priorbortezomib allowed
More than 3 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas) and recovered
More than 4 weeks since prior immunotherapy or biologic therapy
More than 2 weeks since prior steroid therapy (group II only)
No prior anti-vascular endothelial growth factor therapy
More than 4 weeks since prior full-field radiotherapy (2 weeks for limited-field radiotherapy)
No prior radiation to > 25% of bone marrow
More than 4 weeks since major surgery (e.g., laparotomy) (2 weeks for minor surgery)
No concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary other therapy considered investigational
No concurrent prophylactic colony-stimulating factors
No concurrent therapeutic anticoagulation
No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, and phenobarbital), rifampin, or Hypericum perforatum (St. John's Wort)
No concurrent participation in any other study involving a pharmacologic agent (e.g., drugs, biologics, immunotherapy, or gene therapy), either for symptom control, or therapeutic intent