Phase I Study of Paclitaxel (Taxol) and Bortezomib (Velcade) in Patients With Refractory Solid Tumor Malignancies Involving an Activated MAPK Pathway
Phase I Study of Paclitaxel (Taxol) and Bortezomib (Velcade) in Patients With Refractory Solid Tumor Malignancies Involving an Activated MAPK Pathway
RATIONALE: Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving paclitaxel together with bortezomib may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of paclitaxel and bortezomib in treating patients with metastatic or unresectable malignant solid tumors.
OBJECTIVES:
Primary
Secondary
OUTLINE: Patients receive paclitaxel IV over 1 hour and bortezomib IV on days 1, 8, and 15. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Blood samples are collected at baseline and periodically during course 1 for pharmacokinetic and biomarker studies. Blood samples are analyzed for plasma concentrations of paclitaxel by high performance liquid chromatography and for Bim protein levels and phosphorylation status by western blotting. Tumor tissue samples, if available, are analyzed to evaluate the presence of an activated Ras/Raf/MAPK pathway. Tumor tissue samples are analyzed for Ras and/or Raf mutations by nucleic acid extraction and direct sequencing; Ras and/or Raf overexpression by western blotting; Ras activation assay; and/or phospho-ERK by western blotting and IHC.
DISEASE CHARACTERISTICS:
Histologically confirmed malignant solid tumor that involves an activated Ras/Raf/MAPK pathway, including the following:
Metastatic or unresectable disease
Standard curative or palliative measures do not exist or are no longer effective
No newly diagnosed, untreated, or uncontrolled brain metastases
PATIENT CHARACTERISTICS:
ECOG performance status 0-2
ANC ≥ 1,500/μL
WBC ≥ 3,500/μL
Platelet count ≥ 100,000/μL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST/ALT ≤ 2.5 times ULN (≤ 5 times ULN for tumor involvement of the liver)
Creatinine ≤ 2 times ULN
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No neuropathy ≥ grade 1 with pain within the past 14 days
No active infections
No myocardial infarction within the past 6 months
No NYHA class III or IV heart failure
No uncontrolled angina
No severe uncontrolled ventricular arrhythmias
No evidence of acute ischemia or active conduction system abnormalities by ECG
No hypersensitivity to bortezomib, boron, or mannitol
No serious medical or psychiatric illness likely to interfere with study participation
PRIOR CONCURRENT THERAPY: