A Phase 1 Study of PS-341 in Combination With Docetaxel in Patients With Advanced Solid Tumors
A Phase 1 Study of PS-341 in Combination With Docetaxel in Patients With Advanced Solid Tumors
Phase I trial to study the effectiveness of combining bortezomib with docetaxel in treating patients who have advanced solid tumors. Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining bortezomib with docetaxel may kill more tumor cells
OBJECTIVES:
I. Determine the maximum tolerated dose of bortezomib and docetaxel in patients with advanced solid tumors.
II. Determine the toxicity and tolerability of this regimen in these patients. III. Determine the biologic correlates of proteasome inhibition of bortezomib and determine the effects of this inhibition on the pharmacokinetics of docetaxel in these patients.
IV. Determine the antitumor efficacy of this regimen in these patients.
OUTLINE: This is a dose-escalation study.
For course 1, patients receive docetaxel IV over 1 hour on days 1 and 8 and bortezomib IV over 3-5 seconds on days 9 and 12. Patients then receive 1 week of rest. For course 2 and all subsequent courses, patients receive docetaxel on days 1 and 8 and bortezomib on days 2, 5, 9, and 12. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 2-6 patients receive escalating doses of bortezomib and docetaxel until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which no more than 1 of 6 patients experiences dose-limiting toxicity.
PROJECTED ACCRUAL: A minimum of 24 patients will be accrued for this study.
Inclusion Criteria:
Histologically confirmed solid tumor for which standard curative or palliative measures do not exist or are no longer effective
No known brain metastases
Performance status - ECOG 0-2
Performance status - Karnofsky 50-100%
More than 12 weeks
WBC at least 3,000/mm^3
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
Hemoglobin at least 8 g/dL
Bilirubin normal
AST and ALT no greater than 1.5 times upper limit of normal (ULN) and alkaline phosphatase no greater than 2.5 times ULN
Alkaline phosphatase no greater than 5 times ULN (unless bone-derived) and AST and ALT less than 1.5 times ULN
Creatinine normal
Creatinine clearance at least 60 mL/min
No symptomatic congestive heart failure
No unstable angina pectoris
No cardiac arrhythmia
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 3 months after study
No prior allergic reactions attributed to taxanes (e.g., docetaxel or paclitaxel) or compounds of similar chemical or biological composition
No prior allergic reactions to compounds similar to bortezomib or other study agents
No known hypersensitivity to corticosteroids
No predicted intolerance to regular, repeated administration of corticosteroids (e.g., poorly controlled diabetes or significant osteoporosis/osteopenia)
No ongoing or active infection
No other uncontrolled concurrent illness that would preclude study participation
No psychiatric illness or social situation that would preclude study participation
No peripheral neuropathy grade 2 or greater
At least 4 weeks since prior chemotherapy (6 weeks for carmustine, nitrosoureas, or mitomycin) and recovered
Prior taxanes allowed
At least 4 weeks since prior radiotherapy and recovered
No other concurrent investigational agents
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent anticancer agents or therapies (commercial or investigational)