A Phase 1 Study of PXD101 in Combination With Bortezomib (PS-341) in Patients With Advanced Solid Tumors and Lymphoma
A Phase 1 Study of PXD101 in Combination With Bortezomib (PS-341) in Patients With Advanced Solid Tumors and Lymphoma
This phase I trial is studying the side effects and best dose of PXD101 and bortezomib in treating patients with advanced solid tumors or lymphomas. PXD101 and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PXD101 may also cause cancer cells to look more like normal cells, and to grow and spread more slowly. Giving PXD101 together with bortezomib may kill more cancer cells.
OBJECTIVES:
I. Evaluate the safety profile and determine the maximum tolerated dose of PXD101 in combination with bortezomib in patients with advanced solid tumors or lymphomas.
II. Determine the pharmacokinetics of the combination of PXD101 and bortezomib in these patients.
III. Evaluate selected biomarkers of drug effect in these patients. IV. Evaluate the activity of this regimen, in terms of objective response rate, in these patients.
OUTLINE: This is a dose-escalation study.
Patients receive PXD101 IV over 30 minutes on days 1-5 and bortezomib IV on days 1, 4, 8, and 11 (2, 5, 8, and 11 during course 1). Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-9 patients receive escalating doses of bortezomib and PXD101 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Blood is collected at baseline and periodically during course 1 of study treatment for pharmacokinetic studies.
After completion of study treatment, patients are followed periodically for 4 weeks.
Inclusion Criteria:
Histologically or cytologically confirmed solid tumor or lymphoma that is refractory to standard therapy or for which no standard therapy exists
No active, untreated, or symptomatic brain metastases
ECOG performance status 0-2
Life expectancy ≥ 12 weeks
WBC ≥ 3,000/mm^3
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Bilirubin ≤ 1.5 mg/dL
AST and ALT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN in the presence of liver metastases)
Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to PXD101, bortezomib, boron, or mannitol
No peripheral neuropathy > grade 1
No uncontrolled intercurrent illness, including, but not limited to, any of the following:
No significant cardiovascular disease, including any of the following:
No marked baseline prolongation of QT/QTc interval (repeated demonstration of a QTc interval > 500 msec), long QT syndrome, or required use of concurrent medication during PXD101 administration that may cause torsade de pointes
No severe medical or psychiatric problems of that would preclude study compliance
At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, carmustine, or mitomycin C)
At least 4 weeks since prior radiotherapy and recovered
At least 2 weeks since prior palliative radiotherapy to sites involving < 35% of bone marrow reserve
At least 4 weeks since prior investigational agents
At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor
No prior stem cell or bone marrow transplantation
No concurrent radiotherapy or immunotherapy
No concurrent hormonal therapy
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent investigational agents
No other concurrent anticancer agents or therapies