Bortezomib and Topotecan Hydrochloride in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To assess the safety and feasibility of combining PS-341 with topotecan in patients with advanced solid tumor malignancies.

II. To define the maximum tolerated dose (MTD) of topotecan when administered in combination with a fixed dose of PS-341 and to described the toxicities at each dose studied.

III. To evaluate the pharmacokinetics of topotecan when given in combination with PS-341 at MTD.

SECONDARY OBJECTIVES:

I. To perform laboratory correlative studies on patients tissue investigating potential predictors of response.

OUTLINE:

PART I (completed as of 09/06/06; all patients enrolled in study after 09/06/06 are enrolled in part II): Patients receive escalating doses of topotecan hydrochloride IV over 30 minutes on days 1 and 8 followed 6 hours later by bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity.

PART II: Patients receive bortezomib IV on days 1, 4, 8, and 11 followed 6 hours later by escalating doses of topotecan hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity.

In both parts of the study, patients who achieve a response may receive additional courses of treatment.

After completion of study treatment, patients are followed periodically.

Inclusion

• Histologic proof of solid tumor malignancy
• ANC >= 1500/microliter
• PLT >= 150,000/microliter
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• AST =< 2.5 x ULN or AST =< 5 x ULN if liver involvement
• Serum creatinine =< 1.5
• Life expectancy >= 12 weeks
• ECOG performance status 0, 1, or 2
• Subjects with asymptomatic brain metastases are allowed

Exclusion

• ECOG PS 3 or 4
• Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients must not have received chemotherapy or radiation therapy for at least four weeks, and they must have recovered from any toxicities of previous treatment (ongoing grade 1 dermatologic toxicities are allowable)
• Eligible patients should not be taking enzyme-inducing anticonvulsants due to the potential of pharmacokinetic interactions
• Pregnant and nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device [IUD] or abstinence, etc.)
• Other concurrent chemotherapy, immunotherapy, or radiotherapy
• HIV-positive patients receiving anti-retroviral therapy (HAART); there is a potential for pharmacokinetic interactions
• Bisphosphonate therapy (e.g. pamidronate or zoledronate) will not be considered investigational agents for the purpose of trial eligibility
• Pre-existing grade >= 2 neuropathy
• No previous treatment with PS-341 allowed, however there is no limit to other prior therapy with chemotherapy, including topotecan, and radiation therapy