RATIONALE:

Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE:

This phase I trial is studying the side effects and the best dose of carfilzomib in treating patients with relapsed or refractory chronic lymphocytic leukemia(CLL),small lymphocytic lymphoma(SLL), or prolymphocytic leukemia (PLL).

PRIMARY OBJECTIVES:

I. To determine the dose limiting toxicity (DLT) and maximal tolerated dose (MTD) of carfilzomib in patients with relapsed or refractory Chronic Lymphocytic Leukemia(CLL) / Small Lymphocytic Lymphoma (SLL) and Prolymphocytic Leukemia (PLL).

II. To evaluate the safety and toxicity profile of carfilzomib in relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL)/prolymphocytic leukemia (PLL).

SECONDARY OBJECTIVES:

I. To evaluate efficacy of carfilzomib therapy in relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL)/prolymphocytic leukemia (PLL) to justify future phase II studies.

II. To determine the degree and duration of cellular proteosome inhibition induced by carfilzomib and relationship of this to pharmacodynamics, response and toxicity.

III. To determine the pharmacokinetics (plasma and cellular) of carfilzomib and relationship of this to proteosome inhibition, pharmacodynamics, response, and toxicity.IV. To examine the effect of carfilzomib on pharmacodynamic parameters including cytokines, changes in downstream targets including NF-kappa B (p50/p65 binding; I-kappa B level, P-I-kappa B level,select target genes), p53 (p53 nuclear levels, p53 nuclear binding, and select target genes), ER stress proteins, and p73.

OUTLINE: This is a dose-escalation study of carfilzomib.Patients receiving carfilzomib intra-venous(IV) over 30 minutes once daily, on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

• Previously treated patients with a diagnosis of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or prolymphocytic leukemia (PLL) by NCI Criteria with intermediate or high risk B-Cell chronic lymphocytic leukemia (CLL)(Modified Rai stage) satisfying at least one of the criteria for active disease requiring treatment;patients with a history of Richter's transformation are eligible if they now have evidence of chronic lymphocytic leukemia (CLL) only, with < 10% large cells in the bone marrow
• Massive or progressive splenomegaly and/or lymphadenopathy; or need for cytoreduction for stem cell transplant
• Anemia (hemoglobin < 11 g/dl) or thrombocytopenia (platelets < 100 x 10^9/L)
• Presence of weight loss > 10% over the preceding 6 month period
• NCI grade 2 or 3 fatigue
• Fevers > 100.5 °C or night sweats for greater than 2 weeks without evidence of infection
• Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of less than 6 months
• Creatinine Clearance (CrCl) > 15mL/min
• Alanine aminotransferase (ALT) < 3X upper limit of normal (ULN)
• Bilirubin =< 2 times the upper limit of normal, unless disease related
• Platelets >= 20 x 10^9/L and absence of active bleeding
• Patients must have an ECOG (Eastern Cooperative Oncology Group) performance status =< 2
• Patients must not have secondary cancers that result in a life expectancy of <2 years or that would confound assessment of toxicity in this study
• Patients of all racial/ethnic groups are eligible for the study if they meet eligibility criteria outlined-
• Patients must provide written informed consent

Exclusion Criteria:

• Absence of previously treated chronic lymphocytic leukemia (CLL)
• Female subject that is pregnant or breastfeeding; women of childbearing potential and men must agree to use adequate contraception prior to study entry, duration of study participation,and 30 days following study completion; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately;confirmation that the subject is not pregnant must be established by a negative serum -human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women
• Patients with congestive heart failure (CHF)in whom pre-treatment hydration would be prohibitive;New York Heart Association (NYHA) Class III/IV CHF is excluded
• Patients who have had treatment for chronic lymphocytic leukemia (CLL) within 2 weeks, although palliative steroids are acceptable
• Patient unable to give written informed consent
• Failure to recover from toxicity of previous radiotherapy or chemotherapy to grade 1
• Patients with active infections requiring intravenous (IV) antibiotic/antiviral therapy are not eligible for entry onto the study until resolution of the infection; patients on prophylactic antibiotics or antivirals are acceptable
• Patients who have previously taken bortezomib