Study of Carfilzomib in Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL) or Prolymphocytic Leukemia (PLL)
Study of Carfilzomib in Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL) or Prolymphocytic Leukemia (PLL)
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