High-dose HMG-CoA Inhibitor Simvastatin for Patients With Relapsed CLL: Pilot Trial and Pharmacokinetic-pharmacodynamic Studies

Inclusion Criteria

Eligibility Criteria:

- Patients must have histologically or cytologically confirmed chronic lymphocytic
leukemia (CLL). Criteria for diagnosis are as per the WHO classification of
hematologic tumors (Jaffe 2001). As per the 1996 NCI guidelines for CLL "[second-line
or later] treatment of CLL is generally palliative in intent; therefore, patients who
have relapsed may be followed without therapy until they experience disease-related
symptoms or progressive disease, with deterioration of blood counts, discomfort from
lymphadenopathy or hepatosplenomegaly, recurrent infections, or associated autoimmune
disorders" (Cheson 1996).

- Age >18 years. Because no dosing or adverse event data are currently available on the
use of high-dose simvastatin in patients <18 years of age, children are excluded from
this study.

- Life expectancy of greater than 6 months.

- ECOG performance status #2 or better.

- Patients must have normal organ and marrow function as defined below:

- total bilirubin within normal institutional limits unless resulting from
documented hemolysis

- AST(SGOT)/ALT(SGPT) ≤1.5 X institutional upper limit of normal

- creatinine ≤ 1.5 institutional upper limit of normal OR

- creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal

- Creatine phosphokinase ≤ 1.5 institutional upper limit of normal

- Patients with active infections requiring systemic antibiotics should be excluded
until resolution of infection

- The effects simvastatin on the developing human fetus at the studied therapeutic dose
are unknown. For this reason and because HMG-CoA reductase inhibitors may be
teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Patients may not be receiving any other investigational agents.

- Patients with known brain or nervous system disease should be excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to simvastatin.

- Patients receiving any medications or substances that are inhibitors or inducers of
CYP3A4 are ineligible. Lists including medications and substances known or with the
potential to interact with the CYP3A4 isoenzymes are provided in the appendix.

- Patients may not take other anti-cholesterol treatments during this study. Patients
who were previously taking anti-cholesterol treatment prior to study entry must be
off the anti-cholesterol medications for 14 days before enrolling on this trial.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, diarrhea, myopathy, or psychiatric illness/social situations that would
limit compliance with study requirements.

- Pregnant women are excluded from this study because HMG-CoA reductase inhibitors are
a drug class with the potential for teratogenic or abortifacient effects. Because
there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with simvastatin, breastfeeding should be
discontinued if the mother is treated with simvastatin.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with simvastatin.