Perifosine in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Perifosine in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Perifosine inhibits the AKT pathway (a way cells communicate with each other). This pathway
 is felt to be important in the development of several types of cancers including chronic
 lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). It is thought perifosine may
 be able to block this pathway and lead to an improvement in the CLL or SLL. The purpose of
 this trial is to see if perifosine is an effective treatment for relapsed or refractory CLL
 or SLL. Another purpose of this study is to look at the effect perifosine has on cells.
Chronic lymphocytic leukemia and small B-cell lymphocytic lymphoma represent different
 manifestations of the same disease. CLL/SLL (hereafter denoted by CLL) is a clonal disorder
 of small B lymphocytes expressing a characteristic morphology and immunophenotype. The B
 cells express CD19, dim CD 20, dim CD 5, CD 23, CD 43, CD 79a, and weakly express surface
 immunoglobin. CLL can present asymptomatically in 25% of patients when diagnosed on a
 complete blood count. It also can present with diffuse painless lymphadenopathy and, in a
 smaller number of patients, B symptoms.

 CLL is characterized by accumulation of circulating B cells predominantly in the G0 phase of
 the cell cycle. These cells are resistant to apoptosis. CLL has been found to have aberrant
 signaling in several pathways including NF-kB, Akt/PI3K, and JNK/STAT pathways. Akt is
 important in promoting CLL survival and viability, as seen in in vitro experiments where
 blocking its activity results in apoptosis. Thus an AKT inhibitor may lead to increased
 apoptosis and may have a role in the treatment of this disease.

 Treatment options for CLL range from a watch and wait approach to high dose chemotherapy with
 stem cell support. Currently, there is no consensus on the best treatment regimen, since no
 treatment has been shown to improve survival in randomized prospective clinical trials. New
 approaches to treatment, especially those with lower toxicity rates, are needed.

 Perifosine has been shown to inhibit or otherwise modify signaling through a number of
 different signal transduction pathways, including Akt, MAPK, and JNK. These pathways are
 involved in the development of cancers and resistance to chemotherapy. Perifosine is of
 particular interest, especially due to the difficulty in discovery of drugs that inhibit
 these pathways with minimal toxicity. The effect of perifosine on CLL cells has been tested
 in the laboratory and has been shown to be an active agent against primary CLL cells in
 vitro.
Inclusion Criteria:

 -  A diagnosis of CLL or SLL based on iwCLL diagnostic criteria.

 -  Prior therapy for CLL (no limit on number of prior regimens).

 -  Patients requiring therapy, based on at least one of the iwCLL criteria.

 -  18 years of age or older.

 -  Performance status ECOG 0, 1, or 2.

 -  An estimated or measured creatinine clearance ≥30 ml/min at study enrollment.

 -  AST, ALT, and total bilirubin ≤ 2.5 times the upper limit of normal, unless due to
 CLL/SLL.

 -  Female subject who is either post-menopausal or surgically sterilized or male or
 female subject willing to use an acceptable method of birth control for the duration
 of the study therapy and for 2 weeks after study therapy completion.

 Exclusion Criteria:

 -  Female subject is pregnant or lactating.

 -  Patient has received other investigational drugs for this disease within 14 days of
 enrollment.

 -  Patient with known HIV prior to enrollment.

 -  Serious medical or psychiatric illness likely to interfere with participation in this
 clinical study.

 -  Patients with another malignancy within the last three years (from documentation of
 remission) other than basal or squamous cell skin cancer or CIS of the cervix or early
 stage prostate cancer not requiring systemic treatment.

 -  Patients who underwent allogeneic stem cell transplant and have at least 2% donor
 cells engrafted will be excluded.

 -  Significant cardiac or vascular events within 6 months: acute MI, unstable angina,
 severe peripheral vascular disease (ischemic pain at rest class 3 or worse,
 non-healing ulcers/wounds, congestive heart failure (NHYA class ≥ 2), uncontrolled
 cardiac arrhythmias.

 -  Known severe hypersensitivity to perifosine or any component of the formulation.

 -  Life expectancy less than six months due to co-morbid illness

 -  Active autoimmune hemolytic anemia or immune thrombocytopenia, requiring current
 steroid therapy.

 -  De novo prolymphocytic leukemia (PLL) or PLL arising from CLL (≥ 55% prolymphocytes).

 -  Richter's transformation