Phase I/II Study of the Combination of Bendamustine, Rituximab and MK-2206 in the Treatment of Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Inclusion Criteria:

- Diagnosis of chronic lymphocytic leukemia (CLL) according to the NCI criteria or
small lymphocytic lymphoma (SLL) according to the WHO criteria, including the prior
documentation of:

- Biopsy-proven SLL

- Diagnosis of CLL as evidence by all of the following:

- Peripheral blood B-cell count of > 5 x 10^9/L consisting of small- to
moderate-size lymphocytes

- Immunophenotyping consistent with CLL defined as:

- The predominant population of lymphocytes share both B-cell antigens
[CD19, CD20 (typically dim expression), or CD23] as well as CD5 in the
absence of other pan-T-cell markers (CD3,CD2, etc.)

- Clonality as evidenced by Κ or λ light chain expression (typically dim
immunoglobulin expression) or other genetic method (e.g.,
immunoglobulin heavy chain variable [IGHV]analysis)

- Splenomegaly, hepatomegaly, or lymphadenopathy are not required for
the diagnosis of CLL

- Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by
demonstrating a negative fluorescence in situ hybridization (FISH) analysis for
t (11;14) (IgH/CCND1) on peripheral blood or tissue biopsy, or negative
immunohisto chemical stains for cyclin D1 on involved tissue biopsy

- Demonstrated progression after one or two prior lines of CLL therapy

- Rituximab monotherapy does not count as a prior line of therapy

- Progressive disease with any one of the following characteristics based on standard
criteria for treatment as defined by the NCI-WG 1996

- Symptomatic CLL characterized by any one of the following:

- Weight loss ≥ 10% within the previous 6 months

- Extreme fatigue attributed to CLL

- Fevers > 100.5° F for 2 weeks without evidence of infection

- Drenching night sweats without evidence of infection

- Evidence of progressive bone marrow failure with hemoglobin< 11 g/dL or platelet
count < 100 x 10^9/L

- Massive or rapidly progressive splenomegaly (> 6 cm below left costal margin)

- Massive (> 10 cm) or rapidly progressive lymphadenopathy

- No primary refractory disease defined by progression while receiving or within 6
months of completion of a chemoimmunotherapy regimen, such as fludarabine phosphate,
cyclophosphamide and rituximab or pentostatin, cyclophosphamide and rituximab

- No FISH abnormality of 17P deletions (phase II only)

- Patients with 17Pdeletions are included in Phase I but will be excluded in Phase
II unless enough activity is found in the Phase I

- No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic
treatment

- Patients who have a positive Coombs test but no evidence of hemolysis are NOT
excluded from participation

- Life expectancy ≥ 12 months

- ECOG performance status 0, 1, or 2

- ANC ≥ 1,000/mm³

- Platelet count ≥ 30,000/mm³ (without transfusion)

- Hemoglobin ≥ 8 g/dL

- Cytopenias due to bone marrow failure are common in patients with relapsed CLL
requiring treatment, so normal bone marrow function is NOT required

- Total or direct bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless due to
Gilbert disease)

- SGOT (AST) and SGPT (ALT) ≤ 2.5 times ULN

- Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min/1.73m2

- Negative pregnancy test

- Not pregnant or nursing

- No men or women of childbearing potential who are unwilling to employ adequate
contraception

- Ability to complete patient diaries and questionnaire(s) by themselves or with
assistance

- Willing to return to North Central Cancer Treatment Group (NCCTG) enrolling
institution for follow-up

- Willing to provide blood samples for correlative research purposes

- Willing to provide bone marrow aspirate for correlative research purposes

- Able to swallow whole tablets

- Nasogastric or G tube administration is not allowed

- No co-morbid systemic illnesses or other severe concurrent disease that, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens including, but not limited to, any of the
following:

- New York Heart Association Class III or IV heart disease

- Recent myocardial infarction (< 1 month)

- Uncontrolled infection

- Known infection with the human immunodeficiency virus (HIV/AIDS)and/or patients
taking highly active antiretroviral therapy (HAART)

- Infection with known chronic, active hepatitis C

- Positive serology for hepatitis B (HB) defined as a positive test for HBsAg

- In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb
status), a HB DNA test will be performed and, if positive, the subject will
be excluded

- Uncontrolled diabetes defined as HbA1c ≥ 8 or fasting blood glucose ≥ 140mg/dL

- None of the following:

- History of significant ventricular arrhythmia in the last 5 years including
ventricular tachycardia or ventricular fibrillation

- QTc prolongation on baseline ECG (defined as a QTc interval > 450msec for males
and QTc interval > 470 msec for females)

- Ventricular arrhythmia on baseline ECG (ventricular tachycardia or ventricular
fibrillation ⥠3 beats in a row)

- Second or third degree heart block

- No other active primary malignancy that requires treatment or limits survival to < 24
months

- No medications or substances that are inducers of CYP450 3A4 ≤ 12 days prior to
registration

- No prior treatment with bendamustine

- No prior treatment with any experimental Akt inhibitors

- No more than 1 prior purine nucleoside-based therapy (i.e., fludarabine, pentostatin,
or cladribine)

- No more than 1 prior alkylating agent-based therapy (i.e., cyclophosphamide or
chlorambucil)

- No more than 2 total prior lines of therapy for CLL

- No concurrent medication known to cause prolonged QTc

- Not receiving any other investigational agent concurrently that would be considered
as a treatment for the primary neoplasm

- No major surgery ≤ 28 days prior to registration

- No radiotherapy ≤ 4 weeks prior to registration

- No concurrent corticosteroids

- Low-doses of steroids (< 10 mg of prednisone or equivalent dose of other
steroid) for treatment of non-hematologic medical conditions allowed

- Prior use of corticosteroids is allowed

- No medications or substances that are strong or moderate inhibitors ofCYP450 3A4 ≤ 7
days prior to registration