This phase I/II trial studies the side effects and best dose of v-akt murine thymoma viral oncogene homolog 1 (Akt) inhibitor MK2206 when given together with bendamustine hydrochloride and rituximab and to see how well they work in treating patients with refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Akt inhibitor MK2206 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving Akt inhibitor MK2206 with bendamustine hydrochloride and rituximab may be an effective treatment for relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma.

PRIMARY OBJECTIVES:

I. To assess the safety and maximum tolerated dose (MTD) of MK-2206 (Akt inhibitor MK2206) in combination therapy with bendamustine (bendamustine hydrochloride)-rituximab in relapsed chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients. (Phase I) II. To assess the rate of complete response (CR) of MK-2206 in combination with bendamustine-rituximab in relapsed CLL or SLL patients. (Phase II)

SECONDARY OBJECTIVES:

I. To assess clinical efficacy of MK-2206 in combination with bendamustine-rituximab as demonstrated by analysis of overall response rate (CR, complete response with incomplete bone marrow recovery [CRi], clinical complete response [CCR], near partial response [nPR] and partial response [PR]), duration of response, and treatment free survival.

II. To assess the toxicity profile of MK-2206 in combination with bendamustine-rituximab.

TERTIARY OBJECTIVES:

I. Evaluation of whether the established CLL prognostic factors (cluster of differentiation [CD]38, CD49d, immunoglobulin heavy chain variable [IGHV], fluorescence in situ hybridization [FISH] and zeta-chain-associated protein kinase 70 [ZAP-70]) predict responses to the combination therapy of MK2206, with bendamustine-rituximab.

II. Minimal residual disease will be evaluated after treatment in patients who achieve a clinical response; minimal residual disease (MRD) status will be explored in relation to both the quality and duration of response.

III. Evaluation of the effects of the addition of MK-2206 to bendamustine-rituximab on B cell receptor initiated, phosphoinositide 3-kinase (PI3K)/Akt downstream signal pathways, apoptosis analysis and leukemic cell activation status, as well as multiple cytokine profiles and key gene expression analysis with focus on leukemic cells.

IV. Evaluation of marrow stromal cells (MSC)-CLL biology including the effects of the addition of MK-2206 to bendamustine-rituximab on CLL marrow stromal cell (MSC) proliferation, migration and cytokine production, as well as the adhesion capacity between MSC and leukemic cells.

OUTLINE: This is a phase I, dose-escalation study of Akt inhibitor MK2206 followed by a phase II study.

Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29 of course 1); rituximab intravenously (IV) on day 1 (day 8 of course 1); and bendamustine hydrochloride IV over 30-60 minutes on days 1-2 (days 8-9 of course 1). Treatment repeats every 28 days (35 days for course 1 and 84 days for course 6) for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 or 12 months for 3 years.

Inclusion Criteria:

• Diagnosis of chronic lymphocytic leukemia (CLL) according to the National Cancer Institute (NCI) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria; this includes previous documentation of:

  • Biopsy-proven SLL or

  • Diagnosis of CLL according to NCI working group criteria as evidenced 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 kappa (Κ) or lambda (λ) light chain expression (typically dim immunoglobulin expression) or other genetic method (e.g., immunoglobulin heavy chain variable [IGHV] analysis)
      • NOTE: 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 immunohistochemical stains for cyclin D1 on involved tissue biopsy

• Demonstrated progression after one or two prior lines of CLL therapy; note: 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-Working Group (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° Fahrenheit (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

• Life expectancy >= 12 months

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) unless due to Gilbert's disease; if total bilirubin is > 1.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 ULN

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 times ULN

• Creatinine =< 1.5 times ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 x ULN

• A non-transfused platelet count >= 30 x 10^9/L

• Neutrophil count (absolute neutrophil count [ANC]) >= 1 x 10^9/L

• Hemoglobin (Hgb) >= 8 g/dL

• Note: cytopenias due to bone marrow failure are common in patients with relapsed CLL requiring treatment; accordingly, normal bone marrow function is NOT required for participation

• Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

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

• Provide informed written consent

• 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 (body fluid) for correlative research purposes

• MAYO ROCHESTER ONLY: willing to provide bone marrow core biopsy tissue for correlative research purposes

• Willing to provide bone marrow biopsy for central pathology review (all patients)

• Able to swallow whole tablets; NOTE: nasogastric or gastrostomy (G) tube administration is not allowed; tablets must not be crushed or chewed

Exclusion Criteria:

• Prior treatment with bendamustine

• Prior treatment with any experimental Akt inhibitors

• More than 2 previous purine nucleoside based-therapy (i.e. fludarabine, pentostatin, or cladribine)

• More than 2 previous alkylating agent based-therapy (i.e. cyclophosphamide, chlorambucil)

• More than 3 total prior lines of therapy for CLL

• Primary refractory disease as defined by progression while receiving or within 6 months of completion of a chemoimmunotherapy regimen such as fludarabine, cyclophosphamide and rituximab (FCR) or pentostatin, cyclophosphamide and rituximab (PCR)

• PHASE II ONLY: FISH abnormality of 17P deletions; (note: patients with 17P deletions will be included in Phase I but will be excluded in Phase II unless enough activity is found in the Phase I)

• Pregnant women

• Nursing women

• Men or women of childbearing potential who are unwilling to employ adequate contraception

• Co-morbid systemic illnesses or other severe concurrent disease which, 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 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/acquired immune deficiency syndrome [AIDS]) and/or patients taking highly active antiretroviral therapy (HAART) as further severe immunosuppression with this regimen may occur
  • Infection with known chronic, active hepatitis C
  • Positive serology for hepatitis B (HB) defined as a positive test for hepatitis B surface antigen (HBsAg); in addition, if negative for HBsAg but hepatitis B core antibody (HBcAb) positive (regardless of hepatitis B surface antibody [HBsAb] status), a HB deoxyribonucleic acid (DNA) test will be performed and if positive the subject will be excluded
  • Uncontrolled diabetes defined as hemoglobin A1c (HbA1c) >= 8 or fasting blood glucose >= 140 mg/dL

• Any of the following:

  • History of significant ventricular arrhythmia in the last 5 years including: ventricular tachycardia or ventricular fibrillation
  • Corrected QT (QTc) prolongation on baseline electrocardiogram (ECG) (defined as a QTc interval > 450 msec for males and QTc interval > 470 msec for females)
  • Currently using a medication known to cause prolonged QTc which cannot be discontinued; note: other medications with possible risk of prolonged QTc are allowed but should be used with caution; patients using these medications should be monitored accordingly
  • Ventricular arrhythmia on baseline ECG (ventricular tachycardia or ventricular fibrillation >= 3 beats in a row)
  • Second or third degree heart block

• Receiving any other investigational agent concurrently which would be considered as a treatment for the primary neoplasm

• Other active primary malignancy requiring treatment or which limits survival to < 24 months

• Any major surgery =< 28 days prior to registration

• Any radiation therapy =< 4 weeks prior to registration

• Current use of corticosteroids; EXCEPTION: low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical conditions; NOTE: previous use of corticosteroids is allowed

• Active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; NOTE: patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation

• Receiving any medications or substances that are strong or moderate inhibitors of cytochrome P450 3A4 (CYP450 3A4); use of the following strong or moderate inhibitors are prohibited =< 7 days prior to registration:

  • Strong inhibitors of CYP3A4

    • Indinavir
    • Nelfinavir
    • Ritonavir
    • Clarithromycin
    • Itraconazole
    • Ketoconazole
    • Nefazodone
    • Saquinavir
    • Telithromycin

  • Moderate inhibitors of CYP3A4

    • Aprepitant
    • Erythromycin
    • Fluconazole
    • Grapefruit juice
    • Verapamil
    • Diltiazem

• Receiving any medications or substances that are inducers of CYP450 3A4; use of the following inducers is prohibited =< 12 days prior to registration

  • Inducers of CYP3A4

    • Efavirenz
    • Nevirapine
    • Carbamazepine
    • Modafinil
    • Phenobarbital
    • Phenytoin
    • Pioglitazone
    • Rifabutin
    • Rifampin
    • St. John's wort