Akt Inhibitor MK2206, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

• MTD of Akt Inhibitor MK2206 in combination with bendamustine hydrochloride and rituximab (Phase I) [ Time Frame: After course 1 ] [ Designated as safety issue: Yes ]
  The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized. The number and severity of all adverse events will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.
• Proportion of complete response to Akt Inhibitor MK2206 in combination with bendamustine hydrochloride and rituximab in patients with CLL or SLL (Phase II) [ Time Frame: Up to 84 days ] [ Designated as safety issue: No ]
  A complete response is defined to be a CR or CRi noted as the objective status.

• MTD of MK-2206 in combination with bendamustine hydrochloride and rituximab (phase I) [ Designated as safety issue: Yes ]
• Proportion of complete response to MK-2206 in combination with bendamustine hydrochloride and rituximab in patients with CLL or SLL (phase II) [ Designated as safety issue: No ]

• Overall response rate (CR, CRi, CCR, nPR, or PR) in these patients [ Time Frame: 3 months post-treatment ] [ Designated as safety issue: No ]
  Exact binomial 95% confidence intervals for the true overall response rate will be calculated.
• Duration of response and treatment-free survival of these patients [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  The distribution of duration of response will be estimated using the method of Kaplan-Meier.
• Minimal-residual disease in these patients [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Adverse events of Akt Inhibitor MK2206 in combination with bendamustine hydrochloride and rituximab [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
  The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be utilized. The number and severity of all adverse events will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.
• IgVH gene mutation, CD38, CD49d, ZAP-70 and FISH status [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  These factors will be summarized and used to help characterize the types of patients accrued to this trial. In addition, we will explore differences in the distributions of these risk factors by clinical outcome (responders vs. nonresponders or by quality of response if a large proportion of patients respond). Nonparametric quantitative comparisons by group will be made as appropriate (Fisher's exact, Wilcoxon rank sum, or Kruskal-Wallis test).

• Overall response rate (CR, CRi, CCR, nPR, or PR) in these patients [ Designated as safety issue: No ]
• Duration of response and treatment-free survival of these patients [ Designated as safety issue: No ]
• Minimal-residual disease in these patients [ Designated as safety issue: No ]
• Adverse events of MK-2206 in combination with bendamustine hydrochloride and rituximab [ Designated as safety issue: Yes ]

This phase I/II trial studies the side effects and best dose of Akt inhibitor MK2206 when given together with bendamustine hydrochloride and rituximab and to see how well it works 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 together with bendamustine hydrochloride and rituximab may kill more cancer cells

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 CLL or 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, CRi, CCR, nPR and 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 (CD38, CD49d, IGHV, FISH and 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. 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, 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 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 multicenter, 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); bendamustine hydrochloride intravenously (IV) over 30-60 minutes on days 1-2 (days 8-9 of course 1); and rituximab IV on day 1 (day 8 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.

Blood and bone marrow samples are collected at baseline and periodically during study for correlative studies.

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.

• B-cell Chronic Lymphocytic Leukemia
• Recurrent Small Lymphocytic Lymphoma
• Refractory Chronic Lymphocytic Leukemia
• Stage I Chronic Lymphocytic Leukemia
• Stage II Chronic Lymphocytic Leukemia
• Stage III Chronic Lymphocytic Leukemia
• Stage IV Chronic Lymphocytic Leukemia

• Drug: Akt inhibitor MK2206
  Given PO
  Other Name: MK2206
• Drug: bendamustine hydrochloride
  Given IV
  Other Names:

  • bendamustin hydrochloride
  • bendamustine
  • cytostasan hydrochloride
  • Treanda
• Other: diagnostic laboratory biomarker analysis
  Correlative studies
• Biological: rituximab
  Given IV
  Other Names:

  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan

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
• 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
• 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