Everolimus and Bortezomib in Treating Patients With Relapsed or Refractory Lymphoma

DISEASE CHARACTERISTICS:

• Histologically confirmed relapsed or refractory Non-Hodgkin lymphoma (NHL), according to the World Health Organization (WHO)/Revised European-American Lymphoma Classification, including any of the following subtypes:

  • Mantle cell lymphoma
  • Hairy cell leukemia
  • Grade I, II, or III follicular lymphoma
  • Marginal zone B-cell lymphoma
  • Small lymphocytic lymphoma/B-cell chronic lymphocytic leukemia (SLL/CLL)
  • Lymphoplasmacytic lymphoma (with or without Waldenstrom macroglobulinemia)
• History of transformed lymphoma and relapsed or refractory diffuse large B cell lymphoma are included if patients are ineligible for or refuse hematopoietic stem cell transplant
• Cutaneous B and T cell lymphoma are permitted. Cutaneous T cell lymphoma must be refractory to 1 prior systemic therapy (topical therapy, photopheresis, and radiation are not considered systemic therapy. Transformed B and T cell cutaneous lymphoma are permitted.

• Relapsed or refractory nodal, leukemic, and extranodal T cell lymphomas are eligible. Subtypes that are eligible include:

  • Anaplastic large cell lymphoma
  • Angioimmunoblastic T cell lymphoma
  • PTCL-NOS
  • Nasal or disseminated extranodal T/NK lymphoma
  • Enteropathy-associated T cell lymphoma
  • Hepatosplenic gamma/delta T cell lymphoma
  • Subcutaneous panniculitis-like T cell lymphoma
  • T-prolymphocytic leukemia
  • Adult T-cell leukemia/lymphoma
  • Large granular lymphocytic leukemia
  • Aggressive NK leukemia
• Refractory to or relapsed after receiving ≥ 1 prior treatment regimen for lymphoma (which may have included prior autologous stem cell transplantation) AND demonstrated evidence of progressive disease by clinical and/or radiographic characteristics

• Measurable disease by radiographic criteria (≥ 2 cm by CT scan)

  • Patients with leukemic forms of SLL/CLL must have an absolute lymphocytosis > 5 times 10^9/L with a B-cell phenotype and > 30% bone marrow lymphocytes
• No plasma cell myeloma or Hodgkin lymphoma
• No uncontrolled brain or leptomeningeal metastases, including ongoing requirement for glucocorticoids for brain or leptomeningeal metastases

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless attributed to active hemolysis or ineffective erythropoiesis)
• AST or ALT ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement by lymphoma)
• ANC ≥ 1,500/μL
• WBC ≥ 3,000/μL
• Platelet count ≥ 100,000/μL
• Hemoglobin ≥ 9.0 g/dL
• Creatinine ≤ 1.5 times ULN
• Fasting cholesterol > 300 mg/dL (or > 7.75 mmol/L)
• Fasting triglycerides > 2.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Histologic confirmation of diagnosis, either are initial diagnosis or at any subsequent relapse. Biopsy is not required at relapse, but is suggested
• No other malignancies within the past 3 years, except for adequately treated carcinoma of the cervix, basal cell or squamous cell carcinoma of the skin, or curatively treated low-risk prostate cancer

• No severe and/or uncontrolled medical condition that would preclude study participation, including the following:

  • Unstable angina pectoris
  • New York Heart Association class III or IV symptomatic congestive heart failure
  • Myocardial infarction within the past 6 months
  • Serious uncontrolled cardiac arrhythmia
  • Severely impaired lung function
  • Any active (acute or chronic) or uncontrolled infection and/or disorder
  • Liver disease (e.g., viral hepatitis B or C, cirrhosis, chronic active hepatitis, or chronic persistent hepatitis)
  • Known history of HIV seropositivity
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, or malabsorption syndrome)
  • Non-malignant medical illness that is uncontrolled or whose control may be jeopardized by study therapy

• None of the following diabetic conditions:

  • Diabetes mellitus currently requiring insulin therapy
  • Preexisting poorly controlled diabetes mellitus (e.g., hemoglobin A1c value > 9% within the past 4 weeks)
  • Uncontrolled diabetes, defined by fasting serum glucose > 1.5 times ULN (off medications)
• No preexisting peripheral neuropathy ≥ grade 2
• No active bleeding diathesis
• No known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients, or to bortezomib, boron, or mannitol
• No history of noncompliance to medical regimens
• No personal, medical, or psychiatric reason that would preclude compliance with study requirements

PRIOR CONCURRENT THERAPY:

• More than 4 weeks since prior chemotherapy or investigational drug
• More than 3 months since prior monoclonal antibody
• More than 1 week since prior and no concurrent strong P450/CY3PA4 inhibitors
• No prior allogeneic stem cell transplantation
• No prior small bowel resection that may significantly alter the absorption of everolimus
• No concurrent immunization with attenuated live vaccine
• No concurrent chronic treatment with systemic steroids or other immunosuppressive agents
• No other concurrent investigational or anticancer agents