Lenalidomide and Temsirolimus in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma or Non-Hodgkin Lymphoma

• Safety and tolerability of the combination of lenalidomide and temsirolimus (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
• Maximum-tolerated dose (MTD) based on the incidence of dose-limiting toxicity (DLT) as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
• Complete and overall response rate (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

• Safety and tolerability of the combination of lenalidomide and temsirolimus (Phase I) [ Designated as safety issue: Yes ]
• Complete and overall response rate (Phase II) [ Designated as safety issue: No ]

• Progression-free survival (PFS) (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Kaplan-Meier curves will be generated for PFS stratified by histology; median PFS times will be determined and 90% confidence intervals derived as described in Brookmeyer and Crowley.
• Overall survival (OS) (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Kaplan-Meier curves will be generated for OS stratified by histology; median OS times will be determined and 90% confidence intervals derived as described in Brookmeyer and Crowley.

• Progression-free survival (Phase II) [ Designated as safety issue: No ]
• Overall survival (Phase II) [ Designated as safety issue: No ]

This phase I/II trial is studying the side effects and the best dose of lenalidomide when given together with temsirolimus and to see how well it works in treating patients with relapsed or refractory Hodgkin lymphoma or non-Hodgkin lymphoma. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Lenalidomide may also stop the growth of Hodgkin lymphoma or non-Hodgkin lymphoma by blocking blood flow to the cancer. Temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide together with temsirolimus may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To determine the safety, toxicity, and maximum tolerated dose of lenalidomide when combined with temsirolimus in patients with relapsed lymphomas. (Phase I) II. To determine complete and overall response rate of lenalidomide plus temsirolimus in patients with relapsed lymphomas as stratified by histology: follicular lymphoma, diffuse large B-cell lymphoma, and lymphoma NOS (including Hodgkin lymphoma, T-NHL, lymphoplasmacytic lymphoma, mantle cell lymphoma). (Phase II) III. To determine duration of response, progression-free survival, and overall survival of lenalidomide plus temsirolimus in patients with relapsed lymphomas as stratified by histology: diffuse large B-cell lymphoma, follicular lymphoma, and lymphoma NOS (including Hodgkin lymphoma, T-NHL, lymphoplasmacytic lymphoma, mantle cell lymphoma). (Phase II)

SECONDARY OBJECTIVES:

I. To determine mTOR pathway activation in pre-treatment tumor tissue. II. To determine angiogenic and microenvironmental status of pre-treatment tissue and peripheral blood samples, and to evaluate changes following treatment with temsirolimus and lenalidomide.

III. To determine differentially expressed genes associated with differences in clinical response and in progression-free survival (PFS) in patients with DLBCL and FL (Groups A and B, respectively).

IV. To determine a methylation signature predictive of clinical response and PFS in patients with DLBCL and FL (Groups A and B, respectively).

OUTLINE: This is a multicenter, phase I, dose-escalation study of lenalidomide followed by a phase II study.

Patients in the phase II portion are stratified according to non-Hodgkin lymphoma (NHL) histology (diffuse large-B-cell lymphoma vs follicular lymphoma vs lymphoma not otherwise specified [Hodgkin lymphoma, T-NHL, marginal zone lymphoma, and lymphoplasmacytic lymphoma]).

Patients receive lenalidomide orally (PO) on days 1-21 and temsirolimus intravenously (IV) over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 2 courses may continue therapy for up to 52 weeks.

Some patients undergo blood samples collection at baseline and periodically during study for laboratory analysis by ELISA and flow cytometry. Tumor tissues from biopsies are also analyzed.

• Adult Grade III Lymphomatoid Granulomatosis
• Adult Nasal Type Extranodal NK/T-cell Lymphoma
• Anaplastic Large Cell Lymphoma
• Angioimmunoblastic T-cell Lymphoma
• Cutaneous B-cell Non-Hodgkin Lymphoma
• Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
• Hepatosplenic T-cell Lymphoma
• HIV-associated Hodgkin Lymphoma
• Intraocular Lymphoma
• Nodal Marginal Zone B-cell Lymphoma
• Noncutaneous Extranodal Lymphoma
• Peripheral T-cell Lymphoma
• Recurrent Adult Burkitt Lymphoma
• Recurrent Adult Diffuse Large Cell Lymphoma
• Recurrent Adult Diffuse Mixed Cell Lymphoma
• Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
• Recurrent Adult Grade III Lymphomatoid Granulomatosis
• Recurrent Adult Hodgkin Lymphoma
• Recurrent Adult Immunoblastic Large Cell Lymphoma
• Recurrent Adult Lymphoblastic Lymphoma
• Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
• Recurrent Grade 1 Follicular Lymphoma
• Recurrent Grade 2 Follicular Lymphoma
• Recurrent Grade 3 Follicular Lymphoma
• Recurrent Mantle Cell Lymphoma
• Recurrent Marginal Zone Lymphoma
• Recurrent Mycosis Fungoides/Sezary Syndrome
• Recurrent Small Lymphocytic Lymphoma
• Small Intestine Lymphoma
• Splenic Marginal Zone Lymphoma
• Testicular Lymphoma
• Waldenström Macroglobulinemia

• Drug: lenalidomide
  Given PO
  Other Names:

  • CC-5013
  • IMiD-1
  • Revlimid
• Drug: temsirolimus
  Given IV
  Other Names:

  • CCI-779
  • cell cycle inhibitor 779
  • Torisel
• Other: laboratory biomarker analysis
  Correlative studies

Inclusion Criteria:

• Histologically confirmed relapsed or refractory lymphoma

  • Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) (phase I)

  • Mature NHL, including the following cell types (phase II):

    • Diffuse large B-cell lymphoma (DLBCL) with germinal center versus non-germinal center phenotype as established by IHC
    • Follicular lymphoma
    • Lymphoma not otherwise specified (e.g., HL, T-NHL, marginal zone lymphoma, lymphoplasmacytic lymphoma)
  • No chronic lymphocytic leukemia or small lymphocytic lymphoma

• No bone marrow biopsies (with the exception of lymphoplasmacytic lymphoma) as sole means of diagnosis

  • Fine needle biopsies not allowed
• Must have received prior therapy

• Measurable disease, defined as any tumor mass > 1 cm

  • Non-measurable disease alone, including the following, is not allowed:

    • Bone lesions
    • Ascites
    • Pleural/pericardial effusion
    • Lymphangitis cutis/pulmonis
    • Bone marrow

    • Waldenstrom's macroglobulinemia

      • For Waldenstrom's macroglobulinemia measurable disease is defined as ≥ 1 lesion with a single diameter of > 2 cm by CT or bone marrow involvement > 10% malignant cells and quantitative monoclonal protein (IgM, IgG, IgA) > 1,000 mg/dL
• No known CNS involvement
• No patients with relapsed or refractory DLBCL or HL who are eligible and willing to undergo potentially curative stem cell transplantation
• ECOG performance status 0-2
• ANC ≥ 1,000/μL
• Platelet count ≥ 75,000/μL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless due to Gilbert syndrome)
• AST/ALT ≤ 2.5 times ULN
• Creatinine clearance ≥ 60 mL/min
• Fasting serum cholesterol ≤ 350 mg/dL
• Fasting serum triglycerides ≤ 2.5 times ULN
• Not pregnant or nursing
• Two negative pregnancy tests (i.e., first test within 10-14 days before lenalidomide and second test within 24 hours of starting lenalidomide)
• Fertile patients must agree to continue abstinence or begin using 2 methods of effective contraception (one highly effective and one additional effective method) at the same time for ≥ 28 days prior to start lenalidomide

• HIV-positive patients allowed provided the following criteria are met:

  • No AIDS-defining illness
  • CD4 count ≥ 400 cells/mm^3
• No history of allergic reactions attributed to compounds of similar chemical or biological composition to temsirolimus or lenalidomide

• No currently active second malignancy other than nonmelanoma skin cancers

  • Patients who have completed anticancer therapy for second malignancy and are considered by their physicians to have < 30% risk of relapse allowed

• No deep venous thrombosis/pulmonary embolism (DVT/PE) within the past 3 months

  • Patients with DVT/PE > 3 months ago must receive prophylactic aspirin or low-molecular weight heparin

• No uncontrolled intercurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness and/or social situations that would limit compliance with study requirements
• No other concurrent anticancer commercial agents or therapies
• Any number of prior therapies allowed, including prior autologous transplantation
• More than 4 weeks since prior and no other concurrent chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
• More than 7 days since prior and no concurrent antiretroviral therapy (including HAART)

• No corticosteroids within the past 14 days except for maintenance of non-malignant disease

  • Prednisone or equivalent maintenance therapy dose < 10 mg/day
  • No concurrent dexamethasone or other steroidal antiemetics
• No concurrent pegfilgrastim
• No other concurrent investigational agents