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

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 not otherwise specified (NOS) (including Hodgkin lymphoma, T-cell
non-Hodgkin lymphoma [T-NHL], lymphoplasmacytic lymphoma, and 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 mammalian target of rapamycin (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 diffuse large B-cell
lymphoma (DLBCL) and follicular lymphoma (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 phase I, dose-escalation study of lenalidomide followed by a phase II
study.

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.

After completion of study treatment, patients are followed up for 1 year.

Inclusion Criteria:

- Histology: bone marrow biopsies (with the exception of lymphoplasmacytic lymphoma) as
the sole means of diagnosis are not acceptable; fine needle aspirates are not
acceptable

- Phase I: previously treated, histologically confirmed Hodgkin and non-Hodgkin
lymphomas; the only exception to a requirement for a lymph node biopsy is
lymphoplasmacytic lymphoma, which can be diagnosed based on morphologic evidence
in the bone marrow plus the appropriate paraprotein

- Phase II: previously treated, histologically confirmed mature non-Hodgkin
lymphoma (NHL) stratified by histology:

- Group A: diffuse large B-cell lymphoma (NOTE: all patients with DLBCL must
have germinal center vs. non-germinal center phenotype established via
immunohistochemistry)

- Group B: follicular lymphoma

- Group C: lymphoma NOS (including Hodgkin lymphoma, T-NHL, marginal zone
lymphoma, lymphoplasmacytic

- No limit to number of prior therapies; prior autologous transplantation is allowed

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Absolute neutrophil count (ANC) >= 1,000/uL

- Platelet count >= 75,000/uL

- Total bilirubin =< 1.5 times upper limit of normal (ULN) (unless due to Gilbert's)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 times ULN

- Creatinine clearance >= 60 mL/min as determined by calculated Cockcroft-Gault equation

- Fasting serum cholesterol =< 350 mg/dL

- Fasting serum triglycerides =< 2.5 times ULN

- All patients are required to have measurable disease; non-measurable disease alone is
not acceptable; any tumor mass > 1 cm is acceptable; lesions that are considered
non-measurable include the following:

- Bone lesions (lesions if present should be noted)

- Ascites

- Pleural/pericardial effusion

- Lymphangitis cutis/pulmonis

- Bone marrow (involvement by lymphoma should be noted)

- For Waldenstrom's macroglobulinemia, measurable disease is defined as at least
one lesion with a single diameter of greater than 2 cm by computed tomography or
bone marrow involvement with greater than 10% malignant cells and quantitative
monoclonal protein (immunoglobulin M [IgM], IgG, IgA) greater than 1,000 mg/dL

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 25 mIU/mL within 10 - 14 days and again within 24
hours prior to starting cycle 1 of lenalidomide; further, they must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control: one highly effective method and one additional effective method AT THE
SAME TIME, at least 28 days before starting lenalidomide; FCBP must also agree to
ongoing pregnancy testing; men must agree to use a latex condom during sexual contact
with a FCBP, even if they have had a successful vasectomy; a FCBP is a sexually mature
woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has
not been naturally postmenopausal for at least 24 consecutive months (i.e., has had
menses at any time in the preceding 24 consecutive months); all patients must be
counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal
exposure

- Ability to understand and the willingness to sign a written informed consent document

- Patients who are human immunodeficiency virus (HIV) positive are allowed to
participate BUT must meet the following criteria:

- No acquired immune deficiency syndrome (AIDS)-defining illness, AND

- Cluster of differentiation (CD) 4 count >= 400 cells/mm^3, AND

- No anti-retroviral therapy (including high-active antiretroviral therapy [HAART])
within 7 days of starting protocol therapy, AND

- Patient may not take concurrent anti-retroviral therapy (including HAART) while
on protocol

- NOTE: it is not generally recommended to suspend anti-retroviral therapy
(including HAART); the medical team enrolling a patient who suspends
anti-retroviral therapy for the purpose of study participation must have a
documented note reviewing the potential risks/benefits with the patient in the
medical chart

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients who are receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or
biological composition to temsirolimus or lenalidomide used in study

- Patients requiring active anti-retroviral therapy for HIV are excluded

- No "currently active" second malignancy, other than non-melanoma skin cancers;
patients are not considered to have a "currently active" second malignancy if they
have completed anti-cancer therapy and are considered by their physicians to be at
less than 30% risk of relapse

- No history (within 3 months of study entry) of deep venous thrombosis/pulmonary
embolism (DVT/PE); patients with a distant history (greater than 3 months before study
entry) of DVT/PE are eligible, but should receive prophylactic aspirin or low
molecular weight heparin

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Patients with relapsed/refractory DLBCL or HL who are eligible and willing to undergo
potentially curative stem cell transplant

- Patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are
excluded

- No corticosteroids within 14 days prior to study, except for maintenance therapy for a
non-malignant disease; maintenance therapy dose may not exceed 10 mg/day prednisone or
equivalent; any patient on steroid therapy must receive thromboembolic prophylaxis