Combination Chemotherapy and Lenalidomide in Treating Patients With Newly Diagnosed Stage II-IV Peripheral T-cell Non-Hodgkin's Lymphoma

PRIMARY OBJECTIVES:

I. To assess the safety and efficacy of lenalidomide in combination with standard induction
therapy (CHOEP- cyclophosphamide, doxorubicin [doxorubicin hydrochloride], etoposide,
vincristine [vincristine sulfate] and prednisone) in patients with newly diagnosed stage II,
III and IV peripheral T-cell lymphoma not otherwise specified (NOS), anaplastic large cell
lymphoma (anaplastic lymphoma receptor tyrosine kinase [ALK] negative) (ALK positive if
International Prognostic Index [IPI] 3, 4, or 5), angioimmunoblastic T-cell lymphoma,
enteropathy associated T-cell lymphoma or hepatosplenic gamma delta T-cell lymphoma.

II. To establish the maximum tolerated dose of lenalidomide in combination with CHOEP
chemotherapy. (Phase I) III. To assess the efficacy (complete response rate) of this
combination. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate overall response rate (complete response [CR] + partial response [PR]) of the
combination of lenalidomide and CHOEP chemotherapy.

II. To evaluate the safety and tolerability of the regimen. III. To assess the 2 year
progression free survival (PFS) and overall survival (OS) using this regimen.

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

Patients receive cyclophosphamide intravenously (IV), doxorubicin hydrochloride IV and
vincristine sulfate IV on day 1, etoposide IV over 30-60 minutes on days 1-3, prednisone
orally (PO) on days 1-5, and lenalidomide PO on days 1-10. Treatment repeats every 21 days
for 6 courses in the absence of disease progression or unacceptable toxicity. Patients
responding after 6 courses of treatment may then undergo an autologous stem cell transplant
or receive maintenance lenalidomide at the discretion of the physician or patient choice as
follows:

TRANSPLANT: Patients undergo autologous stem cell transplant per standard of care.

MAINTENANCE LENALIDOMIDE: Patients receive lenalidomide PO on days 1-21. Treatment repeats
every 28 days for up to 12 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Inclusion Criteria:

- Histologically confirmed new diagnosis of stage II, III and IV peripheral T-cell
non-Hodgkin's lymphoma not otherwise specified (NOS), anaplastic large cell lymphoma
(ALK negative) (ALK positive if IPI 3, 4, or 5), angioimmunoblastic T-cell lymphoma,
enteropathy associated T-cell lymphoma, hepatosplenic gamma delta T-cell lymphoma

- Pathology material: hematoxylin and eosin (H&E) stain and immunohistochemistry (IHC)
slides or a representative formalin-fixed paraffin-embedded (FFPE) tissue block along
with the pathology report from initial diagnosis, should be sent to be reviewed, and
the diagnosis confirmed by Mayo Clinic department (retrospective diagnostic review:
treatment may commence prior to the Mayo Clinic review)

- No prior therapy with the exception of prior radiation therapy and/or prednisone
alone, at the discretion of the investigator based on current diagnosis and clinical
condition; this prednisone treatment will not count toward the 6 cycles of treatment
given in the study

- Expected survival duration of > 3 months

- Karnofsky performance status > 70

- Absolute neutrophil count (ANC) > 1000 cells/mm^3, unless cytopenias due to
non-Hodgkin lymphoma (NHL) (i.e., bone marrow involvement or splenomegaly)

- Platelet count > 100,000/uL or > 75,000/uL if bone marrow (BM) involvement or
splenomegaly

- Total bilirubin =< 1.5 x upper normal limit, or =< 3 x upper normal limit if
documented hepatic involvement with lymphoma, or =< 5 x upper normal limit if history
of Gilbert's disease

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
normal limit (=< 5 x upper normal limit if documented hepatic involvement with
lymphoma)

- Serum creatinine < 2.0 mg/dL or calculated creatinine clearance (CrCl) > 45 mL/min
(Cockcroft-Gault)

- Prothrombin time (PT) or international normalized ratio (INR), and partial
thromboplastin time (PTT) =< 1.5 x upper limit of normal unless patient is receiving
anticoagulants; if patient is on warfarin therapy, levels should be within therapeutic
range

- If currently not on anticoagulation medication, willing and able to take aspirin (81
or 325 mg) daily; if aspirin is contraindicated, the patient may be considered for the
study if on therapeutic dose warfarin or low molecular weight heparin; patients unable
to take any prophylaxis are not eligible

- Patients with measurable disease; patients with non-measurable but evaluable disease
may be eligible after discussion with the principal investigator (PI); baseline
measurements and evaluations must be obtained within 6 weeks of registration to the
study; abnormal positron emission tomography (PET)/computed tomography (CT) scans will
not constitute evaluable disease, unless verified by CT scan or other appropriate
imaging

- Patients with measurable disease must have at least one objective measurable disease
parameter; a clearly defined, bi-dimensionally measurable defect or mass measuring at
least 1.5 cm in diameter on the CT portion of a PET/CT or CT scan or magnetic
resonance imaging (MRI) (if appropriate) will constitute measurable disease; proof of
lymphoma in the liver is required by a confirmation biopsy; skin lesions can be used
as measurable disease provided bi-dimensional measurements are possible

- All study participants must be registered into the mandatory Revlimid Risk Evaluation
and Mitigation Strategy (REMS) program, and be willing and able to comply with the
requirements of the REMS program

- Women must not be pregnant or breast-feeding

- Females of reproductive potential must adhere to the scheduled pregnancy testing
as required in the Revlimid REMS program

- All females of childbearing potential must have a blood test within 2 weeks prior
to registration to rule out pregnancy

- Pregnancy testing is not required for post-menopausal or surgically sterilized
women

- Male and female patients of reproductive potential must agree follow accepted birth
control measures

- Patient must be able to adhere to the study visit schedule and other protocol
requirements

- Patients must be willing to give written informed consent, and sign an institutionally
approved consent form before performance of any study-related procedure not part of
normal medical care as noted above; with the exception of 1 cycle of chemotherapy
based on current diagnosis and clinical condition, with the understanding that consent
may be withdrawn by the subject at any time without prejudice to future medical care

- No serious disease or condition that, in the opinion of the investigator, would
compromise the patient's ability to participate in the study

Exclusion Criteria:

- Pregnant or breast feeding females

- Known seropositive for or active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); patients who are
seropositive ( i.e. hepatitis B core antibody positive; quantitative deoxyribonucleic
acid [DNA] negative) are eligible with appropriate prophylaxis

- Major surgery within 2 weeks of study drug administration

- Prior malignancies within the past 3 years with exception of adequately treated basal
cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or
breast; prostate cancer of Gleason grade 6 or less with stable prostate-specific
antigen (PSA) levels

- Patients with a diagnosis of other peripheral T-cell lymphoma (PTCL) histologies other
than those specified in the inclusion criteria

- Contraindication to any of the required concomitant drugs or supportive treatments,
including hypersensitivity to all anticoagulation and antiplatelet options, or
antiviral drugs

- Any other clinically significant medical disease or condition laboratory abnormality
or psychiatric illness that, in the Investigator's opinion, may interfere with
protocol adherence or a subject's ability to give informed consent

- Known hypersensitivity to thalidomide or lenalidomide

- The development of erythema nodosum if characterized by a desquamating rash while
taking thalidomide, lenalidomide or similar drugs

- Ejection fraction of < 45% by either multi gated acquisition scan (MUGA) or
echocardiogram (ECHO)