Combination Chemotherapy and Pralatrexate as First-Line Therapy in Treating Patients With Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To evaluate in a Phase II study a preliminary estimate of the complete response (CR) rate
of a new chemotherapy regimen involving Cyclophosphamide, Etoposide, Vincristine and
Prednisone (CEOP) alternating with Pralatrexate (P) as front line therapy for patients with
Stage II, III and IV Peripheral T-Cell NHL not otherwise specified (NOS), Anaplastic large
cell lymphoma (ALK negative), Angioimmunoblastic T-cell lymphoma, Enteropathy associated
T-cell lymphoma, Hepatosplenic gamma delta T-cell lymphoma followed by an optional stem cell
transplant with high dose chemotherapy and Autologous stem cell transplant.

SECONDARY OBJECTIVES:

I. To evaluate partial response (PR). II. To evaluate overall response (CR+PR). III. To
evaluate the safety and tolerability of the regimen IV. To assess the 2 year event free
survival (EFS) and overall survival (OS) using this regimen.

V. To assess the percentage of patients who proceeded with transplant. VI. To evaluate the
ability to collect peripheral blood stem cells after this regimen.

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) and vincristine IV on day 1, etoposide
IV on days 1-3 or orally (PO) once daily (QD) on days 2-3, and prednisone PO QD on days 1-5
(CEOP administration). Patients also receive pralatrexate IV over 3-5 minutes on days 15, 22,
and 29 (P administration). Treatment repeats every 42 days for up to 6 courses in the absence
of disease progression or unacceptable toxicity.

Patients with Complete Response (CR) or Partial Response (PR), per investigators discretion,
may then undergo hematopoietic stem cell collection and administration of standard
preparative regimen followed by hematopoietic stem cell transplantation.

After completion of study treatment, patients are followed up for 2 years (transplant
patients) or periodically.

Inclusion Criteria:

- Histologically confirmed new diagnosis of Stage II, III and IV peripheral T-cell NHL
not otherwise specified (NOS), anaplastic large cell lymphoma (ALK negative) (ALK
positive if international prognostic index [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, immunohistochemistry [IHC] and
pathology report from initial diagnosis, if slides are not available, then 8 unstained
slides of 4 micron thickness or a representative block should be sent) will be
reviewed, and the diagnosis confirmed by University Nebraska Medical Center (UNMC)
pathology department (retrospective diagnostic review: treatment may commence prior to
the UNMC review)

- No prior therapy with the exception of prior radiation therapy and 1 cycle of
chemotherapy based on current diagnosis and clinical condition

- Age 19 years or older (the age of consent in Nebraska); age 18 years or older
(applicable to states where the age of majority is 18)

- Expected survival duration of >= six months

- Karnofsky Performance Status >= 70

- Absolute neutrophil count (ANC) >= 1000 cells/mm^3, unless due to lymphoma involvement
of the bone marrow

- Platelet Count >= 100 mm^3, unless due to lymphoma involvement of the bone marrow

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

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

- Serum potassium within normal range

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

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

- 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) scans will not constitute evaluable
disease, unless verified by computed tomography (CT) scan or other appropriate imaging

- Patients with measurable disease must have at least one objective measurable disease
parameter; a clearly defined, bidimensionally measurable defect or mass measuring at
least 2 cm in diameter on a CT scan will constitute measurable disease; proof of
lymphoma in the liver is required by a confirmation biopsy

- Women must not be pregnant or breast-feeding due to teratogenic effects of
chemotherapy

- 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; 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 positive for human immunodeficiency virus (HIV), human T-lymphotropic virus type
1 (HTLV-1), or infectious hepatitis, type A, B or C or active hepatitis

- 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, antiviral
drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment

- 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

- Concomitant administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and
trimethoprim/sulfamethoxazole will not be allowed, since these may result in delayed
clearance of pralatrexate