This regimen aims to become the first line treatment for peripheral T cell lymphoma, using nivolumab with the standard of care chemotherapy.

Patients in this study will receive nivolumab in combination with the standard of care dose-adjusted EPOCH (etoposide, prednisone, vincristine, doxorubicin, cyclophosphamide) for six 21 day cycles. Patients will then have an autologous stem cell transplant or continue to receive maintenance therapy with nivolumab.

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Ability to sign and date the consent form.

2. Stated willingness to comply with all study procedures and be available for the duration of the study.

3. Be a male or female aged 18-80.

4. Histologically confirmed new diagnosis of Stage II, III or 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 (MEITL and EATL), Hepatosplenic T-cell lymphoma, y/8 T-cell lymphoma, Subcutaneous panniculitis-like T-cell lymphoma, and Nodal T-cell lymphomas with T-follicular helper phenotype.

5. Available pathology material (fine needle aspirate is inadequate) for review at the University of Colorado.

6. No prior therapy with the exception of prior radiation therapy and/or 1 cycle of chemotherapy (may be any chemotherapy regimen or even prednisone alone) based on current diagnosis and clinical condition. If given cytotoxic chemotherapy (one cycle only, e.g. CHOP), this cycle of treatment will count toward the 6 cycles of treatment given in the study.

7. ECOG performance status 0 - 2.

8. Laboratory status as follows:

   • ANC > 1000 cells/mm3, unless cytopenias due to lymphoma (i.e., bone marrow involvement or splenomegaly)
   • Platelet Count > 100,000 /μL, or > 50,000 /μL if bone marrow 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, Appendix)
   • PT or INR, and 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.

9. Patients with measurable disease. Measurable disease is defined as having 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 MRI (if appropriate) will constitute measurable disease. Proof of lymphoma in the liver is required by a confirmation biopsy unless there is measurable disease by imaging. Skin lesions can be used as measurable disease provided bi-dimensional measurements are possible. Patients with non-measurable but evaluable disease may be eligible after discussion with the PI. Abnormal PET/CT scans will not constitute evaluable disease, unless verified by the CT scan portion, CT scan, or other appropriate imaging.

10. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 180 days after the last study treatment. A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

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

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. An additional malignancy treated with palliative intent within the past 2 years. Malignancies in patients who have completed definitive treatment with curative intent >1 year will be permitted after discussion with the PI. 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 PSA levels are allowed.
2. Patients with a diagnosis of other PTCL histologies other than those specified in the inclusion criteria.
3. Primary T-cell CNS lymphoma; however, secondary CNS disease is not an exclusion criteria.
4. Pregnant or breastfeeding females.
5. Contraindication to any of the required concomitant drugs or supportive treatments.
6. 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.
7. Ejection fraction of <45% by either MUGA or ECHO.
8. Has immunodeficiency or is being treated with immuno-suppressive therapy (aside from medications used to treat lymphoma) within 7 days of first dose of study treatment. Inhaled or topical steroids are accepted. Prednisone used to treat adrenal insufficiency in the absence of auto-immune disease is also acceptable.
9. Auto-immune condition requiring immuno-suppressive disease modifying therapy within the prior 2 years. Replacement therapy, e.g. levothyroxine for thyroiditis or insulin for diabetes are acceptable.
10. History of non-infectious pneumonitis requiring immuno-suppressive therapy.
11. Active hepatitis B or C (with measurable virus or antigen in serum) or HIV. Patients who are seropositive because of hepatitis B virus vaccine or have a history of hepatitis B (with no measurable virus or antigen in serum) are eligible.
12. Prior PD-1 or PD-L1 antibody treatment.
13. Has received a live virus vaccine in 30 days preceding start of therapy.

up to 100 days after last dose of nivolumab