Phase II Study of Mogamulizumab With DA-EPOCH in Patients With Aggressive T Cell Lymphoma

This is a single arm, open label, multicenter phase 2 study of DA-EPOCH and Mogamulizumab in patients with newly diagnosed or relapsed/refractory (for CTCL only) aggressive T-cell lymphomas including ATLL and transformed Mycosis Fungoides/Sézary syndrome (MF/SS). The hypothesis is that this combination is effective and will produce a CR rate of 80%. DA-EPOCH and Mogamulizumab will be administered for 6 cycles and depending on the histology, consolidative strategies including SCT will be considered. Response assessments will occur at pre-specified intervals. Dose adjustments for specific toxicities with drugs are detailed in the protocol. Based on statistical analysis, a maximum of 36 patients will need to be accrued to evaluate for disease response based on historical control.

Inclusion Criteria:

1. Male/female patients who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of T-cell Non-Hodgkin lymphoma (T-NHL) will be enrolled in this study.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 unless compromised by lymphoma with anticipated benefit from chemotherapy as determined and documented by the investigator.
3. Histologically confirmed T-cell Non-Hodgkin lymphoma (T-NHL), including but not limited to:
   • Peripheral T-cell lymphoma not otherwise specified (PTCL nos)
   • Angioimmunoblastic T-cell lymphoma (AITL)
   • Anaplastic large-cell lymphoma (ALCL)
   • Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF)/sezary syndrome patients for whom multi-agent chemotherapy is indicated
   • Transformed mycosis fungoides/Sezary syndrome
   • Enteropathy-associated T-cell lymphoma (EATL)
   • Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL)
   • Hepatosplenic T- cell lymphomas
   • Gamma delta T cell lymphomas
   • Adult T-cell lymphoma leukemia (ATLL)
   • T-prolymphocytic leukemia with nodal or visceral involvement
4. Prior therapy- patients with aggressive T cell lymphoma may have received one cycle of CHOP, CHOEP or EPOCH before enrollment, if necessary, to control the disease.
5. For patients with peripheral T-cell lymphoma (PTCL): At least one measurable target lesion ≥ 1.5 cm
6. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
   • Not a woman of childbearing potential (WOCBP) OR
   • A woman of childbearing potential (WOCBP) - must have a negative serum or urine pregnancy test during screening and must agree to follow instructions for using acceptable contraception (Appendix 5) from the time of signing consent, and at least 180 days (6 months) after her final dose of mogamulizumab.
7. A male patient must agree to use a contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least at least 180 days (6 months) after her final dose of mogamulizumab and refrain from donating sperm during this period.
8. Adequate organ and bone marrow function resulted ≤ 10 days prior to first dose of protocol-indicated treatment unless compromised by disease involvement of bone marrow, spleen, or liver as determined and documented by the investigator.
9. Patients previously treated with anti-CD4 antibody or alemtuzumab are eligible provided their CD4+ cell counts are ≥ 200/mm.

Exclusion Criteria:

1. Has received prior systemic anti-cancer therapy including investigational agents ≤ 3 weeks prior to first dose of study treatment on Cycle 1, Day 1. Skin directed treatments, including topicals and radiation within 2 weeks of study treatment. However, patients with rapidly progressive malignant disease may be enrolled prior to this period after discussion with the sponsor investigator.
2. Has received radiotherapy within 2 weeks of start of study treatment. Patients must have recovered from all radiation-related toxicities, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
3. If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
4. Patients on any immunomodulatory drug for concomitant or intercurrent conditions other than T-cell lymphoma or who have received any of these agents within 4 weeks of treatment, including but not limited to the following, will be excluded: low dose or oral methotrexate; azathioprine; iv immunoglobulin; low dose or oral cyclophosphamide; cyclosporine; mycophenolate; infliximab; etanercept; leflunomide; adalimumab; lenalidomide; abatacept; rituximab; anakinra; interferon-β; IL-2 and natalizumab. . Concurrent use of topical steroids or therapies for CTCL is allowed as indicated in the protocol.
5. Pregnant or breast-feeding females. A WOCBP who has a positive urine pregnancy test within 72 hours of treatment start. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
6. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg,FluMist®) are live attenuated vaccines and are not allowed.
7. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

   Note: Patients who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

8. Active uncontrolled infection requiring systemic therapy (patients must be afebrile for ≥ 48 hours and off antibiotics prior to treatment). If fever is attributed to tumor fever (B symptom) then these criteria would not apply.
9. Active myocarditis, regardless of etiology; or New York Heart Association (NYHA) functional classification III-IV heart failure.
10. Known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
11. Diagnosed with a malignancy, not treated under the study (hormonal therapy for breast or prostate cancer excepted), in the past 2 years. However, patients with non- melanoma skin cancers, melanoma in situ, localized cancer of the prostate with current prostate-specific antigen of < 0.1 ng/mL, treated thyroid cancer or cervical carcinoma in situ or ductal/lobular carcinoma in situ of the breast with in the past 2 years may enroll as long as there is no current evidence of disease.
12. Known severe hypersensitivity (≥Grade 3) to mogamulizumab and/or any of its excipients and /or EPOCH or any of its excipients.
13. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority.
14. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
15. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
16. Has a known history of active TB (Bacillus Tuberculosis).
17. Prior allogeneic stem cell transplant within last 2 years or active graft vs. host disease (GVHD).
18. Known active autoimmune disease will be excluded if the disease requires active medical treatment. (For example, Graves' disease; systemic lupus erythematosus; rheumatoid arthritis; Crohn's disease; psoriasis).