This is a Phase I Trial to assess the feasibility of Romidepsin combined with Brentuximab Vedotin for patients requiring Systemic Therapy for Cutaneous T-cell Lymphoma.

This is a traditional "3+3" phase 1 dose de-escalation design testing up to 3 dose levels of romidepsin in conjunction with brentuximab vedotin in patients with untreated or previously treated (up to 2 prior systemic regimens, including photopheresis) CTCL. Dose-limiting toxicities (DLT) will be determined during cycle 1. The first 3 subjects will begin at dose level 1. If no DLT is encountered another 3 subjects will be enrolled at the same dose level. The maximum tolerated dose (MTD) will be the dose level at which ≤ 1 of 6 of subjects experience DLT. If more than one subject at any one dose level encounters a DLT, the dose will be de-escalated for all subsequent subjects. Should no DLTs occur, the investigators will not escalate beyond dose level 1. Once the MTD has been confirmed, the investigators will enroll an additional 9 patients in a toxicity refinement cohort for a total of 15 evaluable patients at the MTD.

Treatment will continue for up to 16 cycles (one cycle is 28 days) or until disease progression or toxicities, whichever occurs first. Drugs can be continued after 16 cycles if a patient has derived a clinical benefit from treatment after discussion with the sponsor-investigator.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed diagnosis of mycosis fungoides (MF), Sezary syndrome (SS) or primary cutaneous CD30-positive lymphoproliferative disorder, including lymphomatoid papulosis and primary cutaneous ALCL (pc-ALCL)as defined by the WHO classification of Tumors of Hematopoietic and Lymphoid tissue.

   Please note that tumor samples for patients with MF or SS can be CD30 negative and do not have to be CD30 positive on either flow cytometry or immunohistochemistry for patients to be eligible.

2. Patients with MF/SS must have stage IB, IIA, IIB, III or IV disease; patients with primary cutaneous CD30-positive lymphoproliferative disorder must have multifocal symptomatic or extensive lesions requiring systemic treatment.

3. Patients must require systemic treatment.

4. Patients can have received up to 2 lines of systemic treatment. Psoralen plus ultraviolet light therapy (PUVA) is not considered to be a systemic therapy.

5. Age > 18 years.

6. ECOG performance status 0, 1 or 2.

7. Patients must have acceptable organ and marrow function as defined below:

   • Absolute neutrophil count > 1,500/mcL
   • Platelets > 100,000/mcL
   • Total bilirubin within normal institutional limits
   • AST/ALT (SGOT/SGPT) < 2 times institutional normal limits
   • Creatinine within normal institutional limits OR
   • Creatinine clearance > 60 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal

8. Women of child-bearing potential (WOCBP) must have a negative pregnancy test

9. Ability to understand and willingness to sign a written informed consent and HIPAA consent document.

10. Patients with HIV who are not receiving cytochrome p450 inhibitors, and who have a minimum of 300+ CD4+ cells/mm3, an undetectable viral load, and no history of AIDS indicator conditions.

Exclusion Criteria:

1. Patients who have not had resolution of clinically significant toxic effects of prior anticancer therapy to ≤grade 1 as per by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE, v.4.0).
2. Grade 2 or greater neuropathy.
3. Patients may not be receiving any other investigational agents.
4. Patients with known CNS involvement.
5. Patients must not receive concurrent systemic or topical steroids or other skin directed therapy while on study except as outlined in 5.2.2
6. Patients who have experienced allergic reactions to monoclonal antibodies.
7. Patients who have received prior HDAC inhibitors, or brentuximab vedotin, except for patients who were exposed to above drugs only for a short time (less than 8 weeks), did not progress while on treatment, and did not have intolerable toxicity but were discontinued for another reason (e.g., comorbidity) may be permitted to enter the study after discussion with the sponsor-investigator.
8. 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.
9. Pregnant or breast feeding. Refer to section 4.4 for further detail.
10. Second malignancies that require active treatment with the exception of breast or prostate cancer on endocrine therapy.