Poly ICLC, Radiation, and Romidepsin for Advanced Cutaneous T Cell Lymphoma

Histone deacetylase inhibitors in epigenetic therapy are one of the most active anti-tumor
agents in patients with relapsed and refractory CTCL despite their suppressive effects on T
cell function, yet the overall response rate and response duration with these agents remains
suboptimal. Immune stimulatory agents may be the ideal therapy to combine with HDACI. To
date, no one has evaluated whether the abscopal effect of radiation with and without the
additional immune stimulation of a TLR-3 agonist can augmented the efficacy of anti-tumor
directed epigenetic therapy in mycosis fungoides (MF) patients. The investigators hypothesize
that a combined modality immuno-chemotherapy may be highly effective in patients with
advanced MF.

This is a phase I study. It involves two arms of patients (A and B) who will be treated
following a standard 3+ 3 design. Patients on Arm A are the ones who are initiating HDACI
therapy, and patients on Arm B are the ones with stable disease or partial response with
HDACI treatment. Both groups receive HDACI, plus at level 1, focal lesional radiation; at
level 2, radiation in combination with Poly ICLC. Each arm will be evaluated and escalated
independently.

Inclusion Criteria:

- Must have prior biopsy at any time point diagnostic for confirmed MF stage IIA-IVA,
and must have failed at least one standard therapy (topical or systemic).

- Must have a skin lesion of at minimum 2 cm, in a location amenable to radiation and a
minimum of 2 additional measurable skin lesions distant from the radiation site.

- Must be either initiating therapy with romidepsin (Arm A) or currently receiving
romidepsin with documented stable disease (SD) or partial response (PR) (Arm B).

- Patient may have had any prior topical or systemic therapy except for total electron
beam irradiation. Patients must be a minimum of 2 weeks from topical therapy and 4
weeks from systemic therapies, phototherapy, or local radiation therapy before
enrollment except for HDACI if they are in Arm B. Patients are allowed to take weak
potency topical corticosteroids if patient has been on a stable dose for more than a
month.

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >70%)

- Life expectancy of greater than 6 months

- Patients must have normal organ and marrow function as defined below:

- leukocytes >=2,500/mcL

- absolute neutrophil count >=1,000/mcL

- platelets >=50,000/mcL

- total bilirubin: within normal institutional limits

- AST(SGOT, aspartate aminotransferase)/ALT(SGPT, alanine aminotransferase) =<2.5 X
institutional upper limit of normal

- creatinine: within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.

- Age >=18 years

- The effects of focal radiation and HDACI on the developing human fetus are unknown.
For this reason and because agents as well as other therapeutic agents used in this
trial are known to be tetragenic, women of child-bearing potential and men must agree
to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation. Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks, or topical therapy
within 2 weeks prior to entering the study or those who have not recovered from
adverse events due to agents administered more than 4 weeks earlier. Patients are
allowed to take weak potency topical corticosteroids if patient has been on a stable
dose for more than a month.

- Patients who are receiving any other investigational agents.

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to HDACI, TLR-agonist, or patients with known history of pre-existing
auto-immune disease.

- Concurrent therapy with systemic corticosteroids or other immunosuppressive
medications.

- 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.

- Pregnant women are excluded from this study HDACI is a class agent with the potential
for teratogenic or abortifacient effects. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
HDACI, breastfeeding should be discontinued if the mother is treated with HDACI and
radiation. Woman of childbearing age and men sexually active with woman of
childbearing age must agree to an acceptable method of birth control (double barrier)
while on study.

- Patients with known HIV infection are ineligible because this immunomodulatory therapy
requires a normal and functional T cell repertoire. If this study is found to be safe,
effective, and immunogenic, HIV positive patients may be included in future studies.