Topical Romidepsin to Treat Early-Stage Cutaneous T-Cell Lymphoma

Background:

- Romidepsin is a histone deacetylase inhibitor which has demonstrated efficacy and
tolerability as an infusion in later stages of cutaneous T-cell lymphoma (CTCL).

- Early stages of CTCL are typically treated with skin-directed therapies, which may lose
efficacy over time and have adverse effects (i.e. risk of secondary skin cancers,
difficulty of use).

- A topical form of romidepsin may be helpful in the treatment of early-stage CTCL.

Objectives:

- Primary - To define the maximal tolerated dose (MTD) of topical romidepsin for
early-stage CTCL when administered three times weekly, then escalated first in
concentration, followed by increased frequency and lastly over increasing body surface
areas.

- Secondary - To assess histone acetylation in topical romidepsin-treated skin.

- Secondary - To assess in a pilot fashion clinical efficacy of topical romidepsin in
early stage cutaneous T-cell lymphoma.

- Secondary - To perform pharmacokinetic monitoring of blood levels of romidepsin in
topically treated patients.

Eligibility:

-Patients age greater than or equal to 18 with confirmed early-stage (stage IA, IB, or IIA)
cutaneous T-cell lymphoma.

Design:

- A Cohorts of Three design to define the MTD of topical romidepsin in Aquaphor ointment
initially applied overnight, three times weekly for 4 weeks, then escalated first in
concentration, followed by increased frequency and lastly over increasing body surface
areas.

- Skin toxicities, systemic toxicities, and disease response will be assessed throughout
the study.

- The primary focus of the first part of the protocol will be to evaluate local skin
toxicity, beginning with dose level 1 of 0.05 percent topical romidepsin on 25 cm(2)
target area (0.005 mg/ cm(2). If tolerated, progress to higher dose levels of 0.25
percent (0.025 mg/ cm(2); dose level 2) and then 0.5 percent (0.05 mg/ cm(2); dose level
3) topical romidepsin on 25 cm(2) target area. Systemic toxicity will also be monitored.

- To date, we have completed the first 4 dose levels and have not yet established
cutaneous MTD. To achieve this, we will proceed to the second part of the protocol,
which will increase the concentration to 1%, then increase the frequency to daily
application, then progress to 2% concentration, then 4% concentration, and then applying
to progressively larger body surface areas. Our aim is to more fully address systemic
toxicity by increasing drug concentration, application frequency, and body surface area
(BSA) treated. We will utilize topical romidepsin at the MTD on increasing BSA (lesional
& nonlesional skin): multiple lesions up to 3% BSA (dose level 4), multiple lesions up
to 25% BSA (dose level 7A), 50% BSA (dose level 7B), and 75% or > BSA (dose level 7C).

- INCLUSION CRITERIA:

1. Patients must have a pathologically confirmed diagnosis of CTCL based on a skin
biopsy, utilizing standard histological criteria based on cytological,
architectural, and immunophenotypic findings. In cases with equivocal
histological features, the diagnosis may be verified or confirmed through the use
of clonal T-cell gamma gene rearrangement, as detected by PCR amplification and
primer sets specific for the T-cell receptor gamma chain genes.

2. Patients must have early stage CTCL (Stage IA, IB, or IIA as defined by TNM
staging system).

3. Patients must:

1. be age greater than or equal to 18 years.

2. have evaluable disease.

3. have a performance status of ECOG 0-1.

4. be either on no therapy or only on topical therapy for early stage CTCL.
Patients must have stopped light therapy (i.e. PUVA, UVB) for at least 2
weeks prior to the use of study medication. Patients must have stopped
topical therapies (i.e. corticosteroids or nitrogen mustard) to designated
target sites or areas to be treated with study medication for at least 2
weeks prior to the use of study medication. (Topical therapies for CTCL may
be continued to non-adjacent, non-target lesions while on protocol.)
Patients may have received other HDACI therapy but must have stopped
systemic therapy 4 weeks prior to use of study medication.

5. be able to give written informed consent.

6. be willing to return to the National Cancer Institute for follow-up.

4. 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 participating in this study, she should inform her
treating physician immediately. The effects of romidepsin on the developing human
fetus are unknown. For this reason and because HDAC Inhibitor agents are known to
be teratogenic, patients that are pregnant or lactating will be excluded from
this trial.

5. Laboratory values:

Within 7 days prior to registration: absolute neutrophil count greater than or
equal to 1000/microL, platelets greater than or equal to 100,000/microL,
bilirubin (total and direct) less than or equal to 1.5 times upper limit of
normal, and AST less than or equal to 3 times upper limit of normal, creatinine
less than or equal to 1.5 times upper limit of normal, or documented creatinine
clearance of greater than or equal to 60mL/min

6. Cardiac findings:

Within 4 weeks of registration: ECG [patients should not have QTc prolongation (greater
than 480 msec) and/or rhythm abnormality; allowance of other EKG changes will be at
discretion of the investigator based on consultation with a cardiologist] and
echocardiogram [demonstrating normal ejection fraction].

EXCLUSION CRITERIA:

1. Prior or concurrent malignancies that have not been curatively treated with the
exception of malignancies that have been curatively treated and without recurrence in
the preceding 5 years, non-melanoma skin cancers, low grade cervical cancer and
prostate cancer.

2. Current or previous CNS metastasis.

3. Chemotherapy within 4 weeks, 6 weeks for nitrosoureas or mitomycin C, and 8 weeks for
UCN-01.

4. HIV seropositivity.

5. Pregnant or breast-feeding patients.

6. 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.

7. Use of known CYP3A4 inhibitors within 3 days prior to receiving romidepsin ointment
treatment.

Inclusion of Women and Minorities:

Subjects from both genders and all racial/ethnic groups are eligible for this study if they
meet the eligibility criteria.