Vorinostat in Patients With Primary Cutaneous T-Cell Lymphoma

PRIMARY OBJECTIVES:

I. To determine the objective response rate to treatment with dose-adjusted Vorinostat
schedule in subjects with cutaneous T-cell lymphoma (CTCL) who did not receive prior
systematic therapy or have been treated with single agent targretin (bexarotene).

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of dose-adjusted Vorinostat schedule when
administered to patients with primary cutaneous T-cell lymphoma who did not receive prior
systematic therapy or have been treated with single agent targretin.

II. To determine the time to objective response in subjects with CTCL treated with
dose-adjusted schedule of Vorinostat as primary therapy.

III To determine the duration of objective response in subjects with CTCL.

IV. To determine the time to loss of objective response.

V. To determine the objective response rate of extracutaneous manifestations of CTCL (lymph
node enlargement, Sezary cells in peripheral blood).

VI. To compare the efficacy, toxicity and tolerability of dose-adjusted schedule to currently
recommended flat dose of Vorinostat in subjects with CTCL.

OUTLINE: Patients are assigned to 1 of 2 treatment arms according to age (< 65 vs >= 65 years
old).

COHORT I (>= 65 years old): Patients receive 200 mg vorinostat orally (PO) once daily (QD) on
days 1-28. Treatment repeats every 28 days for 6 courses in the absence of disease
progression or unacceptable toxicity.

COHORT II (< 65 years old): Patients receive 400 mg vorinostat PO QD on days 1-28. Treatment
repeats every 28 days for 6 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for at least 30 days.

Inclusion Criteria:

- Males or non-pregnant females

- Histologically confirmed diagnosis of CTCL, including mycosis fungoides and/or Sezary
syndrome

- Documentation of diagnosis by histologic examination should be available

- Subjects with CTCL stages IB, IIA, IIB, III, or IVA who have not received any prior
systemic therapies

- Anticipated life expectancy greater than 6 months

- Performance status 0, 1, or 2 by Eastern Cooperative Oncology Group (ECOG) criteria

- Written informed consent to participate in the study

- Absolute neutrophil count (ANC) >= 1,000/mcL

- Platelets >= 75,000/mcL

- Hemoglobin >= 9 g/dL

- Prothrombin time or international normalized ratio (INR) =< 1.5 x upper limit of
normal (ULN) unless receiving therapeutic anticoagulation

- Partial thromboplastin time (PTT) =< 1.2 times the ULN unless the patient is receiving
therapeutic anticoagulation

- Serum creatinine =< 1.5 X ULN OR calculated creatinine clearance >= 60 mL/min for
patients with creatinine levels > 1.5 X institutional ULN; creatinine clearance should
be calculated per institutional standard

- Serum total bilirubin =< 2 X ULN

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic aminotransaminase [SGOT])
and alanine aminotransferase (ALT) (serum glutamic pyruvic aminotransaminase [SGPT])
=< 3.0 X ULN

- Alkaline Phosphatase (liver fraction) =< 3.0 X ULN

Exclusion Criteria:

- Proven or suspected extracutaneous visceral CTCL involvement (M1) (CTCL stage IVB)

- Presence of lymphadenopathy is permitted

- ECOG performance status > 2

- Concomitant use of any anti-cancer therapy or immune modifier

- Concomitant use of any investigational agent or device

- Concomitant therapy with any other anti-CTCL therapy, or radiation therapy (topical
corticosteroids or low dose oral corticosteroids [=< 10 mg/day prednisone or
equivalent] will not be excluded, but if used, the dose and schedule must be stable
during the two weeks immediately prior to study entry)

- Use of any previous systemic therapy (except single agent targretin), total skin
electron beam (TSEB) therapy or extracorporeal photopheresis

- Evidence of clinically significant (uncontrolled) hypo- or hyperthyroidism

- Poorly controlled diabetes mellitus as evidenced by hemoglobin (Hgb)A1c > 6.5 mg/dl

- Recent (in the past 6 months) medically significant cardiac event (i.e. myocardial
infarction, cardiac surgery)

- Presence of congestive heart failure (New York Heart Association [NYHA] class IV) or
angina (NYHA class IV) or presence of a medically significant arrhythmia

- Congenital long QT syndrome

- Corrected QT interval > 480 msec on screening electrocardiogram (ECG)

- Presence of uncontrolled hypertension manifested by systolic blood pressure >= 180
mmHg and/or diastolic blood pressure >= 100 mmHg

- Documented current active infection with human immunodeficiency virus (HIV), Hepatitis
B, Hepatitis C, and/or cytomegalovirus (CMV)

- Presence of uncontrolled bacterial or viral infection (subject may be receiving
chronic antimicrobial therapy)

- History of culture-documented bacteremia in the previous 2 weeks

- Concurrent therapy with any histone deacetylase (HDAC)-like compound; patients treated
with valproic acid for epilepsy may enroll after a 30 day washout period

- Recent change (in the past 2 weeks) in the doses or regimens of medication used for
any chronic non-oncologic conditions for reasons of worsening of chronic illness
(change in doses of chronic medications associated with improvement in a chronic
illness are not exclusion criteria)

- Presence of any acute or chronic non-oncologic disease which, in the opinion of the
investigator, is medically uncontrolled

- History of a prior malignancy with the exception of cervical intraepithelial
neoplasia; non-melanoma skin cancer; adequately treated localized prostate carcinoma
with prostate specific antigen (PSA) < 1.0; or who has undergone potentially curative
therapy with no evidence of that disease for five years, and/or who is deemed at low
risk for recurrence (< 30% probability) by his/her treating physician

- Patient with a "currently active" second malignancy, other than nonmelanoma skin
cancer and carcinoma in situ of the cervix, should not be enrolled

- Any significant medical or psychiatric condition that, in the opinion of the
investigator, might prevent the subject from complying with all required study
procedures

- Women of childbearing potential must have a pregnancy test within 28 days prior to
registration, and must use an adequate method of contraception to avoid pregnancy
throughout the study and for a period of at least 3 months after the study

- Females of childbearing potential and sexually active males, if indicated, must be
willing and able to use two methods of contraception that are adequate to prevent or
minimize risk of pregnancy for the duration of the study; one of which must be a
barrier method

- Patient has symptomatic ascites or pleural effusion (a patient who is clinically
stable following treatment for these conditions is eligible)

- Patient has had allogeneic transplant

- Patient has a history of a gastrointestinal surgery or other procedures that might, in
the opinion of the investigator, interfere with the absorption or swallowing of the
study drugs