Phase I Dose-finding and Preliminary Efficacy Study of the Istodax® in Combination With Doxil® for the Treatment of Adults With Relapsed or Refractory Cutaneous T-cell Lymphoma

This a multi-center, single arm, open-label, Phase I dose-finding and preliminary efficacy
study of the combination of the histone deacetylase inhibitor romidepsin (Istodax®) in
combination with doxorubicin HCl liposomal (Doxil®) for adult patients with relapsed or
refractory cutaneous T-cell lymphoma after at least one prior line of systemic therapy.

STUDY ENDPOINTS:

Primary:

MTD will be determined by standard "3+3" dose escalation of romidepsin with a fixed dose of
doxorubicin HCl liposomal. Participants will be followed throughout therapy and all adverse
events recorded, graded, and given likelihood of relevance to study therapies. Toxicity will
be graded by the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.

Secondary:

- Response will be assessed by a global response score integrating change in skin disease
as measured by the modified severity-weighted assessment tool (mSWAT) score, change in
lymph node size, change in visceral disease, and changes in peripheral blood Sézary
cells by flow cytometry. CR/PR assignment requires confirmatory assessment in 4 weeks.
Skin scores, clinical lymph node, liver and spleen exam, and Sézary cell count
assessment will occur on Day 1 of each cycle. Contrasted CT scan of the neck, chest,
abdomen and pelvis will be performed at screening for all patients. In patients with
lymphadenopathy and/or organomegaly at screening, contrasted CT scans of the neck,
chest, abdomen, and pelvis will occur at the end of every third cycle of therapy, within
1 week of cycle 8 completion, and every 6 months for one year after maximal response.
All patients will have contrasted CT scans of the neck, chest, abdomen, and pelvis at
the time of concern for disease progression in lymph nodes and/or viscera.TTR is the
time of the first romidepsin dose to the time of documented objective response (PR/CR).
DOR is the time from first objective response (PR or CR) until disease progression.

- TTP will be measured from the time of the first romidepsin dose until disease
progression.

- Pruritus will be assessed monthly using a 100 mm visual analog scale. Quality of life
will be assessed monthly by FACT-G, Skindex-29, and ItchyQOL questionnaires.

Exploratory:

Skin lesions will be punch biopsied (two contiguous 5mm biopsies) prior to beginning therapy
as standard care of care. Any leftover tissue will be collected for research with consent of
patient. Optional single 5mm punch biopsies will be obtained on day 15 of Cycle 2 after
infusion of romidepsin, and at disease relapse.

Inclusion Criteria:

1. Able to understand and voluntarily sign an informed consent form.

2. Age ≥18 years at the time of signing the informed consent form.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Biopsy-proven, measurable, Stage IB-IVB relapsed or refractory cutaneous T-cell
lymphoma after 2 lines of skin-directed therapy or one prior line of systemic therapy
(Note: extracorporeal photopheresis will be considered a systemic therapy for this
study)

5. All cancer therapy, including radiation, hormonal therapy and surgery, must have been
discontinued at least 4 weeks prior to treatment in this study. The only exceptions
are participants with erythroderma who have been on corticosteroids for prolonged
periods of time (>60 days) without change may continue use of either low dose systemic
steroid (equivalent to <10 mg per day of prednisone) or low potency topical steroids
are eligible for this study if the frequency and dosage steroids has not changed for
60 days prior to the study. These participants should continue on the same dose of
systemic/topical steroid throughout the study period unless they achieve a complete
response at which time steroids can be discontinued. Patients are allowed to continue
any medications with known activity in T cell lymphomas at the pre-enrollment doses
for conditions other than T cell lymphomas (ie, steroids for sarcoidosis) , as long as
there is evidence of T cell lymphoma progression while patients were on these agents.

6. ECOG performance status of ≤ 2 at study entry.

7. Laboratory test results within these ranges:

- Absolute neutrophil count ≥750/mm³

- Platelet count≥75,000/mm³

- Total bilirubin ≤ 2 x ULN

- AST (SGOT) and ALT (SGPT) ≤ 3 x ULN.

- Creatinine < 2 mg/dL

8. Disease free of prior malignancies for ≥ 5 years with exception of currently treated
basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or
breast. Patients with early stage of prostate cancer under clinical surveillance
without therapy are eligible

9. Negative serum pregnancy test at the time of enrollment for females of childbearing
potential.

10. For males and females of child-producing potential, use of effective contraceptive
methods during the study to include 2 methods of contraception, one being a condom.

11. Life expectancy >90 days.

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form.

2. Pregnant or breast feeding females.

3. Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.

4. Use of any other experimental drug or therapy within 28 days of baseline except
topical therapy for mycosis fungoides which must be discontinued 14 days prior to
initiation of study therapy.

5. Prior allogeneic hematopoietic cell transplant.

6. Prior solid organ transplant.

7. Cumulative anthracycline exposure greater than 300 mg/m2 doxorubicin equivalents.

8. Known active viral infection with human immunodeficiency virus (HIV), hepatitis B
virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of prior
hepatitis B virus vaccination are eligible.

9. Central nervous system or meningeal involvement

10. Any known cardiac abnormalities including:

- Congenital long QT syndrome

- Baseline QTc interval ≥ 480 milliseconds;

- Myocardial infarction within 6 months of C1D1. Subjects with a history of
myocardial infarction between 6 and 12 months prior to C1D1 who are asymptomatic
and have had a negative cardiac risk assessment (treadmill stress test, nuclear
medicine stress test, or stress echocardiogram) since the event may participate

- Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV)
block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50
beats/min)

- Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II- IV. In
any patient in whom there is doubt, the patient should have a stress imaging
study and, if abnormal, angiography to define whether or not CAD is present

- An ECG recorded at screening showing evidence of cardiac ischemia (ST depression
of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, the
patient should have a stress imaging study and, if abnormal, angiography to
define whether or not CAD is present

- Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class
II to IV definitions (see Appendix 10) and/or ejection fraction <40% by MUGA scan
or <50% by echocardiogram and/or MRI

- A known history of sustained ventricular tachycardia (VT), ventricular
fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently
addressed with an automatic implantable cardioverter defibrillator (AICD)

- Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or
other causes

- Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients with a
history of hypertension controlled by medication must be on a stable dose (for at
least one month) and meet all other inclusion criteria

- Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
doses of beta-blockers)

- Any cardiac finding that is deemed ineligible at the discretion of the
investigator

11. Patients taking drugs leading to significant QT prolongation and unable to stop drugs
prior to treatment

12. Concomitant use of CYP3A4 inhibitors or inducers unless able to stop medication(s)
prior to starting study therapies