Everolimus in Treating Cutaneous T-cell Lymphoma

Cutaneous T-cell lymphoma is a rare form of lymphoma of the skin. While early stages are
usually confined to the skin, later stages may spread to blood, lymph nodes and other
organs. At this point, patients usually require systemic chemotherapy. This study will
investigate the effect of everolimus as a treatment for patients diagnosed with CTCL that
has either not responded to previous treatments or has recurred despite previous treatments.
Everolimus is the common name for the commercial drug Afinitor® (Novartis). It is approved
by the U.S. Food and Drug Administration (FDA) for use in kidney and brain cancer. In
several different forms of lymphomas, everolimus is used as an investigational drug, which
means it has not been approved by the FDA for this group of diseases.

Everolimus blocks a protein (mTOR) that helps cells and tumors to grow. Earlier studies have
indicated that the drug everolimus may work against lymphomas including cutaneous T-cell
lymphomas. Participation in this study will last as long as the study doctor believes
disease has not gotten worse, and patients continue to tolerate the study medication for a
maximum of 1 year. Once off the treatment, patients will be followed for two years.

Inclusion Criteria:

- Clinically and histologically confirmed diagnosis of CTCL (at least stage IB for
mycosis fungoides and Sézary syndrome, and T2 and/or refractory to at least one prior
treatment for CTCL other than mycosis fungoides/Sézary syndrome)

- Relapsed or refractory disease after at least one standard systemic treatment
including extracorporeal photopheresis (ECP), oral bexarotene, interferon, HDAC
inhibitors

- ≥18 years old

- WHO performance status ≤ 2

- Life expectancy ≥ 6 months

- ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >9 g/dL

- Serum bilirubin ≤ 1.5 x ULN

- ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)

- INR ≤1.5 (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin
or on a stable dose of LMW heparin for >2 weeks at time of randomization)

- Serum creatinine ≤ 1.5 x ULN

- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L

- Fasting triglycerides ≤ 2.5 x ULN.

Exclusion Criteria:

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of stating study drug

- Treatment with any investigational drug within the past 4 weeks

- Patients, who have had major surgery or significant traumatic injury within 4 weeks
of starting study drug, patients who have not recovered from the side effects of any
major surgery, or patients that may require major surgery during the study

- Patients receiving chronic, systemic treatment with corticosteroids or any
immunosuppressive agent other than topical or inhaled corticosteroids

- Patients receiving immunization with attenuated live vaccines within one week of
study entry or during study period

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York heart Association Class III or IV

- unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or
any other clinically significant cardiac disease

- severely impaired lung function as defined as spirometry and DLCO that is 50% of the
normal predicted value and/or O2 saturation that is 88% or less at rest on room air

- uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (Note: Optimal
glycemic control should be achieved before starting trial therapy.)

- active (acute or chronic) or uncontrolled severe infections

- liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).

- A known history of HIV seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus

- Patients with an active, bleeding diathesis

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Adequate contraception
must be used throughout the trial and for 8 weeks after the last dose of study drug,
by both sexes.

- Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception, during the study and for 8 weeks after the end of treatment

- Patients who have received prior treatment with an mTOR inhibitor

- Patients with a known hypersensitivity to everolimus or other rapamycins or to its
excipient

- History of noncompliance to medical regimens

- Patients unwilling to or unable to comply with the protocol