A phase III study of lenalidomide maintenance after debulking with gemcitabine or liposomal doxorubicin +/- radiotherapy in patients with advanced cutaneous T-cell lymphoma not previously treated with intravenous chemotherapy.

Primary cutaneous T-cell lymphomas (CTCLs) are a heterogenous group of
lymphomas, classified according to the WHO/EORTC classification of cutaneous
lymphomas. Collectively, they are rare, with a prevalence of approximately
1-2/100,000 persons. Mycosis fungoides is the most common type, accounting for
nearly 50% of primary CTCL. Classical mycosis fungoides, its variants and
subtypes usually run an indolent course. However, patients with advanced stages
of the disease have a poorer prognosis. Erythrodermic CTCL with various degrees
of blood involvement, including Sézary syndrome, also have a more aggressive
course. Several studies have shown the stage-dependant prognosis of this
disease. A revised staging and classification of mycosis fungoides and Sézary
syndrome has been recently published by ISCL and EORTC.
Due to the rarity of CTCL, very few randomized trials have been performed in
this disease. EORTC consensus recommendations for the treatment of mycosis
fungoides/Sézary syndrome have been published. Treatment of advanced stage
disease is largely empirical, based on small non-randomized, uncontrolled
studies with response data. Depending on extent and staging of cutaneous
lymphoma, the age and physical condition of the patient, and the presence of
concurrent disease, treatment strategies can be topical or systemic. Available
topical treatment strategies include glucosteroids, retinoids, Carmustin or
HN2, available systemic treatments options include interferon alpha, oral
re(x/t)inoids, and low dose methotrexate or other chemotherapeutical drugs,
either as single agents or in combination. These treatments can be combined
with phototherapy, radiotherapy or photopheresis in erythrodermic stage. In
patients with advanced stage disease, treatments frequently induce partial
responses or complete responses with relapse after a few months, but the
prognosis becomes increasingly poor with subsequent lines of therapy.
Recently developed treatments include histone deacetylase inhibitors,
proteosome inhibitors, monoclonal antibodies and lenalidomide.
Lenalidomide is related to thalidomide, and like thalidomide it has both
immunomodulatory and anti-angiogenic properties which may confer antitumor and
antimetastatic effects. Lenalidomide more potently regulates cellular immune
and cytokine responses, while having a
better clinical risk-benefit profile than thalidomide. In early phase II
trials, Lenalidomide seems to have more anti-tumor activities than thalidomide.
Lenalidomide has an antiproliferative effect on several cell types, and has
immunomodulatory, anti-inflammatory, and anti-angiogenic effects. Lenalidomide
has been studied in a number of clinical trials, predominantly in the
indication of multiple myeloma (MM), but also for myelodysplastic syndrome
(MDS), lymphomas, Crohn's disease and solid tumors. More than 5,000 patients
have received the drug for multiple myeloma, alone.
Lenalidomide was selected for this study because it showed activity in other
hematological maligancies (multiple myeloma and 5q- myelodysplatic syndrome),
is reasonably well tolerated, and in a 25 patient open phase 2 trial,
demonstrated activity in CTCL, achieving a 28% PR responses. In that study,
lenalidomide was administered orally on an outpatient basis. The first fifteen
patients received 25 mg daily for 21 days with 7 days rest of a 28-day cycle,
the same schedule which is proposed in the present protocol. The remaining ten
patients in that protocol began with a dose of 10 mg and escalated as tolerated
in 5 mg increments to a maximum of 25 mg. The median patient age was 60 years
(range, 47-83) andpatients received a median of 6 prior treatment regimens
(range, 2-9). All but seven of the patients had advanced stage disease. All
responses were seen within the group that started at the 25 mg dose. Seven
patients in that study achieved a partial response which was defined as a
Composite Assessment of Index Lesion Disease Severity ratio less than or equal
to 0.5, with no new clinically abnormal lymph nodes, no progression of existing
clinically abnormal lymph nodes, and no new cutaneous tumors. Patients who
responded did so after a median of 9 cycles of therapy, with a median time to
best response of 6 months. Seven patients went off protocol due to toxicity.
The most common side effects reported were anemia, fatigue/malaise, skin
burning, pruritis, diarrhea, and lower leg edema.

This prospective, multi-center study will determine the benefit of maintenance
treatment with lenalidomide in this difficult to treat group of patients. The
importance of this study is that if this maintenance treatment is indeed
effective it will give considerable health-gain for these patietns.

To determine if maintenance treatment with lenalidomide prolongs progression
free survival in patients with advanced stage CTCL that has not
been previously treated with intravenous chemotherapy except the chemotherapy
received in the preceeding debulking stage. Patients will be randomized to
either receive the maintenance therapy or not, and these two study arms will be
compared in terms of the difference in progression free survival.

Debulking
All patients must receive one of the two permitted debulking regimens:
* Gemcitabine administered on days 1, 8, and 15 of a 28-day cycle at a dose of
1000 to 1200 mg/m2 intravenously over 30 minutes for a total of four cycles.
(or)
* Liposomal Doxorubicin administered on days 1 and 15 of a 28-day cycle at a
dose of 20 mg/m2 intravenously over one hour for a total
of four cycles.
* Local low-dose/energy ionizing radiation therapy may be used as part of the
debulking process to treat tumor lesions that do not respond after
three cycles of debulking chemotherapy.


Lenalidomide
This study centers on the ability of maintenance treatment with lenalidomide to
prolong the response achieved by these debulking regimens.
Arm 1: Observation
Arm 2: Lenalidomide, 25mg po d1-21, q 28 days.
Treatment in arm 2 continues until progression, toxicity, patient refusal or
death, or maximum treatment duration.
Maximum treatment duration: 560 days.

Half of the patietns will be assigned to treatmetn with Lenalidomide. During
treatment of these patietns blood samples will be drawn to monitor for
tocicity.

The extenst of the burden associated with participation will be the visits of
the hospital, pregnancy testing and blood drawing.

Hospital visits
The hospital visits will include a pretreatment visit (complete work-up
including: physical exam, medical history, WHO perfprmance status, pregnancy
test, blood count, blood chemistry, thyroid test, 12 lead ECG, disease
assesment), every 4 weeks (to assess adverse events), every 8 weeks (physical
exam, medical history, WHO performance status, blood count, disease assesment)
and a post treatment visit (complete work-up including: physical exam, medical
history, WHO perfprmance status, pregnancy test, blood count, blood chemistry).

Pregnancy testing
Before each cycle pregnancy testing will be performed if applicable (only in
lenalidomide arm)

Blood drawing
Blood drawing is performed routinously on the following days:
Cyclus 1: day 1,2,4,8,15, 22.
Cyclus 2: day 1,8,15,22.
Cyclus 3: day 1,15.
Cyclus 4 and all subsequent cycli: day 1.

Riscs associated with participationa are the potential adverse effects of
Lenalidomide:

Side Effects of any grade occurring in about 10% or more of patients
* Fatigue or feeling tired;
* Anemia or a decrease in red blood cells that can cause tiredness;
* Neutropenia or a decrease in white blood cells;
* Thrombocytopenia or a decrease in platelets;
* Constipation or infrequent or difficult bowel movements;
* Diarrhea or loose/frequent bowel movements;
* Nausea;
* Loss of appetite;
* Back pain;
* Joint pain;
* Muscle cramps;
* Swelling of the arms and legs;
* Problems falling asleep or staying asleep;
* Fever;
* Cough;
* Shortness of breath or difficulty catching your breath;
* Upper respiratory infection;
* Rash;
* Itching and dry skin;
* Lack or loss of strength;
* Dizziness;
* Headache.

Serious side effects occurring in about 1% or more of patients and not listed
above
* Neutropenia or a decrease in white blood cells that can make the patient
prone to infection associated with a fever;
* Pulmonary embolism or blood clot in or around the lungs;
* Deep vein thrombosis or blood clots in a larger blood vessel;
* Atrial fibrillation or irregular heartbeat;
* Progression of the disease being studied;
* Pneumonia or an infection of the lungs;
* Sepsis or an infection of the blood;
* Dehydration;
* Kidney failure.

Rare cases of the following events have been reported:
* Angioedema- an allergic skin disease characterized by patches of swelling
involving the skin and/or the lining of the nose, mouth, and gastrointestinal
tract.
* Stevens-Johnson syndrome and toxic epidermal necrolysis- serious allergic
skin reactions that begin as a rash in one area and later cover more of the
body leading to detachment of the top layer of skin (could be body-wide).
* Tumor lysis syndrome- metabolic complication that can occur during or without
treatment of cancer. These complications are caused by the break-down products
of dying cancer cells and include hyperkalemia (high potassium),
hyperphosphatemia (high phosphorus), hyperuricemia and hyperuricosuria (high
uric acid in blood and urine) , hypocalcemia (low calcium), and consequent
acute uric acid nephropathy and acute renal failure (kidney damage).
* Rhabdomyolysis, a serious condition involving the destruction of skeletal
muscle that can lead to kidney failure. Signs and symptoms include dark, red,
or cola colored urine and muscle tenderness, stiffness, aching (myalgia) or
weakness.

Possibly there is a slightly increased risk for the development of secondary
malignancies.