Maintenance Lenalidomide in Lymphoma

Describe succinctly and clearly the past findings which justify the plan for this project. A
summary of the relevant literature in the area of interest and reports of previous studies
should be included.

For majority of lymphoma patients who relapse after complete response or who are primary
refractory to initial treatment, a combination of salvage chemotherapy followed by high dose
chemotherapy and ASCT is considered the standard of care. Sensitivity to salvage
chemotherapy affects the outcome after ASCT. Traditionally, the response to salvage
chemotherapy prior ASCT was determined by conventional computed tomography (CT) scans using
size criteria. In the past several years, it has been shown that functional imaging with PET
scans using fluorodeoxyglucose (FDG) provides additional information to anatomic imaging
with CTs. Recently, PET scans have been incorporated into the response assessment as
published by the Imaging Subcommittee of International Harmonization Project in Lymphoma.
These days, most institutions use PET/CT scans which incorporate functional imaging with PET
scan fused with low dose non-contrast enhanced CT scan.

We have previously reported the outcome of patients with relapsed/refractory lymphomas who
continued to have residual FDG avid PET (positive) lesions after salvage chemotherapy and
prior to ASCT. This group of patients included those who had excellent anatomic response by
size criteria, but continued to have persistent hypermetabolic FDG activity within the
residual lesions. We found that PET positive patients have an extremely poor chance of
durable remission after ASCT. In the PET negative group, the median PFS was 19 months with
54% of patients without progression at 12 months after ASCT. In the PET positive group, the
median PFS was 5 months with only 7% of patients without progression at 12 months after
ASCT. We concluded that, for patients with PET positive residual disease after salvage
chemotherapy and prior to ASCT, novel therapeutic approaches and agents need to be
investigated.

Lenalidomide is a proprietary IMiD® compound of Celgene Corporation. IMiD® compounds have
both immunomodulatory and anti-angiogenic properties which could confer antitumor and
antimetastatic effects. Although the exact antitumor mechanism of action of lenalidomide is
unknown, a number of mechanisms are postulated to be responsible for lenalidomides activity
against hematological malignancies. Lenalidomide has been demonstrated to possess
anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced endothelial
cell migration, due at least in part to inhibition of Akt phosphorylation response to bFGF.
In addition, lenalidomide has a variety of immunomodulatory effects. Lenalidomide stimulates
T cell proliferation, and the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta
and IL-6 and modulates IL-12 production. Up-regulation of T cell derived IL-2 production is
achieved at least in part through increased AP-1 activity. The increased levels of
circulating cytokines augment natural killer cell number and function, and enhance natural
killer cell activity.

Clinical activity of lenalidomide in various lymphoma subtypes has been documented in
several phase II trials. In patients with relapsed/refractory mantle cell lymphoma, the
overall response rate (ORR) was 53% with PFS at 12 month 40%. In patients with aggressive
lymphoma (mostly diffuse large B-cell subtype), the ORR was 35% with PFS at 12 months about
25%. There also have been many case reports of patients who achieved durable complete
response to lenalidomide after failing multiple cytotoxic chemotherapy regimens.

Most clinical studies of lenalidomide in patients with active lymphoma used dose of 25 mg
daily on days 1-21 in 28 day cycle which is the dosing recommended for active multiple
myeloma. While lenalidomide was well tolerated in the lymphoma studies, the dose of 25 mg is
associated with high risk of developing cytopenias including grade 3 neutropenia in 25-40%
of patients and thrombocytopenia in 12-20%. Our group reported that low dose lenalidomide at
10 mg daily (continuous dosing) in combination with weekly dexamethasone can be effective in
patients with active relapsed/refractory low grade and mantle cell lymphomas. The continuous
dose of 10 mg daily has also been used in treatment of chronic lymphocytic leukemia/small
lymphocytic lymphoma.

Lenalidomide has been used as maintenance therapy in multiple myeloma, but there is limited
experience with maintenance lenalidomide in lymphoma patients. Two large clinical trials of
maintenance lenalidomide in patients with multiple myeloma after ASCT have shown benefit in
PFS over observation. These studies used daily dosing of lenalidomide at 10 mg or 15 mg
which were well tolerated over long term administration.

Revlimid® (lenalidomide) is currently indicated for the treatment of patients with
transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes
associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic
abnormalities. Revlimid® is also approved in combination with dexamethasone for the
treatment of patients with multiple myeloma that have received at least one prior therapy.

The most frequently reported adverse events reported during clinical studies with
lenalidomide in oncologic and non-oncologic indications, regardless of presumed relationship
to study medication include: anemia, neutropenia, thrombocytopenia and pancytopenia,
abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, itching, infections,
sepsis, pneumonia, UTI, Upper respiratory infection, atrial fibrillation, congestive heart
failure, myocardial infarction, chest pain, weakness, hypotension, hypercalcemia,
hyperglycemia, back pain, bone pain, generalized pain, dizziness, mental status changes,
syncope, renal failure, dyspnea, pleural effusion, pulmonary embolism, deep vein thrombosis,
CVA, convulsions, dizziness, spinal cord compression, syncope, disease progression, death
not specified and fractures.

Complete and updated adverse events are available in the Investigational Drug Brochure and
the IND Safety Letters.

Rationale for Treatment in this Setting:

Our previously reported data and similar studies from other institutions indicate that
patients with PET positive lesions after salvage chemotherapy and prior ASCT do very poorly.
In our study, patients with residual PET positive lesions before ASCT had median PFS of 5
months with only 7% of patients without progression at 12 months after ASCT. It can be
speculated that patients with PET positive lesions prior ASCT harbor chemotherapy resistant
lymphoma cells in their tumors. Since the mechanism of action of lenalidomide differs from
traditional cytotoxic chemotherapy, the use of this novel agent in this group of patients is
an attractive concept. The immunomodulary properties of lenalidomide over the maintenance
period of 24 months could improve the overall outcome of patients following ASCT. Since
there is a valid concern that lenalidomide could cause severe cytopenias when used early
after ASCT, we proposed to administer dose 10 mg of lenalidomide daily with an option of
dose modification to 5 mg daily according to previously defined toxicity criteria. The daily
maintenance dosing of lenalidomide at 10 mg has been used in patients with multiple myeloma
after ASCT and improved PFS in two large randomized trials.

Inclusion Criteria:

SCREENING STEP A:

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

2. Aged greater or equal to 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 diagnosis of lymphoma (including diffuse large B-cell, mantle cell,
follicular, marginal zone, peripheral T cell, small lymphocytic lymphoma with large
cell transformation, and Hodgkin lymphomas).

5. Completion of at least 2 cycles of salvage chemotherapy, with pre-ASCT PET/CT imaging
showing PET positive residual lesion(s) (SUV greater than 2.5).

6. Disease free of other malignancies for greater or equal to 2 years with exception of
basal cell and squamous cell carcinomas of the skin, or carcinoma in situ of the
cervix or breast.

NOTE: Patients who successfully complete high dose-chemotherapy and ASCT will proceed to
Screening Step B, provided that they achieve hematologic recovery within 100 days of ASCT
(see below).

SCREENING STEP B (performed between days 28-100 post-ASCT):

1. Completion of high-dose chemotherapy with ASCT.

2. Hematologic recovery at 28-100 days after ASCT (defined as ANC greater or equal to
1,000 and platelet count greater or equal to 60,000).

3. All study participants must be registered into the mandatory RevAssist® program, and
be willing and able to comply with the requirements of RevAssist®.

4. ECOG performance status of less than or equal to 2 at study entry (see Appendix B).

5. Patients undergoing planned consolidative radiation therapy must be finished with the
therapy by day 100 after ASCT.

6. Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 to 14 days and
again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions
must be filled within 7 days) and must either commit to continued abstinence from
heterosexual intercourse or begin TWO acceptable methods of birth control, one highly
effective method and one additional effective method AT THE SAME TIME, at least 28
days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy
testing. Men must agree to use a latex condom during sexual contact with a FCBP even
if they have had a successful vasectomy. See Appendix: Risks of Fetal Exposure,
Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

7. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (warfarin
or low molecular weight heparin may be used for patients intolerant of aspirin or at
the discretion of the treating physician).

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 (lactating females must agree not to breast feed
while taking lenalidomide).

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 initiating treatment
with lenalidomide.

5. Known hypersensitivity to thalidomide.

6. The development of erythema nodosum, a blistering or desquamating rash, while taking
thalidomide or similar drugs.

7. Any prior use of lenalidomide.

8. Concurrent use of other anti-cancer agents or therapies during study treatment.

9. Known seropositive for or active viral infection with human immunodeficiency virus
(HIV) or hepatitis B virus (HBV). Patients who are seropositive because of hepatitis
B virus vaccine are eligible.