Thalidomide, Lenalidomide, and Rituximab for Previously Treated Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinemia (WM) is an incurable B-cell lymphoproliferative disorder
characterized by expansion of malignant B-lymphocytes and excessive production of monoclonal
IgM. The survival and proliferation of the neoplastic WM cells is highly dependent on signals
from the microenvironment. Thalidomide and lenalidomide are immunomodulatory agents with
single agent activity in WM. Their use is limited by significant toxicities, including tumor
flare (thalidomide and lenalidomide); sedation, constipation, and neuropathy (thalidomide);
and cytopenias (lenalidomide). Alternating doses of thalidomide and lenalidomide may
alleviate the toxicities, while preserving efficacy since the agents have non-overlapping
toxicities and yet similar hypothesized mechanisms of action. Additionally, starting at a
lower dose of lenalidomide than previously studied in WM may allow for improved tolerability.
A pilot study of daily alternating therapy in subjects with chronic lymphocytic leukemia
demonstrated that the two agents could be combined with non-overlapping toxicity. This phase
II study aims to evaluate the efficacy and safety of daily alternating thalidomide and
lenalidomide plus rituximab (ThRiL) in subjects with previously treated WM.

Subjects will receive thalidomide 50 mg every other day (i.e., every odd day: days 1, 3, 5,
7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27 of a 28 day cycle) alternating with lenalidomide on
every other day (i.e., every even day: days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 &
28 of a 28 day cycle), dosed based upon stepwise incremental dosing. Rituximab 375 mg/m2 will
be administered on days 1, 8, 15 and 22 starting with Cycle 1 and then again on the same
weekly x 4 schedule every 6th cycle thereafter (Cycles 7, 13, 19, etc).

Inclusion Criteria:

- Histologically confirmed diagnosis of WM

- At least one prior systemic therapy

- Measurable disease, defined as quantifiable monoclonal IgM > 1000 mg/dL

- Active disease requiring therapy defined as at least one of the following five
criteria:

1. Rising IgM

2. Hemoglobin < 20 g/dL

3. Platelet count < 100 x 109/L

4. Symptomatic or bulky lymphadenopathy or organomegaly

5. Systemic manifestations of WM, including hyperviscosity, neuropathy, amyloidosis,
cryoglobulinemia, B symptoms.

- note: subjects with symptomatic hyperviscosity or a serum viscosity of > 3.5 CP are
eligible but should undergo plasmapheresis prior to initiation of treatment

- Understand and voluntarily sign an informed consent form

- Age >18 years at the time of signing the informed consent form

- Able to adhere to the study visit schedule and other protocol requirements

- ECOG performance status ≤ at study entry

- Laboratory test results within these ranges:

1. Absolute neutrophil count ≥ 1000/mm³

2. Platelet count ≥ 50,000/mm³

3. Creatinine clearance of ≥ 30 mL/min by Cockroft-Gault formula.

4. Total bilirubin ≤ 1.5 times the ULN, unless abnormality is the result of
Gilbert's disease or the result of the WM

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

- Disease free of prior malignancies for ≥ 2 years with exception of curatively treated
basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma "in situ" of
the cervix or breast.

- All study participants must be registered into the mandatory RevAssist ® (RASP:
RevAssist ® for Study Participants) and S.T.E.P.S. ® (P-TAP: Protocol Therapy
Assistant Program) programs and be willing and able to comply with the requirements of
RevAssist ® and S.T.E.P.S. ®.

- Females of childbearing potential (FCBP)† must have a negative serum or urine
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to
and again within 24 hours of starting treatment and again within 24 hours before the
first dose of lenalidomide AND thalidomide. FCBP 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 and/or thalidomide. 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. All
subjects must be counseled at a minimum of every 28 days about pregnancy precautions
and risks of fetal exposure. See Appendix A: Risks of Fetal Exposure, Pregnancy
Testing Guidelines and Acceptable Birth Control Methods.

- Able to take aspirin 81 or 325 mg daily or low molecular weight heparin as
prophylactic anticoagulation, unless already on therapeutic anticoagulation. Subjects
intolerant to ASA may use warfarin or low molecular weight heparin.

Exclusion Criteria:

- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from providing informed consent.

- 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.

- Concurrent use of other anti-cancer agents or treatments

- Prior treatment with thalidomide or lenalidomide

- Active serious infection not controlled with antibiotics

- Autoimmune hemolytic anemia or thrombocytopenia requiring treatment

- Known positive for HIV

- Active infection with hepatitis B, defined by being positive for HepBsAg or Hep B DNA
by PCR, or hepatitis C

- Pre-existing peripheral neuropathy > grade 2

- Pregnant or breast-feeding females. (Lactating females must agree not to breast feed
while taking lenalidomide and/or thalidomide).

- Disease transformation to an aggressive histology

- Treatment for WM within the past 28 days

- Hypersensitivity to rituximab