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A Phase 2 Trial of Daily Alternating Thalidomide and Lenalidomide Plus Rituximab (ThRiL) for Patients With Previously Treated Waldenstrom Macroglobulinemia

Phase 2
18 Years
Open (Enrolling)
Waldenstrom Macroglobulinemia

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Trial Information

A Phase 2 Trial of Daily Alternating Thalidomide and Lenalidomide Plus Rituximab (ThRiL) for Patients With 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

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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of patients who demonstrate a response (complete, partial, minor) to treatment

Outcome Description:

Response criteria for subjects with WM is based upon the Consensus Panel Recommendations from the Third International Workshop on Waldenstrom Macroglobulinemia. Overall response rate (CR + PR + MR) measured at time of best response.

Outcome Time Frame:

Approximately 24 months

Safety Issue:


Principal Investigator

Peter Martin, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Weill Medical College of Cornell University


United States: Food and Drug Administration

Study ID:




Start Date:

June 2012

Completion Date:

June 2016

Related Keywords:

  • Waldenström Macroglobulinemia
  • WM
  • Waldenstrom Macroglobulinemia



Weill Cornell Medical College New York, New York  10021