Everolimus, Bortezomib and/or Rituximab in Patients With Relapsed/Refractory Waldenstrom's Macroglobulinemia

• Phase II Arm B: To assess the depth of response to the combination of everolimus/bortezomib/rituximab. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Phase I: To determine the safety and maximum tolerated dose (MTD) of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Phase II Study Arm A: To assess the depth of response to the combination of everolimus/rituximab. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• To assess the safety of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab in the Phase II study. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• To assess overall response rate, duration of response, time to progression, and progression free survival in these patients in the Phase II study. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• To identify molecular regulators of response/resistance using tumor samples pre and post-treatment. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

The purpose of this research study is to test the safety of the combination of everolimus, rituximab and bortezomib. Everolimus is a drug that works by preventing cells in your body from growing and dividing. Information from basic and other clinical research suggests that everolimus may also inhibit tumor growth in people with relapsed or refractory lymphoma. The FDA has approved everolimus for the treatment of multiple myeloma, a cancer that is closely related to Waldenstrom's Macroglobulinemia. Rituximab is approved by the FDA for the treatment of non-Hodgkin's lymphoma, which included Waldenstrom's Macroglobulinemia.

• Since we are looking for the highest dose of a combination of study drugs that can be administered safely without severe or unmanageable side effects in participants that have Waldenstrom's Macroglobulinemia, not everyone who participates in this research study will receive the same combination of study drugs or the same dose of the study drug.
• In this research study every 4 week (28 day) period is called a cycle. While on study, participants will receive up to 6 cycles of combination treatment followed by everolimus alone for up to 2 years.
• Participants will take everolimus by mouth everyday, and will receive rituximab intravenously on days 1, 8, 15 and 22 on Cycle 1 and Cycle 4 only. If the participant receives bortezomib, it will be given intravenously on days 1, 8 and 15 of every cycle.
• After the third cycle, tests will be done to see how the disease is responding to the study treatment. If the disease stays the same, or is helped, the participant will continue to get the combination of study treatment for another 3 cycles.

• Drug: Everolimus
  Taken orally on a daily basis
  Other Name: RAD001
• Drug: Rituximab
  Given intravenously on days 1, 8, 15 and 22 of Cycle 1 and Cycle 4 only
  Other Name: Rituxan
• Drug: Bortezomib
  Given intravenously on days 1, 8 and 15 of every cycle
  Other Names:

  • Velcade
  • PS-341

Inclusion Criteria:

• 18 years of age or older
• Patients must have received prior therapies for their WM and have relapsed or refractory WM requiring therapy. Any number of prior therapies is acceptable. Patients must not have been refractory to rituximab. The last rituximab must be at least 3 months prior to the start of treatment. Prior treatment with bortezomib and/or everolimus is permitted.
• Measurable monoclonal IgM protein in the serum OR measurable quantitative immunoglobulin M (serum IgM).
• Lymphoplasmacytic cells in the bone marrow during any previous bone marrow biopsy.
• CD20 positive disease based on any previous bone marrow immuno-histochemistry or flow cytometric analysis performed prior to enrollment.
• ECOG Performance Status 0, 1 or 2
• Laboratory values as outlined in the protocol
• Capable of swallowing intact study medication tablets
• Life expectancy of 12 weeks or greater

Exclusion Criteria:

• Uncontrolled infection
• Other active malignancies
• Cytotoxic chemotherapy 3 weeks or less, or biologic or targeted novel therapy 2 weeks or less, or corticosteroids 2 weeks or less, or radiation therapy 2 weeks or less, or any ancillary treatment considered investigation 2 weeks or less, prior to registration. Patients may be receiving chronic corticosteroids if they are being given for disorders other than WM.
• Pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception throughout the trial and for 8 weeks after the last dose of study treatment.
• Known to be HIV positive, or Hepatitis B positive. If the status of HIV is not known and patients are not at risk, then patients will not be specifically tested for HIV. Patients will be tested for Hepatitis B at time of screening. If patients are not considered high risk and have been vaccinated at an earlier date, results of the test are not required at the time of registration. For patients that are high risk, results must be obtained prior to registration.
• Patient has Grade 2 or higher peripheral neuropathy within 14 days of enrollment
• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection fo basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
• Severely impaired lung function
• Uncontrolled diabetes
• Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
• Impairment of gastrointestinal function or gastrointestinal disease
• Patients with active, bleeding diathesis
• Myocardial infarction within 6 months prior to enrollment or had NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• Hypersensitivity to everolimus or other rapamycins or to is excipients
• Patients who may need or are receiving live vaccines for immunization
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study

• Novartis
• Millennium Pharmaceuticals, Inc.