Everolimus (RAD001) in Primary Therapy of Waldenstrom's Macroglobulinemia

• To assess the overall response and major response rates of RAD001 in patients with previously untreated WM. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To assess the safety and tolerability of RAD001 in symptomatic patients with previously untreated WM. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• To determine time to progression and time to next therapy with single agent RAD001 therapy in previously untreated WM. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

The purpose of this research study is to determine the safety of RAD001(Everolimus) and the highest dose of this drug that can be given to people safely. RAD001(Everolimus) is a drug that works by preventing cells in the body from growing and dividing. Information from basic and Phase I clinical research studies suggests that RAD001 also may help to prevent tumor growth in people with relapsed or refractory lymphoma.

• Participants will take RAD001 orally once a day in the morning. Each treatment cycle lasts for four weeks. Participants will receive up to 48 cycles of treatment.
• During each cycle, participants will be asked to visit the clinic for scheduled tests and exams. They will visit the clinic on the first day of each of the first three cycles, and then once every 3 cycles. During the visits, participants will have a physical exam and blood tests.. Participants may also have CT scans of the chest, abdomen and pelvis as well as a bone marrow aspirate and biopsy.

Inclusion Criteria:

• 18 years of age or older
• Adequate liver and renal function as outlined in the protocol
• Fasting serum cholesterol 300mg/dl or less OR 7.75mmol/L or less AND fasting triglycerides 2.5 x institutional ULN or less.
• Clinicopathological diagnosis of Waldenstrom's macroglobulinemia as defined by consensus panel of the Second International Workshop on Waldenstrom's macroglobulinemia
• No previous therapy for WM
• Measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level of 2 times the upper limit of each institution's normal value or greater is required
• ECOG Performance status of 0-2
• Patients must have a life expectancy of at least 3 months
• Baseline platelet and absolute neutrophil as outlined in the protocol
• INR and PTT 1.5 x normalized ratio or less
• A male subject agrees to use an acceptable method for contraception for the duration of study and for 8 weeks after the last dose of the study drug
• Female subject either post-menopausal or surgically sterilized or willing to use acceptable methods of birth control for the duration of the study and for 8 weeks after the last dose of study drug

Exclusion Criteria:

• Patients experiencing symptomatic hyperviscosity and requiring plasmapheresis. This includes any patient who, in the judgement of the investigator requires urgent response and will not be eligible. These patients have hyperviscosity which includes serum IgM levels of 5000 mg/dL or greater. Symptoms may include nosebleeds, visual complications, fatigue, headaches, confusion, etc.
• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery or patients that may require major surgery during the course of the study.
• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
• Patients should not receive any immunization with attenuated live vaccines within one week of study entry or during study period.
• Patients who have had any severe and/or uncontrolled medical conditions or other conditions that would affect their participation in the study.
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001.
• Female patients that are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods.
• Patients with known hypersensitivity to RAD001 or other rapamycins or to its excipients
• Patients with other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell of the skin
• Patients with known history of HIV seropositivity
• History of noncompliance to medical regimens
• Patients unwilling to or unable to comply with the protocol

• Brigham and Women's Hospital
• Novartis