Ensayos clínicos

Inclusion Criteria:

• Histologically proven diagnosis
• For phase I portion (Arm A, B, C and D), patients must have of one of the following:
  • Relapsed Waldenstrom's macroglobulinemia
  • Relapsed/refractory mantle cell lymphoma; previous treatment with at least one standard regimen and no longer responsive to that regimen
  • Relapsed/refractory follicular lymphoma; previous treatment with at least one standard regimen and no longer responsive to that regimen
  • Relapsed/refractory marginal zone lymphoma; previous treatment with at least one standard regimen and no longer responsive to that regimen
  • Relapsed/refractory small lymphocytic lymphoma; previous treatment with at least one standard regimen and no longer responsive to that regimen
• For phase II portion (Arm E and F), patients must have a diagnosis of symptomatic Waldenstrom's macroglobulinemia, either untreated or relapsed, confirmed by the presence of all of the following:
  • Bone marrow lymphoplasmacytosis with:
    • ≥ 10% lymphoplasmatic cells (measured within 28 days prior to registration) OR
    • Aggregates or sheets of one of the following: lymphocytes, plasma cells or lymphoplasmacytic cells on the bone marrow biopsy (measured within 28 days prior to registration)
  • Measurable disease defined as a quantitative immunoglobulin M (IgM) monoclonal protein of ≥ 1000 mg/dL obtained within 28 days prior to registration
  • Cluster of differentiation 20 (CD20) positive bone marrow or lymph node by immunohistochemistry or flow cytometry obtained within 28 days prior to registration
  • Lymph node biopsy must be done ≤ 28 days prior to registration if used as an eligibility criterion for study entry
  • Serum protein electrophoresis (SPEP) is required to be performed within 28 days prior to registration
• Additional requirements for Waldenstrom's macroglobulinemia (WM) patients (phase I and II):
• In addition to measurable disease, patients must have symptomatic disease defined by one or more of the following:
  • Laboratory studies defining eligibility (hemoglobin [Hgb], platelet count, viscosity) must have been obtained within 28 days prior to registration; if more than one test was obtained, the most recent one will be utilized
  • Hemoglobin ≤ 11 g/dL
  • Hyperviscosity syndrome or measured viscosity level of ≥ 4 centipoise
    • NOTE: for these patients it is strongly recommended that they undergo therapeutic plasmapheresis prior to initiation of therapy
  • Platelet count < 100,000/mm^3
  • Symptomatic lymphadenopathy, splenomegaly, or hepatomegaly
  • Constitutional symptoms including fever, night sweats, or unexplained weight loss (at least 10% of body weight in < 6 months)
  • Symptomatic cryoglobulinemia
• Additional requirements for WM patients (phase I):
  • Patients must have received previous treatment with at least one standard regimen and are no longer responsive to that regimen
  • There must have been at least 21 days since the last regimen and patient must have recovered from any previous treatment-related toxicity to ≤ grade 1
• Additional requirements for WM patients (phase II):
  • For previously treated patients, no more than 4 prior regimens are allowed
  • If last regimen is with rituximab there must have been at least 6 months since last rituximab dose, and if without rituximab there must have been at least 3 months since last regimen
• For all phase I patients, there must have been at least 21 days since last regimen and any previous non-hematologic treatment related toxicity must have resolved to ≤ grade 1
• Patients must not be receiving concurrent steroids > 10 mg prednisone (or equivalent) per day
• Prior irradiation is allowed if ≥ 28 days prior to registration have elapsed since the date of last treatment
• Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x institutional upper limit of normal (ULN), within 28 days prior to registration
  • NOTE: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication; patients cannot be enrolled if they do not meet these criteria on or off lipid lowering medication; patients must start lipid lowering medication and cholesterol and triglycerides must be below said levels before study entry
• Patients must not have had prior exposure to mammalian target of rapamycin (m-TOR) inhibitors (sirolimus, temsirolimus, everolimus)
• Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and sexually active males must use an accepted and effective method of contraception throughout the study and for 8 weeks following discontinuation of everolimus
• Patients must have no history of prior malignancy except for adequately treated basal cell or squamous cell skin cancer or in-situ cervical cancer; the patient may also have had other cancer for which the patient was curatively treated with surgery alone and from which the patient has been disease free for ≥ 5 years
• Platelets ≥ 75,000 mm^3
• Neutrophils ≥ 1,000 mm^3
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 2.5 x institutional ULN
• Direct bilirubin ≤ 1.5 mg/dL
• Serum creatinine ≤ 2.5 mg/dL
• Patients must be tested for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) within 28 days of registration and will not be eligible if found to be positive
• Patients must not have any severe and/or uncontrolled medical condition or other conditions that could affect their participation in the study, including, but not restricted to:
  • Symptomatic congestive heart failure of New York Heart Association class III or IV
  • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 3 months of start of study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant heart disease
  • Severely impaired lung function as defined as spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for Hgb) that is < 50% of the normal predicted value and/or oxygen (O2) saturation < 88% at rest on room air
  • Active (acute or chronic) or uncontrolled severe infections
• Patients must have Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging Network (ACRIN) performance status of ≤ 2
• Patients must not have grade 2 or higher neuropathy
• Patients must not have concurrent use of angiotensin-converting enzyme (ACE) inhibitors (angioedema), and no concurrent use of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers and inhibitors