A Randomized Phase I/II Study of Bortezomib, Rituximab, Dexamethasone and Temsirolimus in Patients With Relapsed Waldenstrom s Macroglobulinemia and Relapsed/Refractory Mantle Cell, Follicular, Marginal Zone or Small Lymphocytic Lymphomas (Phase I), and Untreated/Relapsed Waldenstrom s Macroglobulinemia (Phase II)

Location:

Rochester, Minn.

Trial status:

Open for Enrollment

Why is this study being done?

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of temsirolimus in combination with bortezomib, rituximab, dexamethasone in patients with relapsed Waldenstrom's Macroglobulinemia and relapsed/refractory mantle cell, follicular, marginal zone or small lymphocytic lymphoma. (Phase I) II. To evaluate whether the addition of temsirolimus to the regimen of bortezomib, rituximab, dexamethasone improves progression-free survival in patients with previously untreated or relapsed Waldenstrom's Macroglobulinemia. (Phase II) SECONDARY OBJECTIVES: I. To define and describe the toxicities of temsirolimus in combination with bortezomib, rituximab, and dexamethasone. (Phase I) II. To evaluate time to progression of bortezomib, rituximab, dexamethasone +/- temsirolimus in patients. (Phase II) III. To evaluate major and minor response by 6 cycles of therapy of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) IV. To evaluate time to response and duration of response of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) V. To evaluate toxicity of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) VI. To evaluate time to next therapy of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) VII. To evaluate overall survival of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Phase II) VIII. To describe treatment-related fatigue, physical and functional well-being during and after treatment. (Phase II) IX. To compare the change in treatment related fatigue, physical and functional well-being over 6 cycles of bortezomib, rituximab, dexamethasone +/- temsirolimus. (Quality of Life) X. To prospectively assess health-related quality of life longitudinally (pre-treatment to 3 year follow-up assessment) among trial participants. (Quality of Life) XI. To describe treatment-related peripheral neuropathy associated with bortezomib neurotoxicity. (Quality of Life) OUTLINE: This is a multicenter, phase I, dose-escalation study of temsirolimus followed by a randomized phase II study. PHASE I: Patients receive temsirolimus intravenously (IV) over 30-60 minutes on days 1, 8, 15, and 22; rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses 1 and 4 only); and bortezomib IV or subcutaneously (SC) and dexamethasone orally (PO) on days 1, 8, and 15. Courses repeat every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive rituximab IV over 30-60 minutes on days 1, 8, 15, and 22 (of courses 1 and 4 only) and bortezomib IV or SC and dexamethasone PO on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and rituximab, bortezomib, and dexamethasone as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for 5 years.

Who is eligible to participate?

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 >= 75,000mm^3 - Neutrophils >= 1,000mm^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

Last updated:

6/30/2014

NCT ID:

NCT01381692

IRB Number:

11-005804