Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV Diffuse Large B-cell Lymphoma

This phase I/Ib trial studies the side effects and best dose of carfilzomib when given together with rituximab, ifosfamide, carboplatin, and etoposide and to see how well it works in treating patients with stage I-IV diffuse large B-cell lymphoma that has returned (relapsed) or that has not responded to treatment (refractory). Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, also work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving carfilzomib with rituximab, ifosfamide, carboplatin, and etoposide may be a better treatment for diffuse large B-cell lymphoma.

PRIMARY OBJECTIVES: * I. To estimate the maximum tolerated dose (MTD) and examine the dose-limiting toxicities of carfilzomib when administered in combination with rituximab, ifosfamide, carboplatin, and etoposide (C-R-ICE) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). (Phase I) * II. To assess the toxicity of dose regimen using the Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 4.0). (Phase I) * III. To evaluate the safety of carfilzomib (given at maximum tolerated dose \[MTD\] as determined in Phase I of this study) in combination with R-ICE salvage therapy in relapsed/refractory DLBCL patients. (Phase Ib) * IV. To achieve an overall response rate (complete response \[CR\] and partial response \[PR\]) of 70% after 3 cycles of C-R-ICE in patients between the ages of 18 to 75 with relapsed/refractory cluster of differentiation (CD)20-positive DLBCL previously treated with rituximab-based immunochemotherapy (e.g., rituximab, cyclophosphamide, doxorubicin, vincristine \[vincristine sulfate\], and prednisone \[R-CHOP\], rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin \[REPOCH\], rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine \[R-HyperCVAD\], etc.) induction. (Phase Ib) SECONDARY OBJECTIVES: * I. To determine the feasibility of successful mobilization of autologous stem cells (i.e., minimum of 2 x 10\^6 CD34+ cells/kg should be collected) to be used for autologous stem cell transplant (ASCT) * II. To determine toxicities associated with C-R-ICE salvage therapy * III. To determine the time to progression (TTP), progression-free survival (PFS), and overall survival (OS) followed by ASCT; disease-free survival in CR patients. * IV. To determine the pharmacokinetics/pharmacodynamics relationship between carfilzomib's degree of proteasome inhibition and response rate along with the time course of thrombocytopenia * V. To study differences in clinical outcomes between germinal center B-cell-like (GCB) and non-GCB relapsed/refractory DLBCL following therapy with carfilzomib and R-ICE * VI. Correlative translational research studies to include: phenotypic/genotypic analysis and functional activity (i.e., antibody-dependent cellular cytotoxicity \[ADCC\] and complement-mediated cytotoxicity \[CMC\]) of patient's peripheral blood mononuclear "effector" cells (PBMC), as well as ex vivo analysis of sensitivity of primary tumor cells to various combinations of carfilzomib versus bortezomib +/- rituximab; enzymatic assay for chymotrypsin-like activity to determine the degree of proteasome inhibition in primary DLBCL patient samples and patient PBMC specimens; explorative analysis to identify potential factors predictive of response to therapy will be performed. OUTLINE: This is a phase I, dose-escalation study of carfilzomib, followed by a phase Ib study. Patients receive carfilzomib intravenously (IV) over 10-30 minutes on days 1, 2, 8, and 9; rituximab IV over 3-8 hours on day 3; etoposide IV over 1 hour on days 4-6; carboplatin IV over 1 hour on day 5; and ifosfamide IV over 24 hours on day 5. Treatment repeats every 21-28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 2 years, and then annually for 2 years.