Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV 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.