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.

Inclusion Criteria:

• Histological confirmation of relapsed/refractory CD20 positive diffuse large B-cell lymphoma

• Ann Arbor stage I to stage IV DLBCL at the time of relapsed/refractory disease to be eligible

• Measurable or assessable disease is required; measurable tumor size (at least one node measuring 2.25 cm^2 in bidimensional measurement) per computed tomography (CT) scan, other radiological study, and/or physical exam

• Patients must have received at least 1 prior rituximab-based immunochemotherapy (e.g., R-CHOP, R-EPOCH, etc.)

• >= 2 weeks since major surgery

• Patients must not have any significant toxicity associated with prior surgery, radiation therapy, chemotherapy, or immunotherapy, per principal investigator (PI) discretion

• Life expectancy >= 3 months

• Karnofsky score (KS) >= 50

• Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3.5 times the upper limit of normal within 14 days prior to starting therapy

• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L within 14 days prior to starting therapy*

• Hemoglobin >= 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)*

• Platelet count >= 50 x 10^9/L (>= 20 x 10^9/L if lymphoma involvement in the pretreatment bone marrow is found) within 14 days prior to starting therapy*

• *Note: If patient has cytopenias due to bone marrow involvement, these requirements are not applicable

• Serum creatinine of =< 1.5 mg/dL; if creatinine > 1.5 mg/dL creatinine clearance must be > 60 mL/min within 7 days prior to treatment either measured or calculated using a standard Cockcroft and Gault formula

• Written informed consent in accordance with federal, local, and institutional guidelines

• Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Male subjects must agree to practice contraception

• No known hypersensitivity to murine products

• Patients must have normal baseline cardiac function based upon echocardiogram or gated blood pool scan (multigated acquisition scan [MUGA]) with an ejection fraction >= 50%

• Patients who test positive for hepatitis C (HepC) antibodies (Ab) are eligible provided all of the following criteria are met: bilirubin =< 2 x upper limit of normal; ALT/AST =< 3 x upper limit of normal; and clinical evaluation to rule out cirrhosis

• Specific guidelines will be followed regarding inclusion of relapsed/refractory DLBCL based on hepatitis B serological testing as follows:

  • Hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb) negative, hepatitis B surface antibody (HBsAb) positive patients are eligible

  • Patients who test positive for HBsAg are ineligible (regardless of other hepatitis B serologies)

  • Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status) should have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing done and protocol eligibility determined as follows:

    • If HBV DNA is positive, the subject will be excluded from the study
    • If HBV DNA is negative, the subject may be included but must undergo at least every 2 months HBV DNA polymerase chain reaction (PCR) testing from the start of treatment throughout the duration the treatment course

Exclusion Criteria:

• Patients with non-Hodgkin lymphoma (NHL) other than DLBCL; including "transformed" DLBCL
• Known to be seropositive for human immunodeficiency virus (HIV); an HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk
• Positive serology for HBV defined as a positive test for HBsAg; in addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HepB DNA test will be performed and if positive the subject will be excluded
• Patients with symptomatic brain involvement
• Peripheral neuropathy of grade 2 or greater severity as defined by the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0; patients with grade 2 or higher (NCI-Common Toxicity Criteria [CTC]) neuropathy
• Myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemia
• Uncontrolled intercurrent illness including, but not limited to, active infection, poorly controlled hypertension, diabetes mellitus or other serious medical or psychiatric conditions that could interfere with adherence to or completion of this study
• Pregnant or breastfeeding
• Patient has received other investigational drugs within 4 weeks before enrollment
• Chemotherapy within 3 weeks of the first scheduled study treatment
• Less than 2-years disease free from another primary malignancy (other than squamous or basal cell carcinoma of the skin, "in-situ" carcinoma of the cervix or breast, superficial bladder carcinoma, or previously treated localized prostate cancer with normal prostate-specific antigen [PSA] levels); patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, are considered by their physician to be at less than 30% risk of relapse and at least 2 years have lapsed
• Major surgery, other than diagnostic surgery, within 2 weeks
• Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
• Medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent)
• Prior high-dose chemotherapy (HDC)-ASCT
• Active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating DLBCL at the time of registration to this study is not exclusion for study enrollment