Bendamustine Hydrochloride, Ofatumumab, Carboplatin, and Etoposide in Treating Patients with Relapsed or Refractory Aggressive B-cell Lymphoma

Inclusion Criteria

• Patients with histologically confirmed aggressive B-cell lymphoid malignancy, such as diffuse large B cell lymphoma (DLBCL), including primary mediastinal large B cell lymphoma, T cell rich B cell lymphoma, "double hit" DLBCL, mantle cell lymphoma, any transformed low grade B cell lymphomas or grade 3 follicular lymphoma (grade 3a or 3b) who were refractory to rituximab-cyclophosphamide-hydroxydaunorubicin (doxorubicin hydrochloride)-Oncovin (vincristine sulfate)-prednisone (R-CHOP)-like or any anthracycline based chemotherapy or relapsed after at least one prior combination chemotherapeutic regimen and who are deemed candidates for a salvage type chemotherapy * Relapsed disease: ** Progressive disease after a CR for at least 28 days; progression will be defined according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007) * Refractory disease: ** Subjects must meet one of the following criteria: *** Persistent or progressive lymphoma with a CR of < 28 days duration or with a PR of any duration; subjects must have received at least 3 cycles of RCHOP-like or any anthracycline base chemotherapy or at least 2 full cycles of hyperfractionated cyclophosphamide-vincristine sulfate-Adriamycin (doxorubicin hydrochloride)-dexamethasone (HyperCVAD)-like chemotherapy *** Persistent lymphoma and stable disease after at least 2 cycles of RCHOP-like or any anthracycline base chemotherapy or at least 1 full cycle of HyperCVAD-like chemotherapy (part A and B) *** Progressive disease despite at least 1 cycle of RCHOP-like or any anthracycline base chemotherapy or at least 1 cycle (part A or A and B) of HyperCVAD-like chemotherapy
• Measurable disease, defined by the revised lymphoma criteria (Cheson 2007)
• Absolute neutrophil count >= 1,500
• Platelet count >= 75,000, unless due to underlying lymphoma
• Left ventricular ejection fraction estimated by multi gated acquisition scan (MUGA) scan or 2-dimensional (2D)-echocardiogram of at least 45% cardiology consult is recommended prior to enrollment if a history of coronary artery disease, congestive heart failure (CHF) with estimated left ventricular ejection fraction (LVEF) of < 50% or clinically significant arrhythmia
• Estimated glomerular filtration rate (GFR) must be >= 50 mL/min
• Serum bilirubin =< 1.5 x upper limit of normal (ULN) unless deemed elevated secondary to lymphoma involvement of the liver or known Gilbert's syndrome
• Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 x ULN; unless elevated secondary to lymphoma involvement of the liver
• Alkaline phosphatase =< 2.5 x ULN; unless elevated secondary to lymphoma involvement of the liver
• Performance status of Eastern Cooperative Oncology Group (ECOG) 0-2
• Both potentially autologous stem cell transplant (autoSCT) or allogeneic stem cell transplant (alloSCT) candidates and those who are not transplant candidates are eligible for the study
• Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent
• Female patients of childbearing potential must have a negative serum pregnancy test within 3 days prior to enrollment
• Male and female patients of reproductive potential must use an effective contraceptive method during the study and for a minimum of 1 year after the after study treatment
• Must be able to comply with study and follow up requirements

Exclusion Criteria

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol; concomitant use of corticosteroids is permitted as clinically indicated
• Use of investigational agents within 4 weeks prior to enrollment
• Any anticancer therapy within 3 weeks before study entry; this exclusion does not apply to corticosteroid therapy; the patient must have recovered from all acute toxicities from any previous therapy
• Radioimmunotherapy (i.e. Zevalin) within 8 weeks of enrollment
• Prior treatment with anti-CD20 monoclonal antibody or alemtuzumab within 4 weeks prior to start of therapy
• Autologous stem cell rescue within 12 weeks before study enrollment or those who underwent allogeneic stem cell transplant within one year of enrollment
• Known leptomeningeal or parenchymal brain involvement with lymphoma unless in complete remission after treatment for at least 12 weeks with negative cerebrospinal fluid (CSF) cytology within 2 weeks; prophylaxis of central nervous system (CNS) disease using intrathecal or intraventricular dosing of cytotoxic regimens is permitted and should be performed according to the discretion of the treating physician
• History of serious organ dysfunction or disease involving the heart, kidney, liver or other organ system that may place the patient at undue risk to undergo treatment
• Systemic fungal, bacterial, viral, or other infection if not controlled; defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment (may be enrolled if controlled on treatment)
• Significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results
• Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms
• Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (New York Heart Association [NYHA] III-IV), and arrhythmia unless controlled by therapy, with the exception of extrasystoles or minor conduction abnormalities
• Other malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions: treated non-melanoma skin cancer, any in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed; organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated, or radical prostatectomy or definitive prostate irradiation has been performed
• Positive test for the human immunodeficiency virus (HIV), unless undetectable viral load within 3 months of enrollment (HIV ribonucleic acid [RNA] less than 48 copies/mL) on highly active antiretroviral therapy (HAART) therapy
• Positive serology for hepatitis B (HB) defined as a positive test for hepatitis B surface antigen (HBsAg); patients with prior history of hepatitis B infection, but immune, with only immunoglobulin (Ig)G hepatitis core antibody + (HBcAb +) must be checked for hepatitis B virus titers by polymerase chain reaction (PCR) and if the viral load is undetectable may be enrolled; these patients must receive anti-viral prophylaxis, such as lamivudine 100 mg orally (PO) daily (or an equivalent) starting at least one week prior to cycle 1 and continued through the completion of treatment and for 9 months after the last dose of ofatumumab; hepatitis B virus titers by quantitative PCR and HBsAg should be checked every month (+/- 1 week) while on therapy and every 3 months (+/- 1 month) thereafter for 9 months after the last ofatumumab dose; in the event of an early termination of the clinical trial for any reason, a treating physician will be determining the frequency and the length of follow up studies of hepatitis B virus titers and HBsAg status; it is recommended that the patient remains on prophylactic lamivudine or an equivalent, as above, regardless of whether the study was continued or terminated; in addition, if appropriate consultation with a hepatologist should be obtained
• Positive serology for hepatitis C (HC) defined as a positive test for HC antibody (Ab) if confirmed by HC recombinant immunoblot assay (RIBA) immunoblot assay (for positive HCAb reflexively perform a HC RIBA immunoblot assay on the same sample)
• Pregnant or lactating women