This study will be conducted as a Phase Ib, open-label, non-randomized, single-institution study to evaluate the safety and tolerability of carfilzomib in combination with bendamustine and rituximab in patients with relapsed or refractory NHL and to determine the recommended phase II dose and preliminary efficacy of this combination. The study will have two phases: a dose-escalation phase to determine the maximal tolerated dose of carfilzomib in this combination where participants will be monitored for toxicity, tolerability and response and a dose-expansion phase that will determine the preliminary efficacy in patients with Mantle cell lymphoma or any other disease subtype in which there is a preliminary efficacy signal observed.

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of carfilzomib when combined with bendamustine (bendamustine hydrochloride) and rituximab in patients with relapsed or refractory non-Hodgkin's lymphoma.

SECONDARY OBJECTIVES:

I. To evaluate the preliminary antitumor activity of carfilzomib with bendamustine and rituximab in patients with non-Hodgkin lymphoma (dose escalation) and with specific non-Hodgkin lymphoma (NHL) subtypes (dose expansion).

OUTLINE: This is a dose-escalation study of carfilzomib.

Patients receive carfilzomib intravenously (IV) over 30 minutes twice weekly on days 1, 2, 8, 9, 15, and 16 or weekly on days 2, 9, and 16; bendamustine hydrochloride IV over 60 minutes on days 1 and 2; and rituximab IV over 30-90 minutes on day 9 (course 1 only) and day 1 (subsequent courses). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 weeks for 6 months, every 3 months for 6 months, and then every 6 months thereafter.

Inclusion Criteria:

• Histologically-confirmed B-cell non-Hodgkin's lymphoma (Mantle Cell Lymphoma, Follicular Lymphoma, Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia, Marginal Zone Lymphoma, Diffuse Large B-cell Lymphoma, and Lymphoplasmacytic Lymphoma)
• Must have relapsed or refractory disease after 2 or more prior lines of therapy; 1 line of therapy is allowed, if it included an autologous stem cell transplant and at least 12 weeks have elapsed from Day 0. A line of therapy is defined as a course of therapy that is not interrupted by progressive disease.
• Subjects must have measurable disease of at least 1.5 cm in diameter
• Age ≥ 18 years
• Life expectancy ≥ 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception. FCBP definition: A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months.
• Male subjects must agree to practice contraception for at least 90 days after the last dose of carfilzomib, and must agree not to donate sperm for at least 90 days after the last dose of carfilzomib

Adequate bone marrow function:

• Absolute neutrophil count ≥ 1.0 × 10^9/L
• Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior Cycle 1, Day 1 (subjects may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines)
• Platelet count ≥ 75 × 10^9/L or≥ 50× 10^9/L if there is lymphoma involvement in the bone marrow, independent of platelet transfusion

Adequate hepatic function:

• Serum aspartate aminotransferase (AST) /alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal
• Serum direct bilirubin ≤ 2 mg/dL (unless history of Gilbert's)

Adequate renal function:

• Creatinine clearance (CrCl) ≥ 30 mL/minute, either measured or calculated using a standard formula (eg, Cockcroft and Gault)
• Uric acid If elevated, corrected to within laboratory range prior to dosing

Exclusion Criteria:

• Progressive disease on bendamustine within 6 months of cycle 1, Day 1
• Prior treatment with carfilzomib for lymphoma
• Patient has received other investigational drugs within 21 days prior to Cycle 1, Day 1. Exceptions allowed if greater than four half-lives of the experimental agent ).
• Prior radiation therapy or chemotherapy within 2 weeks prior Cycle 1, Day 1, monoclonal antibody therapy within 4 weeks
• Prior allogeneic transplant
• Active, uncontrolled central nervous system (CNS) involvement by lymphoma
• Pregnant or lactating females
• Major surgery within 14 days prior Cycle 1, Day 1
• Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior Cycle 1, Day 1
• Known human immunodeficiency virus infection
• Active hepatitis C infection (HCV), defined as presence of HCV antibody.
• Unstable angina or myocardial infarction within 6 months prior Cycle 1, Day 1, New York Heart Association (NYHA) Class III or IV heart failure, left ventricular ejection fraction (LVEF) < 40%, uncontrolled angina, history of severe coronary artery disease, history of torsade de pointes, history of symptomatic pulmonary hypertension, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, QTc prolongation >450 msec, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker.
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior Cycle 1, Day 1
• Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
• Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior Cycle 1, Day 1
• Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
• Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
• Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior Cycle 1, Day 1
• Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.