Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV Diffuse Large B-cell Lymphoma
Condition: CD20 Positive; Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Stage I Diffuse Large B-Cell Lymphoma; Stage II Diffuse Large B-Cell Lymphoma; Stage III Diffuse Large B-Cell Lymphoma; Stage IV Diffuse Large B-Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: Carboplatin; Carfilzomib; Etoposide; Ifosfamide; Laboratory Biomarker Analysis; Pharmacological Study; Rituximab
Intervention description: Given IV; Given IV; Given IV; Given IV; Correlative studies; Correlative studies; Given IV
Intervention MeSH terms: Rituximab; Antineoplastic Agents, Immunological; Carboplatin; Etoposide; Etoposide phosphate; Ifosfamide; Isophosphamide mustard; Podophyllotoxin; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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