Ofatumumab in Combination With Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine Sulfate, and Dexamethasone Alternating With Ofatumumab in Combination With Cytarabine and Methotrexate in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma
Condition: Stage I Mantle Cell Lymphoma; Stage II Contiguous Mantle Cell Lymphoma; Stage II Non-Contiguous Mantle Cell Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Mantle Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, Mantle-Cell
Intervention: Autologous Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin Hydrochloride; Laboratory Biomarker Analysis; Methotrexate; Ofatumumab; Vincristine Sulfate
Intervention description: Undergo autologous HDC-ASCT; Given IV; Given IV; Given IV or PO; Given IV; Correlative studies; Given IV; Given IV; Given IV
Intervention MeSH terms: Cytarabine; Dexamethasone; Dexamethasone acetate; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vincristine; Ofatumumab; Antibodies, Monoclonal; BB 1101
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well ofatumumab in combination with cyclophosphamide,
      doxorubicin hydrochloride, vincristine sulfate, and dexamethasone alternating with ofatumumab
      in combination with cytarabine and methotrexate works in treating patients with newly
      diagnosed mantle cell lymphoma (MCL). Monoclonal antibodies, such as ofatumumab, may
      interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy,
      such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, dexamethasone,
      cytarabine, and methotrexate, 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 ofatumumab together with alternating regimens of combination chemotherapy
      may kill more cancer cells.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically documented mantle cell lymphoma with co-expression of CD20 and CD5 and
             lack of CD23 expression by immunophenotyping and at least one of the following
             confirmatory tests: 1) positive immunostaining for cyclin D1; 2) the presence of
             t(11;14) on cytogenetic analysis; OR 3) molecular evidence of B-cell leukemia/lymphoma
             1 (bcl-1)/immunoglobulin heavy locus (IgH) rearrangement

               -  Cases that are CD5-negative and/or CD23-positive will be eligible provided that
                  the histopathology is consistent with mantle cell lymphoma AND positive for
                  cyclin D1, t(11;14), or bcl-1/IgH rearrangement

               -  A tissue block or unstained slides (10 - 20 slides) will be submitted to the
                  Roswell Park Cancer Institute (RPCI) Pathology Department for central pathology
                  review

               -  A diagnosis based on peripheral blood or bone marrow aspirate is allowed; if the
                  diagnosis is based only on blood, in addition to the immunophenotype and
                  molecular confirmation above, a peripheral blood smear must be available for
                  central pathology review; if the diagnosis is based on a bone marrow, the bone
                  marrow core biopsy or aspirate clot tissue block will be submitted to the RPCI
                  Pathology Department: if the tissue block is not available please submit the
                  diagnostic smears for review

          -  Extent of disease: stage I - IV; patients with nodular histology mantle cell lymphoma
             must have Ann Arbor stage III or IV disease to be eligible

               -  Patients with mantle zone type histology will not be eligible

               -  Patients with other mantle cell histologies are eligible regardless of stage

          -  Measurable or assessable disease is required; measurable tumor size (at least one node
             measuring 2.25 cm^2 in bidimensional measurement)

          -  No active central nervous system (CNS) disease defined as symptomatic meningeal
             lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating mantle
             cell lymphoma at the time of registration to this study is not an exclusion for study
             enrollment

          -  Patients must be previously untreated

          -  No prior radiation therapy for mantle cell lymphoma

          -  >= 2 weeks since major surgery

          -  No known hypersensitivity to murine products

          -  No medical condition requiring chronic use of high dose systemic corticosteroids
             (i.e., doses of prednisone higher than 10 mg/day or equivalent)

          -  No human immunodeficiency virus (HIV) infection; patients with a history of
             intravenous drug abuse or any behavior associated with an increased risk of HIV
             infection should be tested for exposure to the HIV virus; patients who test positive
             or who are known to be infected are not eligible; an HIV test is not required for
             entry on this protocol, but is required if the patient is perceived to be at risk

          -  Non-pregnant and non-nursing; women and men of reproductive potential should agree to
             use an effective means of birth control

          -  Patients who test positive for hepatitis C antibody (Ab) are eligible provided all of
             the following criteria are met: 1) total bilirubin =< 2 x upper limit of normal; 2)
             AND aspartate aminotransferase (AST) =< 3 x upper limit of normal; AND 3) liver biopsy
             (pathology) demonstrates =< grade 2 fibrosis and no cirrhosis

          -  Specific guidelines will be followed regarding inclusion of MCL 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 MCL patients are eligible

               -  Patients who test positive for HBsAg are ineligible (regardless of other
                  hepatitis B serologies)

               -  For MCL patients with HBsAg negative, but HBcAb positive (regardless of HBsAb
                  status), should have hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing
                  done and protocol eligibility determined as follows:

                    -  If HBV DNA is positive the subject is excluded

                    -  If HBV DNA is negative, patient 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 study

                    -  Monitoring during the study is required at least every 2 months and during
                       follow-up at a minimum of every 2-3 months up to 6 months after the last
                       dose

                    -  Prophylactic antiviral therapy with lamivudine (3TC) or investigator's
                       preferred antiviral regimen throughout protocol therapy and for 6-12 months
                       thereafter may be initiated at the discretion of the investigator

                    -  If the patients' HBV DNA becomes positive during the study, the investigator
                       should manage the clinical situation as per the standard of care of
                       participating institution; the investigator should weigh the risks and
                       benefits of continuing ofatumumab or discontinuing ofatumumab before
                       appropriate treatment decisions are made for that individual patient

          -  Patients must not have a history of cardiac disease, defined as New York Heart
             Association class II or greater or clinical evidence of congestive heart failure (CHF)

          -  No known hypersensitivity to ofatumumab, humanized antibodies or chemotherapy agents
             throughout the protocol

          -  Left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or
             echocardiogram (ECHO) >= 45%

          -  Neutrophils > 1000/uL

          -  Platelets >= 75,000/uL (unless significant bone marrow involvement with MCL)

          -  Creatinine =< 2.0 mg/dL

          -  Total bilirubin =< 2.0 mg/dL (unless MCL related or attributable to Gilbert's disease)

          -  Urine or serum beta-human chorionic gonadotropin (HCG) or serum HCG = negative (if
             female patient of childbearing potential)

          -  Patient or legal representative must understand the investigational nature of this
             study and sign an Independent Ethics Committee/Institutional Review Board approved
             written informed consent form prior to receiving any study related procedure

          -  Consult with a physician experience in care and management of subjects with hepatitis
             B to manage/treat subjects who are anti-hepatitis B core antibody (HBc) positive

        Exclusion Criteria:

          -  Prior history of HIV-positivity (routine HIV testing is not required pre-treatment)

          -  Positive serology for hepatitis B (HB) defined as a positive test for HBsAg; in
             addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a
             hepatitis B DNA test will be performed and if positive the patient will be excluded

          -  Serious non-malignant disease (e.g., active uncontrolled bacterial, viral, or fungal
             infections) or other medical conditions (including psychiatric) which, in the opinion
             of the Principal Investigator (PI) would compromise other protocol objectives

          -  Presence of symptomatic CNS lymphoma

          -  Pregnant or lactating females

          -  Prior history of radiation or chemotherapy for MCL

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to ofatumumab or other agents used in study

          -  Patients with a "currently active" second malignancy, other than non-melanoma skin
             cancer or in situ carcinoma of the cervix or breast; 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 2-5
             years have lapsed

          -  Major surgery, other than diagnostic surgery, within 2 weeks

          -  Patients with non-Hodgkin lymphoma (NHL) other than MCL

          -  Patients must not have a history of cardiac disease, defined as New York Heart
             Association class II or greater or clinical evidence of congestive heart failure; all
             patients must have a MUGA scan or 2-dimensional (D) echocardiogram indicating an
             ejection fraction of >= 45% within 42 days prior to registration; the method used at
             baseline must be used for later monitoring

          -  Unwilling or unable to follow protocol requirements

          -  Any condition which in the Investigator's opinion deems the patient an unsuitable
             candidate to receive study drug

          -  Received an investigational agent within 30 days prior to enrollment