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

• Proportion of patients who experience complete remission as assessed by HSFCM [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Established when all CR criteria are met and negative flow cytometry examination of peripheral blood and bone marrow biopsy/aspiration collected at baseline, before courses 3 and 5, within 3 weeks after course 6, on day 100 (if HDC-ASCT eligible), and then every 6 months for 3 years.
• Time-to-tumor progression (TTP) [ Time Frame: From baseline until objective tumor progression, as assessed up to 3 years ] [ Designated as safety issue: No ]
  Estimated distributions obtained using the Kaplan-Meier method.
• Progression-free survival (PFS) [ Time Frame: From baseline until objective tumor progression or death, assessed up to 3 years ] [ Designated as safety issue: Yes ]
  Estimated distributions obtained using the Kaplan-Meier method. Estimates of quantities such as median survival will be obtained.
• Overall survival (OS) [ Time Frame: From baseline until death from any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
  Estimated distributions obtained using the Kaplan-Meier method. Estimates of quantities such as median survival will be obtained.
• Frequency of toxicity events [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
  Evaluated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Toxicity rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson.
• Correlation of minimal residual disease (MRD) with TTP, PFS, and OS [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  Assessed in peripheral blood and bone marrow biopsy/aspiration samples collected at baseline, before courses 3 and 5, day 100 (if HDC-ASCT eligible), and then every 6 months for 3 years.
• Correlation of surface CD20 levels, Ki67, and additional cytogenetic abnormalities in pretreatment tumor biopsies with respect to ORR, CRR, TTP, PFS, and OS [ Time Frame: Baseline ] [ Designated as safety issue: No ]
• Relationship between proliferation signature and clinical outcome using quantitative real-time RT-PCR [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  Compared using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.
• Change of serum C3, C4, and CH50 levels and correlation with ORR, CRR, MRR, TTP, PFS, and OS [ Time Frame: Baseline and day 1 ] [ Designated as safety issue: No ]
• Ability of the induction and consolidation therapy to get 70% of patients to autologous stem cell transplantation [ Time Frame: 4-6 weeks after chemotherapy ] [ Designated as safety issue: No ]
  Estimated using simple relative frequencies. The corresponding 95% confidence intervals will be computed using the method proposed in Clopper and Pearson.

• Proportion of patients who experience complete remission as assessed by HSFCM [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
• Time-to-tumor progression (TTP) [ Time Frame: From baseline until objective tumor progression, as assessed up to 3 years ] [ Designated as safety issue: No ]
• Progression-free survival (PFS) [ Time Frame: From baseline until objective tumor progression or death, assessed up to 3 years ] [ Designated as safety issue: Yes ]
• Overall survival (OS) [ Time Frame: From baseline until death from any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
• Frequency of toxicity events [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
• Correlation of minimal residual disease (MRD) with TTP, PFS, and OS [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
• Correlation of surface CD20 levels, Ki67, and additional cytogenetic abnormalities in pretreatment tumor biopsies with respect to ORR, CRR, TTP, PFS, and OS [ Time Frame: Baseline ] [ Designated as safety issue: No ]
• Relationship between proliferation signature and clinical outcome using quantitative real-time RT-PCR [ Time Frame: Baseline ] [ Designated as safety issue: No ]
• Change of serum C3, C4, and CH50 levels and correlation with ORR, CRR, MRR, TTP, PFS, and OS [ Time Frame: Baseline and day 1 ] [ Designated as safety issue: No ]
• Ability of the induction and consolidation therapy to get 70% of patients to autologous stem cell transplantation [ Time Frame: 4-6 weeks after chemotherapy ] [ Designated as safety issue: No ]

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, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. 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 or by stopping them from dividing. Giving ofatumumab together with alternating regimens of combination chemotherapy may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR), and in particular, the complete remission rate (CRR) in previously untreated MCL treated with ofatumumab in combination with aggressive chemo-immunotherapy.

SECONDARY OBJECTIVES:

I. To determine the high sensitivity flow cytometry (HSFCM) complete remission rate (HSFCM-CRR) in previously untreated MCL treated with ofatumumab in combination with aggressive chemo-immunotherapy +/- high dose chemotherapy and autologous stem cell transplant (HDC-ASCT).

II. To determine the time-to-progression (TTP), progression-free survival (PFS) and overall survival (OS) of patients with previously untreated MCL treated with ofatumumab and aggressive chemoimmunotherapy +/- HDC-ASCT.

III. To determine the toxicity profiles of ofatumumab in combination with high dose cytarabine chemoimmunotherapy +/- HDC-ASCT.

IV. To correlate minimal residual disease (MRD) at different time intervals with TTP, PFS, and OS.

V. To correlate surface CD20 levels, Ki67, and additional cytogenetic abnormalities in pretreatment tumor biopsies with respect to ORR, CRR, TTP, PFS, or OS.

VI. To determine the relationship between proliferation signature and clinical outcome using quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR).

VII. To determine changes in surface CD20 levels, Ki67, or gain of additional cytogenetic abnormalities in relapsed/refractory tumor specimens.

VIII. To correlate serum C3, C4, and CH50 levels measured at baseline and at the end of first ofatumumab infusion with ORR, CRR, median response rate (MRR), TTP, PFS and OS.

IX. Evaluate the ability of the induction and consolidation therapy to get 70% of patients to autologous stem cell transplantation.

X. Evaluate the tolerability and CD34+ cell yield following therapy with patient and hyper-fractionated cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and dexamethasone (HyperCVAD)/high-dose cytarabine and methotrexate (HD-MA).

XI. To compare differences in response rate in patients with MCL treated with ofatumumab + HyperCVAD/HD-MA according Cheson and Modified Cheson Criteria.

OUTLINE:

COURSES 1, 3, and 5 (O-HyperCVAD): Patients receive ofatumumab intravenously (IV) on day 1, cyclophosphamide IV over 2 hours every 12 hours for 6 doses on days 3-5, doxorubicin hydrochloride IV continuously over 72 hours on days 6-8, vincristine sulfate IV on days 6 and 13, and dexamethasone IV or orally (PO) on days 3-6 and 13-16.

COURSES 2, 4, and 6 (O-HD-MA): Patients receive ofatumumab IV on day 1, methotrexate IV continuously over 24 hours on day 3, and cytarabine IV over 2 hours every 12 hours on days 4-5.

All courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Eligible patients then undergo standard high dose chemotherapy and autologous stem cell transplant (HDC-ASCT).

After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 3 years, and then as clinically instructed.

• Contiguous Stage II Mantle Cell Lymphoma
• Noncontiguous Stage II Mantle Cell Lymphoma
• Stage I Mantle Cell Lymphoma
• Stage III Mantle Cell Lymphoma
• Stage IV Mantle Cell Lymphoma

• Biological: ofatumumab
  Given IV
  Other Names:

  • Arzerra
  • HuMax-CD20
• Drug: cyclophosphamide
  Given IV
  Other Names:

  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
• Drug: dexamethasone
  Given IV or PO
  Other Names:

  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
• Drug: doxorubicin hydrochloride
  Given IV
  Other Names:

  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
• Drug: vincristine sulfate
  Given IV
  Other Names:

  • leurocristine sulfate
  • VCR
  • Vincasar PFS
• Drug: cytarabine
  Given IV
  Other Names:

  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
• Procedure: autologous hematopoietic stem cell transplantation
  Undergo autologous HDC-ASCT
• Drug: methotrexate
  Given IV
  Other Names:

  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
• Other: laboratory biomarker analysis
  Correlative studies

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 bcl-1/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 tissue block (core biopsy or clot if available) or otherwise the diagnostic smears will be submitted to the RPCI Pathology Department

• 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 because of their relatively favorable prognosis
  • 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 MCL
• >= 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 virus (HBV) 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)

  • MCL patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status), should have HBV 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/μL
• Platelets >= 75,000/μL (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

Exclusion Criteria:

• Prior history of HIV-positivity (routine HIV testing is not required pre-treatment)
• Positive serology for HBV defined as a positive test for HBsAg; in addition, if negative for HBsAg but HBcAb positive, a HBV 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 CHF; all patients must have a MUGA scan or 2-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