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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

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ClinicalTrials.gov Identifier: NCT01527149
Recruitment Status : Active, not recruiting
First Posted : February 6, 2012
Results First Posted : June 23, 2020
Last Update Posted : March 18, 2022
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief 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.

Condition or disease Intervention/treatment Phase
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 Procedure: Autologous Hematopoietic Stem Cell Transplantation Drug: Cyclophosphamide Drug: Cytarabine Drug: Dexamethasone Drug: Doxorubicin Hydrochloride Other: Laboratory Biomarker Analysis Drug: Methotrexate Biological: Ofatumumab Drug: Vincristine Sulfate Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Ofatumumab (O) in Combination With Chemotherapy: Hyper-Fractionated Cyclophosphamide, Doxorubicin, Vincristine and Dexamethasone (O-HyperCVAD) Alternating With Ofatumumab High-Dose Cytarabine and Methotrexate (O-MA) for Patients With Newly Diagnosed Mantle Cell Lymphoma
Actual Study Start Date : December 6, 2011
Actual Primary Completion Date : April 26, 2018
Estimated Study Completion Date : February 8, 2023

Arm Intervention/treatment
Experimental: Treatment (monoclonal antibody and combination chemotherapy)

COURSES 1, 3, and 5 (O-HyperCVAD): Patients receive ofatumumab 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 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 HDC-ASCT.

Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous HDC-ASCT
Other Name: Autologous Stem Cell Transplantation

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Cytarabine
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-Cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosar-U
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Drug: Dexamethasone
Given IV or PO
Other Names:
  • Aacidexam
  • Adexone
  • Aknichthol Dexa
  • Alba-Dex
  • Alin
  • Alin Depot
  • Alin Oftalmico
  • Amplidermis
  • Anemul mono
  • Auricularum
  • Auxiloson
  • Baycuten
  • Baycuten N
  • Cortidexason
  • Cortisumman
  • Decacort
  • Decadrol
  • Decadron
  • Decalix
  • Decameth
  • Decasone R.p.
  • Dectancyl
  • Dekacort
  • Deltafluorene
  • Deronil
  • Desamethasone
  • Desameton
  • Dexa-Mamallet
  • Dexa-Rhinosan
  • Dexa-Scheroson
  • Dexa-sine
  • Dexacortal
  • Dexacortin
  • Dexafarma
  • Dexafluorene
  • Dexalocal
  • Dexamecortin
  • Dexameth
  • Dexamethasonum
  • Dexamonozon
  • Dexapos
  • Dexinoral
  • Dexone
  • Dinormon
  • Fluorodelta
  • Fortecortin
  • Gammacorten
  • Hexadecadrol
  • Hexadrol
  • Lokalison-F
  • Loverine
  • Methylfluorprednisolone
  • Millicorten
  • Mymethasone
  • Orgadrone
  • Spersadex
  • Visumetazone

Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • Doxolem
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Methotrexate
Given IV
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • CL 14377
  • CL-14377
  • Emtexate
  • Emthexat
  • Emthexate
  • Farmitrexat
  • Fauldexato
  • Folex
  • Folex PFS
  • Lantarel
  • Ledertrexate
  • Lumexon
  • Maxtrex
  • Medsatrexate
  • Metex
  • Methoblastin
  • Methotrexate LPF
  • Methotrexate Methylaminopterin
  • Methotrexatum
  • Metotrexato
  • Metrotex
  • Mexate
  • Mexate-AQ
  • MTX
  • Novatrex
  • Rheumatrex
  • Texate
  • Tremetex
  • Trexeron
  • Trixilem
  • WR-19039

Biological: Ofatumumab
Given IV
Other Names:
  • Arzerra
  • GSK1841157
  • HuMax-CD20
  • HuMax-CD20, 2F2

Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine Sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate

Primary Outcome Measures :
  1. Proportion of Patients Experiencing a Complete Response [ Time Frame: 22 weeks ]

    Evaluated according to the International Working Group Response criteria as reported by Cheson et al. and the revised Cheson criteria.

    Complete response is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Typically FDG-avid lymphoma: in patients with PET scan positive before therapy, a posttreatment residual mass of any size is permitted as long as it is PET negative. Variably FDG-avid lymphomas/FDG avidity unknown: in patients with a negative pretreatment PET scan, all lymph nodes and nodal masses must have regressed on CT to normal size (1.5 cm in their greatest transverse diameter for nodes 1.5 cm before therapy). Previously involved nodes that were 1.1 cm to 1.5 cm in their long axis and more than 1)

Secondary Outcome Measures :
  1. Percentage of Participants With Autologous Stem Cell Transplantation [ Time Frame: Up to 6 weeks after the last dose of ofatumumab-chemotherapy, an average of 4 month ]
    Estimated using simple relative frequencies. The corresponding 95% confidence intervals will be computed using the method proposed in Clopper and Pearson.

  2. Change From Baseline in Percentage of Cells Positive for Ki67 [ Time Frame: Baseline and up to 3 years ]
    Mean change from baseline in Percentage of Cells Positive for Ki67 by patient response.

  3. Median of Serum Complement CD20 Levels [ Time Frame: Baseline ]
    Median serum C20 MFI (mean fluorescence intensity)

  4. Number of Participants With at Least One Serious Adverse Event [ Time Frame: Up to 3 years ]
    Evaluated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  5. Minimal Residual Disease (MRD) in Peripheral Blood Samples [ Time Frame: Up to 3 years ]
    Minimal residual disease (MRD) in peripheral blood samples at baseline.

  6. Minimal Residual Disease (MRD) in Bone Marrow Biopsy/Aspiration Samples [ Time Frame: Up to 3 years ]
    Minimal residual disease (MRD) in and bone marrow biopsy/aspiration samples at baseline.

  7. Median Overall Survival (OS) [ Time Frame: From baseline through study completion, an average of 5 years ]
    Estimated distributions obtained using the Kaplan-Meier method. Estimates of quantities such as median survival will be obtained. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

  8. Median Progression-free Survival (PFS) [ Time Frame: From baseline through study completion, an average of 5 years ]
    Estimated distributions obtained using the Kaplan-Meier method. Estimates of quantities such as median survival will be obtained. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

  9. Proliferation Signature Using Quantitative Real-time RT-PCR [ Time Frame: Baseline ]
    Relationship between proliferation signature and clinical outcome will be compared using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.

  10. Proportion of Patients Who Experience Complete Remission as Assessed by HSFCM [ Time Frame: Up to 3 years ]
    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.

  11. Time-to-tumor Progression (TTP) at 3 Years [ Time Frame: From baseline until objective tumor progression, as assessed up to 3 years ]
    Estimated percentage of patients that progressed at 3 years. Time to Progression distributions obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01527149

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United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
United States, Tennessee
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Roswell Park Cancer Institute
National Comprehensive Cancer Network
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Principal Investigator: Francisco Hernandez-ILizaliturri Roswell Park Cancer Institute
  Study Documents (Full-Text)

Documents provided by Roswell Park Cancer Institute:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT01527149    
Other Study ID Numbers: I 201611
NCI-2011-03562 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 201611 ( Other Identifier: Roswell Park Cancer Institute )
First Posted: February 6, 2012    Key Record Dates
Results First Posted: June 23, 2020
Last Update Posted: March 18, 2022
Last Verified: March 2022
Additional relevant MeSH terms:
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Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Dexamethasone acetate
Liposomal doxorubicin
Antibodies, Monoclonal
BB 1101
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents