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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2015 by Roswell Park Cancer Institute
Sponsor:
Collaborators:
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Roswell Park Cancer Institute
ClinicalTrials.gov Identifier:
NCT01527149
First received: December 12, 2011
Last updated: August 27, 2015
Last verified: August 2015
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Roswell Park Cancer Institute:

Primary Outcome Measures:
  • Proportion of patients experiencing a complete response [ Time Frame: 22 weeks ] [ Designated as safety issue: No ]
    Evaluated according to the International Working Group Response criteria as reported by Cheson et al. and the revised Cheson criteria.


Secondary Outcome Measures:
  • Ability of the induction and consolidation therapy to get 70% of patients to autologous stem cell transplantation [ Time Frame: Up to 6 weeks after the last dose of ofatumumab-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.

  • Change in surface CD20 levels, Ki67, and additional cytogenetic abnormalities [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]
    Association between change in CD20 levels, Ki67, and cytogenetic abnormalities and ORR, CRR, TTP, PFS, and OS will be statistically assessed using logistic regression. Wald tests of the model effects will be performed to assess statistical significance.

  • Change of serum complement component (C)3, C4, and complement CH50 (CH50) levels [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]
    Association between change in serum C3, C4, and CH50 levels and ORR, CRR, TTP, PFS, and OS will be statistically assessed using logistic regression. Wald tests of the model effects will be performed to assess statistical significance.

  • Frequency of adverse 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.

  • Minimal residual disease (MRD) in peripheral blood and bone marrow biopsy/aspiration samples [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Association between MRD and TTP, PFS, and OS will be statistically assessed using logistic regression. Wald tests of the model effects will be performed to assess statistical significance.

  • 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. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

  • 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. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.

  • Proliferation signature using quantitative real-time RT-PCR [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • 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. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed.


Estimated Enrollment: 37
Study Start Date: December 2011
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
  • CYCLOPHOSPHAMIDE
  • 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
  • CYTARABINE
  • 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
  • DEXAMETHASONE
  • 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
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • DOXORUBICIN HYDROCHLORIDE
  • 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
  • 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
  • OFATUMUMAB
Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine Sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • VINCRISTINE SULFATE
  • Vincristine, sulfate

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01527149

Locations
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Roswell Park    877-275-7724    ASKRPCI@roswellpark.org   
Principal Investigator: Francisco J. Hernandez-ILizaliturri         
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Nishitha Reddy    615-936-8422    Nishitha.reddy@vanderbilt.edu   
Principal Investigator: Nishitha Reddy         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Comprehensive Cancer Network
Investigators
Principal Investigator: Francisco Hernandez-ILizaliturri Roswell Park Cancer Institute
  More Information

No publications provided

Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT01527149     History of Changes
Other Study ID Numbers: I 201611, NCI-2011-03562, I 201611, P30CA016056
Study First Received: December 12, 2011
Last Updated: August 27, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Mantle-Cell
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
BB 1101
Cyclophosphamide
Cytarabine
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Doxorubicin
Liposomal doxorubicin
Methotrexate
Vincristine
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Alkylating Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Antibiotics, Antineoplastic
Antiemetics
Antimetabolites
Antimetabolites, Antineoplastic
Antimitotic Agents
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 03, 2015