Trial record 1 of 1 for:    NCT01527149
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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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Roswell Park Cancer Institute
Sponsor:
Collaborators:
National Comprehensive Cancer Network
GlaxoSmithKline
Information provided by (Responsible Party):
Roswell Park Cancer Institute
ClinicalTrials.gov Identifier:
NCT01527149
First received: December 12, 2011
Last updated: February 24, 2014
Last verified: February 2014
  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, 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.


Condition Intervention Phase
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
Drug: cyclophosphamide
Drug: dexamethasone
Drug: doxorubicin hydrochloride
Drug: vincristine sulfate
Drug: cytarabine
Procedure: autologous hematopoietic stem cell transplantation
Drug: methotrexate
Other: laboratory biomarker analysis
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:
  • 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.


Estimated Enrollment: 53
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.

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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 69 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 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
  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    877-275-7714    ASKRPCI@roswellpark.org   
Principal Investigator: Francisco J. Hernandez-ILizaliturri         
Weill Medical College of Cornell University Recruiting
New York, New York, United States, 10065
Contact: Peter Martin    646-962-2068    pem9019@med.cornell.edu   
Principal Investigator: Peter Martin         
United States, Tennessee
Vanderbilt-Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232-6838
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
GlaxoSmithKline
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
Study First Received: December 12, 2011
Last Updated: February 24, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Cytarabine
Methotrexate
Liposomal doxorubicin
Dexamethasone
Doxorubicin
Vincristine
Dexamethasone acetate
Dexamethasone 21-phosphate
BB 1101
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on August 18, 2014