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Bortezomib, Rituximab and Combination Chemotherapy in Treating Participants With Mantle Cell Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00477412
Recruitment Status : Active, not recruiting
First Posted : May 23, 2007
Last Update Posted : September 20, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I/II trial studies the side effects and best dose of bortezomib when given with rituximab and chemotherapy drugs and to see how well they work in treating participants with mantle cell lymphoma. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, dexamethasone, methotrexate, and cytarabine, 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 bortezomib, rituximab and combination chemotherapy may work better at treating mantle cell lymphoma.

Condition or disease Intervention/treatment Phase
Mantle Cell Lymphoma Drug: Bortezomib Drug: Cyclophosphamide Drug: Cytarabine Drug: Dexamethasone Drug: Doxorubicin Drug: Methotrexate Biological: Rituximab Drug: Vincristine Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the safety and the maximum tolerated dose (MTD) of bortezomib when added to the combination of rituximab, methotrexate, and cytarabine alternating with bortezomib, rituximab-hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone (hyperCVAD) in patients with untreated aggressive mantle cell lymphoma. (Phase I) II. Evaluate the time to failure (TTF) rate following therapy with bortezomib plus rituximab-hyperCVAD alternating with bortezomib plus rituximab-high dose methotrexate/cytarabine in patients between 18 and 79 years of age with untreated aggressive mantle cell lymphoma. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate overall response rate, complete remission rate, overall survival, and duration of remission. (Phase I) II. Evaluate overall response rate, overall survival, and duration of remission. (Phase II) III. Evaluate toxicity of the combination regimen. (Phase II) IV. Correlate outcome with pretreatment markers. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of bortezomib followed by a phase II study.

Participants receive Drug Combination I during courses 1, 3, 5, and 7 (if needed) and Drug Combination II during courses 2, 4, 6, and 8 (if needed) in the absence of disease progression or unacceptable toxicity.

Drug Combination I: Participants receive rituximab intravenously (IV) over 6 hours on day 1, cyclophosphamide IV over 3 hours twice daily (BID) on days 2-4, doxorubicin IV over 15-30 minutes on day 5, vincristine IV over 15-30 minutes on days 5 and 12, dexamethasone orally (PO) or IV on days 2-5 and 12-15, and bortezomib IV over a few seconds after the first dose of cyclophosphamide and immediately after vincristine and doxorubicin have been given on day 5.

Drug Combination II: Participants receive rituximab IV over 6 hours on day 1, methotrexate IV over 24 hours on day 2, and cytarabine IV over 2 hours every 12 hours on days 3-4.

After completion of study treatment, participants are followed up every 3 months for 1 year, every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Bortezomib (VELCADE) Plus Rituximab-HyperCVAD Alternating With Bortezomib Plus Rituximab-High Dose Methotrexate/Cytarabine in Patients With Untreated Aggressive Mantle Cell Lymphoma
Actual Study Start Date : April 3, 2007
Estimated Primary Completion Date : April 30, 2020
Estimated Study Completion Date : April 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Treatment (combination chemotherapy)

Participants receive Drug Combination I during courses 1, 3, 5, and 7 (if needed) and Drug Combination II during courses 2, 4, 6, and 8 (if needed) in the absence of disease progression or unacceptable toxicity.

Drug Combination I: Participants receive rituximab IV over 6 hours on day 1, cyclophosphamide IV over 3 hours BID on days 2-4, doxorubicin IV over 15-30 minutes on day 5, vincristine IV over 15-30 minutes on days 5 and 12, dexamethasone PO or IV on days 2-5 and 12-15, and bortezomib IV over a few seconds after the first dose of cyclophosphamide and immediately after vincristine and doxorubicin have been given on day 5.

Drug Combination II: Participants receive rituximab IV over 6 hours on day 1, methotrexate IV over 24 hours on day 2, and cytarabine IV over 2 hours every 12 hours on days 3-4.

Drug: Bortezomib
Given IV
Other Names:
  • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
  • LDP 341
  • MLN341
  • PS-341
  • PS341
  • Velcade

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-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 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
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Drug: Dexamethasone
Given PO or IV
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
Given IV
Other Names:
  • Adriablastin
  • Hydroxyl Daunorubicin
  • Hydroxyldaunorubicin

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: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar GB241
  • Rituximab Biosimilar IBI301
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • Rituximab Biosimilar SAIT101
  • RTXM83

Drug: Vincristine
Given IV
Other Names:
  • LEUROCRISTINE
  • VCR
  • Vincrystine




Primary Outcome Measures :
  1. Maximum tolerated dose of bortezomib (Phase I) [ Time Frame: Up to 1 year ]
  2. Incidence of dose limiting toxicity (Phase I) [ Time Frame: Up to 1 year ]
    Will be summarized in frequency tables. Logistic regression analysis will be used to model the dose-toxicity relationship as well as nonparametric smoothing procedures.

  3. Time to failure (Phase II) [ Time Frame: Up to 3 years ]
    Failure will be defined as recurrence/progression of disease or death from either disease or toxicity. Bayesian toxicity monitoring schema will be used to monitor severe toxicity profile in combined therapy. Severe toxicity is defined as at least two episodes of neutropenic fever during treatment courses.


Secondary Outcome Measures :
  1. Failure free survival [ Time Frame: Up to 13 years ]
    Will be estimated using Kaplan-Meier method. The log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be utilized to evaluate the effects of covariates on the time-to-event analysis.

  2. Response duration [ Time Frame: Up to 13 years ]
    Will be estimated using Kaplan-Meier method. The log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be utilized to evaluate the effects of covariates on the time-to-event analysis.

  3. Overall survival [ Time Frame: Up to 13 years ]
    Will be estimated using Kaplan-Meier method. The log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be utilized to evaluate the effects of covariates on the time-to-event analysis.



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 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed diagnosis of previously untreated nodular or diffuse mantle cell lymphoma and their blastoid cytologic variant.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • Serum bilirubin < 1.5 mg/dl and serum creatinine < 2.0 mg/dl within 14 days before enrollment (unless higher levels are due to lymphoma).
  • Platelet count > 100,000/mm^3 within 14 days before enrollment (unless due to lymphoma).
  • Absolute neutrophil count (ANC) > 1,000/mm^3 within 14 days before enrollment (unless due to lymphoma).
  • Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multigated acquisition (MUGA).
  • Patients must be willing to receive transfusions of blood products.
  • Voluntary written Institutional Review Board (IRB)-approved informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
  • Female subject is either post-menopausal for at least 1 year before the Screening visit or surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of birth control, at the same time (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) from the time of signing the informed consent through 30 days after the last dose of study treatment, or agree to completely abstain from heterosexual intercourse.
  • Male subject, even if surgically sterilized (ie, status post vasectomy) agrees to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study treatment, or agree to completely abstain from heterosexual intercourse.

Exclusion Criteria:

  • Human immunodeficiency virus (HIV) infection.
  • Central nervous system (CNS) involvement.
  • Co-morbid medical or psychiatric illnesses that preclude treatment with intense dose chemotherapy.
  • Concurrent or previous malignancy with < 90% probability of survival at 5 years.
  • Patient has >= grade 2 peripheral neuropathy within 14 days before enrollment.
  • Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiography (ECG) abnormality at screening has to be documented by the investigator as not medically relevant.
  • Patient has hypersensitivity to bortezomib, boron or mannitol.
  • Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
  • Participating in clinical trials with other investigational agents not included in this trial within 14 days of the start of this trial and throughout the duration of this trial.
  • Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.

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): NCT00477412


Locations
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United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Luhua (Michael) Wang M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00477412     History of Changes
Other Study ID Numbers: 2006-0697
NCI-2018-01851 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2006-0697 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: May 23, 2007    Key Record Dates
Last Update Posted: September 20, 2018
Last Verified: September 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Dexamethasone
Dexamethasone acetate
Cyclophosphamide
Rituximab
Doxorubicin
Liposomal doxorubicin
Methotrexate
Bortezomib
Cytarabine
Vincristine
BB 1101
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents