Bortezomib and Rituximab in Treating Patients With Mantle Cell Lymphoma Who Have Previously Undergone Stem Cell Transplantation

Sponsor
City of Hope Medical Center (Other)
Overall Status
Completed
CT.gov ID
NCT01267812
Collaborator
National Cancer Institute (NCI) (NIH)
23
Enrollment
2
Locations
1
Arm
109
Actual Duration (Months)
11.5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving bortezomib together with rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving bortezomib and rituximab together works in treating patients with mantle cell lymphoma who have previously undergone stem cell transplantation

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: bortezomib
  • Biological: rituximab
  • Other: laboratory biomarker analysis
  • Other: immunohistochemistry staining method
  • Genetic: RNA analysis
  • Genetic: gene expression analysis
  • Genetic: DNA analysis
  • Other: pharmacological study
  • Other: pharmacogenomic studies
  • Other: Questionnaire Administration
Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. To evaluate the two year disease free survival in mantle cell lymphoma (MCL) patients treated with bortezomib + rituximab after hematopoietic stem cell transplantation (HSCT).
SECONDARY OBJECTIVES:
  1. To evaluate the toxicity profile, safety, overall survival, time to treatment failure, remission duration, and biological markers of mantle cell lymphoma patients treated with bortezomib + rituximab after autologous hematopoietic stem cell transplantation.

OUTLINE: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) over 3-5 seconds and rituximab IV on days 1, 8, 15, and 22. Treatment with bortezomib repeats every 3 months for up to 8 courses and treatment with rituximab repeats every 6 months for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years.

Study Design

Study Type:
Interventional
Actual Enrollment :
23 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Study of Weekly Maintenance Bortezomib and Rituximab in Mantle Cell Lymphoma Post Autologous Hematopoietic Cell Transplantation
Actual Study Start Date :
Oct 3, 2011
Actual Primary Completion Date :
Nov 2, 2020
Actual Study Completion Date :
Nov 2, 2020

Arms and Interventions

ArmIntervention/Treatment
Experimental: Treatment (bortezomib and rituximab)

Doses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles. Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles.

Drug: bortezomib
Given SC or IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
  • Biological: rituximab
    Given IV
    Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
  • Other: laboratory biomarker analysis
    Correlative studies

    Other: immunohistochemistry staining method
    Correlative studies
    Other Names:
  • immunohistochemistry
  • Genetic: RNA analysis
    Correlative studies

    Genetic: gene expression analysis
    Correlative studies

    Genetic: DNA analysis
    Correlative studies

    Other: pharmacological study
    Correlative studies
    Other Names:
  • pharmacological studies
  • Other: pharmacogenomic studies
    Correlative studies
    Other Names:
  • Pharmacogenomic Study
  • Other: Questionnaire Administration
    Other Names:
  • Ancillary Studies
  • Outcome Measures

    Primary Outcome Measures

    1. Two-year Disease-free Survival [Up to five years after initial treatment]

      Assessed by Kaplan-Meier survival analysis. 95% confidence intervals will be calculated using Greenwood's formula.

    Secondary Outcome Measures

    1. Two-year Overall Survival [Up to five years after initial treatment]

      Assessed by Kaplan-Meier survival analysis. 95% confidence intervals will be calculated using Greenwood's formula.

    2. Grade 3 or 4 Toxicities of Bortezomib and Rituximab Treatment [Up to five years after initial treatment]

      Observed toxicities will be summarized in terms of type, severity (graded by NCI CTCAE version 4.0) and attribution.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    19 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must have histological documented or cytological confirmed mantle cell lymphoma; cyclin D1 must be present as evidenced by either fluorescence in situ hybridization (FISH) or immunohistochemical staining

    • Patients must have undergone autologous hematopoietic stem cell transplantation (AHCT) and achieved engraftment by day (D)60-180 as evidenced by absolute neutrophil count (ANC) > 1000/mcL and platelets (Plt) > 75,000/mcL

    • Patients must be in complete remission at D60-180 after AHCT as evidenced by computed tomography (CT) scan of the neck/chest/abdomen (abd)/pelvis or CT/positron emission tomography (PET) scans

    • Voluntary written 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 or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study

    • Male subject agrees to use an acceptable method for contraception for the duration of the study

    • Life expectancy of greater than 3 months

    • Karnofsky > 60%

    • ANC > 1000/mcL

    • Plts > 75,000/mcL

    • Total bilirubin within normal institutional limits, patients with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are eligible

    • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 x institutional upper limit of normal

    • Creatinine up to and including 2 mg/dL

    Exclusion Criteria:
    • Patient has >= grade 2 peripheral neuropathy within 14 days before enrollment and at D60-180 after AHCT; patients who had >= grade 2 peripheral neuropathy within 14 days before enrollment but resolves to grade 1 or lower peripheral neuropathy at D60-D180 after AHCT can be enrolled at this time

    • Patient has > 1.5 x upper limit of normal (ULN) total bilirubin unless history of Gilbert's syndrome

    • 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 electrocardiographic (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 beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women

    • Patient has received other investigational drugs with 14 days before treatment of treatment with bortezomib + rituximab

    • Serious medical or psychiatric illness likely to interfere with participation in this clinical study

    • Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

    • Patients with other active malignancies (no evidence of other cancer or life expectancy greater than 5 years) are ineligible for this study

    • Human immunodeficiency virus (HIV) positive patients or hepatitis B or C positive patients

    • Patients with active central nervous system (CNS) disease or history of brain metastases (mets) are excluded from study

    • Prior exposure to either bortezomib or rituximab is not an exclusion criteria

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1City of Hope Medical CenterDuarteCaliforniaUnited States91010
    2Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattleWashingtonUnited States98109

    Sponsors and Collaborators

    • City of Hope Medical Center
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Matthew Mei, City of Hope Medical Center

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    City of Hope Medical Center
    ClinicalTrials.gov Identifier:
    NCT01267812
    Other Study ID Numbers:
    • 10137
    • NCI-2010-02343
    First Posted:
    Dec 29, 2010
    Last Update Posted:
    Feb 4, 2022
    Last Verified:
    Feb 1, 2021
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleTreatment (Bortezomib and Rituximab)
    Arm/Group DescriptionDoses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles. Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles. bortezomib: Given SC or IV rituximab: Given IV laboratory biomarker analysis: Correlative studies immunohistochemistry staining method: Correlative studies RNA analysis: Correlative studies gene expression analysis: Correlative studies DNA analysis: Correlative studies pharmacological study: Correlative studies pharmacogenomic studies: Correlative studies Questionnaire Administration
    Period Title: Overall Study
    STARTED23
    COMPLETED23
    NOT COMPLETED0

    Baseline Characteristics

    Arm/Group TitleTreatment (Bortezomib and Rituximab)
    Arm/Group DescriptionDoses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles. Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles. bortezomib: Given SC or IV rituximab: Given IV laboratory biomarker analysis: Correlative studies immunohistochemistry staining method: Correlative studies RNA analysis: Correlative studies gene expression analysis: Correlative studies DNA analysis: Correlative studies pharmacological study: Correlative studies pharmacogenomic studies: Correlative studies Questionnaire Administration
    Overall Participants23
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    59
    Sex: Female, Male (Count of Participants)
    Female
    1
    4.3%
    Male
    22
    95.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    6
    26.1%
    Not Hispanic or Latino
    17
    73.9%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    1
    4.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    21
    91.3%
    More than one race
    0
    0%
    Unknown or Not Reported
    1
    4.3%
    Region of Enrollment (participants) [Number]
    United States
    23
    100%

    Outcome Measures

    1. Primary Outcome
    TitleTwo-year Disease-free Survival
    DescriptionAssessed by Kaplan-Meier survival analysis. 95% confidence intervals will be calculated using Greenwood's formula.
    Time FrameUp to five years after initial treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreatment (Bortezomib and Rituximab)
    Arm/Group DescriptionDoses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles. Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles. bortezomib: Given SC or IV rituximab: Given IV
    Measure Participants23
    Number (95% Confidence Interval) [percentage of survival]
    90
    2. Secondary Outcome
    TitleTwo-year Overall Survival
    DescriptionAssessed by Kaplan-Meier survival analysis. 95% confidence intervals will be calculated using Greenwood's formula.
    Time FrameUp to five years after initial treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreatment (Bortezomib and Rituximab)
    Arm/Group DescriptionDoses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles. Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles. bortezomib: Given SC or IV rituximab: Given IV
    Measure Participants23
    Number (95% Confidence Interval) [percentage of survival]
    95
    3. Secondary Outcome
    TitleGrade 3 or 4 Toxicities of Bortezomib and Rituximab Treatment
    DescriptionObserved toxicities will be summarized in terms of type, severity (graded by NCI CTCAE version 4.0) and attribution.
    Time FrameUp to five years after initial treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreatment (Bortezomib and Rituximab)
    Arm/Group DescriptionDoses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles. Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles. bortezomib: Given SC or IV rituximab: Given IV
    Measure Participants23
    Neutropenia
    17
    73.9%
    Lymphopenia
    8
    34.8%
    Pneumonia
    2
    8.7%
    Anemia
    2
    8.7%
    Lung infection
    2
    8.7%
    Skin infection
    1
    4.3%
    Wound infection
    1
    4.3%
    Hypertension
    1
    4.3%
    Thrombocytopenia
    1
    4.3%

    Adverse Events

    Time FrameUp to five years after initial treatment
    Adverse Event Reporting Description
    Arm/Group TitleTreatment (Bortezomib and Rituximab)
    Arm/Group DescriptionDoses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles. Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles. bortezomib: Given SC or IV rituximab: Given IV
    All Cause Mortality
    Treatment (Bortezomib and Rituximab)
    Affected / at Risk (%)# Events
    Total3/23 (13%)
    Serious Adverse Events
    Treatment (Bortezomib and Rituximab)
    Affected / at Risk (%)# Events
    Total7/23 (30.4%)
    Blood and lymphatic system disorders
    Myelodysplastic Syndrome1/23 (4.3%) 1
    General disorders
    Fever2/23 (8.7%) 2
    Infections and infestations
    Skin Infection1/23 (4.3%) 1
    Wound Infection1/23 (4.3%) 1
    Lung Infection1/23 (4.3%) 1
    Human Metapneumovirus Infection1/23 (4.3%) 1
    Febrile Neutropenia1/23 (4.3%) 1
    Meningitis1/23 (4.3%) 1
    Investigations
    Neutrophil Count Decreased1/23 (4.3%) 1
    Other (Not Including Serious) Adverse Events
    Treatment (Bortezomib and Rituximab)
    Affected / at Risk (%)# Events
    Total23/23 (100%)
    Blood and lymphatic system disorders
    Anemia15/23 (65.2%) 46
    Blood and lymphatic system disorders - Other, specify1/23 (4.3%) 1
    Febrile neutropenia1/23 (4.3%) 1
    Cardiac disorders
    Atrial fibrillation1/23 (4.3%) 1
    Sinus bradycardia2/23 (8.7%) 2
    Sinus tachycardia1/23 (4.3%) 1
    Ear and labyrinth disorders
    Hearing impaired6/23 (26.1%) 7
    Tinnitus5/23 (21.7%) 6
    Endocrine disorders
    Endocrine disorders - Other, specify2/23 (8.7%) 2
    Eye disorders
    Blurred vision1/23 (4.3%) 1
    Dry eye1/23 (4.3%) 1
    Eye disorders - Other, specify3/23 (13%) 4
    Watering eyes2/23 (8.7%) 3
    Gastrointestinal disorders
    Abdominal pain4/23 (17.4%) 4
    Bloating3/23 (13%) 4
    Constipation3/23 (13%) 4
    Diarrhea11/23 (47.8%) 16
    Gastrointestinal disorders - Other, specify1/23 (4.3%) 3
    Mucositis oral1/23 (4.3%) 1
    Nausea6/23 (26.1%) 9
    Vomiting3/23 (13%) 4
    General disorders
    Chills8/23 (34.8%) 9
    Edema limbs4/23 (17.4%) 5
    Fatigue21/23 (91.3%) 38
    Fever9/23 (39.1%) 13
    Flu like symptoms2/23 (8.7%) 2
    Gait disturbance3/23 (13%) 5
    Injection site reaction8/23 (34.8%) 9
    Non-cardiac chest pain1/23 (4.3%) 1
    Pain5/23 (21.7%) 5
    Immune system disorders
    Allergic reaction1/23 (4.3%) 1
    Immune system disorders - Other, specify2/23 (8.7%) 3
    Infections and infestations
    Eye infection1/23 (4.3%) 1
    Infections and infestations - Other, specify1/23 (4.3%) 1
    Lung infection3/23 (13%) 4
    Skin infection3/23 (13%) 3
    Upper respiratory infection7/23 (30.4%) 12
    Wound infection1/23 (4.3%) 1
    Injury, poisoning and procedural complications
    Bruising1/23 (4.3%) 1
    Fall1/23 (4.3%) 1
    Vascular access complication1/23 (4.3%) 1
    Investigations
    Alanine aminotransferase increased8/23 (34.8%) 23
    Alkaline phosphatase increased4/23 (17.4%) 5
    Aspartate aminotransferase increased9/23 (39.1%) 19
    Blood bilirubin increased1/23 (4.3%) 1
    Cholesterol high1/23 (4.3%) 1
    Creatinine increased6/23 (26.1%) 17
    Investigations - Other, specify5/23 (21.7%) 37
    Lymphocyte count decreased12/23 (52.2%) 84
    Neutrophil count decreased20/23 (87%) 67
    Platelet count decreased17/23 (73.9%) 59
    Weight gain2/23 (8.7%) 3
    White blood cell decreased20/23 (87%) 89
    Metabolism and nutrition disorders
    Anorexia4/23 (17.4%) 4
    Hypercalcemia1/23 (4.3%) 2
    Hyperglycemia5/23 (21.7%) 10
    Hyperkalemia4/23 (17.4%) 6
    Hypermagnesemia2/23 (8.7%) 3
    Hypernatremia4/23 (17.4%) 5
    Hypertriglyceridemia1/23 (4.3%) 1
    Hyperuricemia2/23 (8.7%) 2
    Hypoalbuminemia2/23 (8.7%) 2
    Hypocalcemia6/23 (26.1%) 10
    Hypoglycemia3/23 (13%) 5
    Hypokalemia3/23 (13%) 4
    Hypomagnesemia2/23 (8.7%) 2
    Hyponatremia6/23 (26.1%) 9
    Hypophosphatemia5/23 (21.7%) 8
    Obesity1/23 (4.3%) 2
    Musculoskeletal and connective tissue disorders
    Arthralgia9/23 (39.1%) 14
    Back pain5/23 (21.7%) 6
    Flank pain1/23 (4.3%) 1
    Generalized muscle weakness4/23 (17.4%) 4
    Muscle weakness lower limb1/23 (4.3%) 1
    Musculoskeletal and connective tissue disorder - Other, specify5/23 (21.7%) 6
    Myalgia4/23 (17.4%) 4
    Pain in extremity3/23 (13%) 4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome1/23 (4.3%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify2/23 (8.7%) 2
    Nervous system disorders
    Dizziness2/23 (8.7%) 2
    Headache3/23 (13%) 5
    Paresthesia6/23 (26.1%) 6
    Peripheral motor neuropathy1/23 (4.3%) 1
    Peripheral sensory neuropathy13/23 (56.5%) 26
    Vasovagal reaction1/23 (4.3%) 1
    Psychiatric disorders
    Agitation1/23 (4.3%) 1
    Anxiety5/23 (21.7%) 6
    Depression2/23 (8.7%) 2
    Insomnia1/23 (4.3%) 1
    Libido decreased1/23 (4.3%) 1
    Psychiatric disorders - Other, specify1/23 (4.3%) 1
    Renal and urinary disorders
    Hematuria1/23 (4.3%) 1
    Proteinuria1/23 (4.3%) 1
    Reproductive system and breast disorders
    Breast pain2/23 (8.7%) 2
    Gynecomastia1/23 (4.3%) 1
    Reproductive system and breast disorders - Other, specify1/23 (4.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis1/23 (4.3%) 1
    Cough9/23 (39.1%) 19
    Dyspnea2/23 (8.7%) 3
    Nasal congestion7/23 (30.4%) 10
    Pleural effusion1/23 (4.3%) 1
    Postnasal drip1/23 (4.3%) 1
    Productive cough9/23 (39.1%) 10
    Sore throat8/23 (34.8%) 11
    Wheezing1/23 (4.3%) 1
    Skin and subcutaneous tissue disorders
    Dry skin2/23 (8.7%) 2
    Hyperhidrosis2/23 (8.7%) 2
    Pruritus3/23 (13%) 3
    Rash acneiform1/23 (4.3%) 1
    Rash maculo-papular4/23 (17.4%) 5
    Skin and subcutaneous tissue disorders - Other, specify5/23 (21.7%) 6
    Skin hyperpigmentation1/23 (4.3%) 1
    Skin ulceration2/23 (8.7%) 2
    Vascular disorders
    Hot flashes1/23 (4.3%) 1
    Hypertension17/23 (73.9%) 43
    Hypotension1/23 (4.3%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleDr. Matthew Mei
    OrganizationCity of Hope
    Phone626-359-8111
    Emailmamei@coh.org
    Responsible Party:
    City of Hope Medical Center
    ClinicalTrials.gov Identifier:
    NCT01267812
    Other Study ID Numbers:
    • 10137
    • NCI-2010-02343
    First Posted:
    Dec 29, 2010
    Last Update Posted:
    Feb 4, 2022
    Last Verified:
    Feb 1, 2021