Study of the Combination of Rituximab, Cyclophosphamide, Doxorubicin, VELCADE, and Prednisone or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Mantle Cell Lymphoma
Condition: Mantle Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, Mantle-Cell
Intervention: Rituximab 375 mg/m^2; Cyclophosphamide 750 mg/m^2; Doxorubicin 50 mg/m^2; VELCADE 1.3 mg/m^2; Prednisone 100 mg/m^2; Vincristine 1.4 mg/m^2
Intervention description: Intravenous rituximab 375 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles.; Intravenous cyclophosphamide 750 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles; Intravenous doxorubicin 50 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles; Intravenous VELCADE 1.3 mg/m^2 on Days 1,4,8, and 11of a 21-day (3 week) cycle for 6 cycles; Oral prednisone 100 mg/m^2 on Day 1 to Day 5 of a 21-day (3 week) cycle for 6 cycles; Intravenous vincristine 1.4 mg/m^2 on Day 1of a 21-day (3 week) cycle for 6 cycles. Maximum of 2 mg. Participants could receive 8 cycles if a response was initially documented at the Cycle 6 assessment.
Intervention MeSH terms: Prednisone; Cyclophosphamide; Rituximab; Doxorubicin; Vincristine; Bortezomib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 487.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a randomized, open-label, multicenter, prospective study to compare the efficacy and
      safety of the combination of VcR-CAP to that of R-CHOP in participants who have newly
      diagnosed mantle cell lymphoma grade II, III or IV and who are ineligible to undergo bone
      marrow transplantation.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female patients 18 years or older (the patient must be at least the legal age
             limit to be able to give informed consent within the jurisdiction the study is taking
             place)

          -  Diagnosis of mantle cell lymphoma MCL (Stage II, III or IV) as evidenced by lymph node
             histology and either expression of cyclin D1 (in association with CD20 and CD5) or
             evidence of t(11;14) translocation, such as by cytogenetics, fluorescent in situ
             hybridization (FISH) or polymerase chain reaction (PCR). Patients with a diagnosis of
             Stage I MCL will not be permitted to enter study.

             - Paraffin embedded biopsy tissue block (preferably of lymph node origin) must be sent
             to the central laboratory for confirmation of MCL diagnosis prior to randomization. In
             China, a paraffin embedded lymph node biopsy tissue block must be sent for central
             confirmation of sample adequacy, prior to randomization

          -  At least 1 measurable site of disease

          -  No prior therapies for MCL

          -  Not eligible for bone marrow transplantation as assessed by the treating physician
             (e.g., age or the presence of co-morbid conditions that may have a negative impact on
             the tolerability to transplantation).

          -  Eastern Cooperative Oncology Group ECOG status ≤2

          -  Absolute neutrophil count (ANC) ≥1500 cells/µL,

          -  Platelets ≥100,000 cells/µL or ≥75,000 cells/µL if thrombocytopenia is considered by
             the investigator to be secondary to MCL (e.g., due to bone marrow infiltration or
             sequestration from splenomegaly).

          -  Alanine transaminase ≤3 x upper limit of normal (ULN)

          -  Aspartate transaminase ≤3 x ULN

          -  Total bilirubin ≤1.5 x ULN,

          -  Calculated creatinine clearance ≥20 mL/min.

          -  Female patients must be post menopausal for at least 1 year (must not have had a
             natural menses for at least 12 months), surgically sterile, or practicing an effective
             method of birth control (e.g., prescription oral contraceptives, contraceptive
             injections, intrauterine device, double-barrier method, contraceptive patch, male
             partner sterilization) and have a negative serum βHCG or urine pregnancy test at
             screening. They must also be prepared to continue birth control measures for at least
             6 months after terminating treatment.

          -  Male patients must agree to use an acceptable method of contraception (for themselves
             or female partners as listed above) for the duration of the study.

          -  All patients (or their legally acceptable representatives) must have signed an
             informed consent document indicating that they understand the purpose of and
             procedures required for the study and are willing to participate in the study.

          -  In order to participate in the pharmacogenomics component of this study, patients (or
             their legally acceptable representative) must have signed the informed consent form
             for pharmacogenomics research indicating willingness to participate in the
             pharmacogenomics component of the study. Acquisition of tumor sample collections is
             required for all patients (where available); all other sample collections are optional

        Exclusion Criteria:

          -  Prior treatment with VELCADE

          -  Prior antineoplastic (including unconjugated therapeutic antibodies), experimental or
             radiation therapy, radioimmunoconjugates or toxin immunoconjugates for the treatment
             of MCL. In the event that a patient has received doxorubicin for the treatment of any
             condition, other than MCL, the maximum dose and exposure received prior to entry into
             this study should not exceed 150 mg/m2.

             - short course (maximum of 10 days, not exceeding 100 mg/day) prednisone or equivalent
             steroids are allowed to treat symptoms in patients with advanced disease who enter the
             screening phase and are waiting to be randomized.

          -  Major surgery (at the discretion of the treating physician and in consultation with
             the sponsor's medical monitor) within 2 weeks before randomization

          -  Peripheral neuropathy or neuropathic pain of Grade 2 or worse (as per the
             investigators assessment)

          -  Diagnosed or treated for a malignancy other than MCL within 1 year of randomization,
             or who were previously diagnosed with a malignancy other than MCL and have any
             radiographic or biochemical marker evidence of malignancy. Patients with completely
             resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ
             malignancy are not excluded.

          -  Active systemic infection requiring treatment and patients with known diagnosis of
             human immunodeficiency virus HIV or active hepatitis B (carriers of hepatitis B are
             permitted to enter study)

          -  History of allergic reaction attributable to compounds containing boron, mannitol, or
             hydroxybenzoates

          -  Known anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine
             proteins or to any component of rituximab including polysorbate 80 and sodium citrate
             dihydrate

          -  Female or male patients of child-bearing potential who will not use adequate
             contraception during the course of the study.

          -  Serious medical (e.g., pericardial disease, cardiac failure [New York Heart
             Association; NYHA Class III or IV, Attachment 12 or left ventricular ejection
             fraction; LVEF <50%], active peptic ulceration, uncontrolled diabetes mellitus, or
             acute diffuse infiltrative pulmonary disease), or psychiatric illness likely to
             interfere with participation in this clinical study

          -  Concurrent treatment with another investigational agent.