Phase II Study of "VIPER" Chemotherapy in Rel/Ref DLBCL
Condition: Non-Hodgkin's Lymphoma
MeSH terms: Lymphoma
Intervention: bortezomib, dexamethasone, ifosfamide; mesna, cisplatin, etoposide, rituximab
Intervention description: VIPER chemotherapy will be administered every 28 days at the following doses:
Dexamethasone 40 mg IV days 1-4
Ifosfamide 1.0 gram/m2 CIVI over 24 hours days 1-4
Mesna 1.0 gram/m2 CIVI over 24 hours days 1-4 (mix solution with ifosfamide)
Cisplatin 25 mg IV days 1-4
Etoposide 100 mg/m2 CIVI over 24 hours days 1-4
Rituximab 500 mg/m2 IV day 1 prior to start of DICE (375 mg/m2 for subsequent cycles)
VELCADE 1.5 mg/m2 on days 2 and 5; VIPER chemotherapy will be administered every 28 days at the following doses:
Dexamethasone 40 mg IV days 1-4
Ifosfamide 1.0 gram/m2 CIVI over 24 hours days 1-4
Mesna 1.0 gram/m2 CIVI over 24 hours days 1-4 (mix solution with ifosfamide)
Cisplatin 25 mg IV days 1-4
Etoposide 100 mg/m2 CIVI over 24 hours days 1-4
Rituximab 500 mg/m2 IV day 1 prior to start of DICE (375 mg/m2 for subsequent cycles)
VELCADE 1.5 mg/m2 on days 2 and 5
Intervention MeSH terms: Dexamethasone; Rituximab; Etoposide; Bortezomib; Ifosfamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: diffuse large b cell

Summary:

      Objectives

      The primary objective of this study is to:

      • determine the complete and partial response rates and the toxicity profile of bortezomib
      (VELCADE, formerly PS-341) when administered in combination with DICE chemotherapy plus
      rituximab (i.e. VIPER) to patients with relapsed or refractory diffuse large B-cell
      non-Hodgkin's lymphoma

      The secondary objectives of this study are to:

        -  assess event free survival and overall survival

        -  assess conversion of chemo-resistant to chemo-sensitive disease

        -  assess the ability to collect stem cells from patients treated with salvage VIPER who
           then undergo autologous stem cell transplantation

        -  perform correlative studies on pre-treatment tumor biopsy specimens; analyses will
           include the assessment of immunohistochemical expression patterns (germinal center B
           cell vs. activated B cell) and NF-κB activity
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed diagnosis of CD20 positive, diffuse large B-cell NHL; de novo
             or transformed histologies are acceptable

          -  Patient must have relapsed after or not responded to at least one standard, upfront
             multi-agent chemotherapy for DLBCL

          -  Measurable PET positive disease, as defined by tumor mass > 1.5 cm in one dimension

          -  Stage II, III, or IV disease

          -  Age > 18 years

          -  Adequate liver and kidney function (total bilirubin < 2 x ULN and creatinine < 2.0
             mg/dl, unless abnormalities are related to lymphoma or Gilbert's disease

          -  Adequate bone marrow reserves (absolute neutrophil count >1500 cells/mm3 and platelet
             count > 100,000, unless cytopenias are the result of marrow infiltration by lymphoma

          -  ECOG performance status < 2

          -  Life expectancy of at least 3 months

          -  Bortezomib-naive

          -  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, intrauterine
             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.

        Exclusion Criteria:

          -  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 (see section 8.4), uncontrolled
             angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
             of acute ischemia or active conduction system abnormalities. Prior to study entry, any
             ECG abnormality at Screening has to be documented by the investigator as not medically
             relevant.

          -  Patient has hypersensitivity to boron or mannitol

          -  Female subject is pregnant or breast-feeding. Confirmation that the subject is not
             pregnant must be established by a negative serum β-human chorionic gonadotropin
             (β-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 or cytotoxic chemotherapy within 14
             days of enrollment

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study

          -  Known HIV infection

          -  Active Hepatitis B or C as defined by positive Hepatitis B surface antigen or
             hepatitis C RNA

          -  Known CNS disease

          -  Pregnant or nursing women

          -  Concurrent treatment with other chemotherapy or anti-lymphoma therapy, including
             corticosteroids, unless on a stable dose of corticosteroids less than the equivalent
             of 20 mg of prednisone each day for treatment of disease not related to lymphoma

          -  Concomitant malignancies or previous malignancies within the last five years, with the
             exception of adequately treated basal or squamous cell carcinoma of the skin or
             carcinoma in situ of the cervix.

          -  Any condition that, in the opinion of the investigator, would prevent the subject from
             being fully compliant with the protocol.