A Phase I Study of Vorinostat and Bortezomib in Children With Refractory of Recurrent Solid Tumors, Including CNS Tumors and Lymphomas
Condition: Lymphoma; Sarcoma; WilmsTumor; Neuroblastoma
MeSH terms: Lymphoma; Sarcoma; Neuroblastoma
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Vorinostat and bortezomib are anti-tumor drugs that have been approved by the Food and Drug
      Administration to treat different kinds of myeloma and lymphoma in adults. The combination of
      these two drugs has been tried in a small number of adults, but it has not been formally
      approved and is experimental, particularly in children. Researchers are interested in
      determining safe and effective treatment doses of vorinostat and bortezomib in children, and
      learning more about how these drugs affect tumor growth and human development.

      Objectives:

        -  To determine safe and effective doses of vorinostat and bortezomib to treat solid tumors
           in children.

        -  To study the effects of vorinostat and bortezomib on blood cells, blood flow, and human
           development.

      Eligibility:

      - Children, adolescents, and young adults between 1 and 21 years of age who have been
      diagnosed with solid tumors that have not responded to treatment.

      Design:

        -  Eligible participants will be screened with a physical examination, blood and tumor
           samples, and imaging studies.

        -  Participants will have 21-day treatment cycles of vorinostat and bortezomib. Vorinostat
           will be given as either tablets or liquid doses on days 1 through 5 and 8 through 12 of
           each cycle. Bortezomib will be given as an intravenous injection on days 1, 4, 8, and 11
           of each cycle. Participants will keep a drug administration diary to record information
           about side effects or other problems with the treatment.

        -  Participants may continue to receive vorinostat and bortezomib for up to 2 years unless
           serious side effects develop or the tumor does not respond to treatment.

        -  Additional blood samples will be taken at regular intervals for the first 3 days after
           the first bortezomib dose and for the first 2 days after the first vorinostat dose of
           the first treatment cycle.
    

Detailed description: 
      Background:

      -The combination of vorinostat and bortezomib has been shown to be synergistic in vitro in a
      variety of malignancies, including hepatoma, multiple myeloma, leukemia, lymphoma, and
      gastrointestinal cancer. Currently several phase 2 adult studies are underway evaluating
      combination therapy.

      Objectives:

        -  To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of the
           combination of oral vorinostat administered on days 1-5 and 8-12 and bortezomib
           administered intravenously on days 1, 4, 8, 11, every 21 days to children with
           refractory or recurrent solid tumors.

        -  To define and describe the toxicities of vorinostat in combination with bortezomib
           administered on this schedule.

        -  To characterize the pharmacokinetics of vorinostat and bortezomib in combination in
           children with refractory or recurrent solid tumors.

        -  Secondary objectives include preliminary definition of the antitumor activity of these
           agents when administered together; and assessment of the biologic activity of bortezomib
           by measuring NF-kappaB activity in peripheral blood mononuclear cells (PBMC) and by
           measuring endoplasmic reticulum stress response using the GRP78 molecular chaperone
           marker in PBMC.

      Eligibility:

        -  Patients greater than12 months and less than or equal to 21 years of age with a
           diagnosis and histologic verification (except patients with instrinsic brain stem
           tumors, optic pathway gliomas or pineal tumors) of measureable or evaluable relapsed or
           refractory solid tumors including CNS tumors and lymphomas are eligible. Current disease
           state must be one for which there is no known curative therapy, or therapy proven to
           prolong survival.

        -  Performance score: Karnofsky greater than or equal to 60% for patients greater than 16
           years of age; Lansky greater than or equal to 60 for patients less than or equal to 16
           years of age.

        -  Must have fully recovered from acute toxic effects from all prior therapy which have
           been completed within the specified prior time frame. Have adequate organ function as
           determined by laboratory evaluation.

      Design:

        -  This is a phase I study of vorinostat administered orally once daily on days 1-5 and day
           8-12 in combination with bortezomib administered intravenously on days 1, 4, 8, and 11
           of a 21 day cycle. Disease evaluation will be performed after cycle 1 and then every 2
           cycles thereafter.

        -  Therapy may continue for up to 2 years in the absence of progressive disease or
           unacceptable toxicity.

        -  Optional participation in correlative biology studies or pharmacokinetic studies will be
           offered.
    

Intervention name(s): Vorinostat (SAHA); Velcade (PS-341, Bortezomib)
Intervention type(s): Drug; Drug
Intervention MeSH terms: Bortezomib; Vorinostat
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Solid Tumors; Maximum Tolerated Dose; Lymphoma; Dose Escalation; Pharmacokinetics; Pediatric Cancer; Solid Tumor; Sarcoma; Wilms Tumor; Neuroblastoma