Trial Information

A Phase I Study of Vorinostat and Bortezomib in Children With Refractory of Recurrent Solid Tumors, Including CNS Tumors and Lymphomas

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.