Trial Information

A Phase 1/2 Study of RO4929097, An Oral Small Molecule Inhibitor of Gamma-Secretase, in Children With Relapsed/Refractory Solid or CNS Tumors, Lymphoma, or T-Cell Leukemia

Background:

- Notch signaling is aberrantly activated in a variety of human tumors including solid
tumors and hematological malignancies including T-cell leukemia (T-ALL) and pediatric
cancers, such as osteosarcoma, gliomas, medulloblastomas, ependymoma, and hematological
malignancies.

- One emerging strategy to inhibit Notch signaling is the use of gamma-secretase
inhibitors (GSIs), which prevent Notch receptor activation cleavage.

- RO4929097 is an orally administered small molecule that is a potent and selective GSI,
which has shown antitumor activity in preclinical studies.

Objectives:

- To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose, and
associated toxicities of RO4929097 administered orally to children with
relapsed/refractory solid tumors or lymphoma on 2 schedules: once daily orally on a 3
day on/4 day off weekly schedule (schedule A) and once daily for 5 consecutive days
weekly schedule (schedule B).

- To determine the MTD and recommended Phase 2 dose, and associated toxicities of
RO4929097 administered with dexamethasone.

- To characterize the pharmacokinetics of RO4929097 in children with refractory cancer.

- To preliminarily define the anti-tumor activity of RO4929097 in children with
refractory solid tumors within the confines of a phase I study.

- To determine initial efficacy on the anti-tumor activity of RO4929097 when combined
with dexamethasone in children with relapsed/refractory T-ALL.

- To study the effects of RO4929097 on components of the Notch signaling pathway in
peripheral blood mononuclear cells and/or T-ALL blasts, to examine archival tumor
samples for expression or amplification of target molecules, and to preliminarily
assess changes after treatment using FDG PET imaging.

Eligibility:

- Patients greater than 12 months and less than or equal to 21 years of age with a
diagnosis and histologic verification (except patients with intrinsic brain stem
tumors, optic pathway gliomas) of measureable or evaluable relapsed or refractory
disease. Current disease state must be one for which there is no known curative
therapy, or therapy proven to prolong survival with an acceptable quality of life.

- Subjects must be able to swallow tablets.

- Patients who are pregnant, are known to be serologically positive for Hepatitis A, B,
C, or have a history of liver disease, or have prolonged QTc are not eligible.

Design:

- This phase I study will first evaluate the safety and pharmacokinetics of RO4929097
administered orally to children with relapsed/refractory solid tumors (Part 1) on 2
schedules: once daily on a 3 day on/4 day off weekly schedule (Schedule A) and once
daily for 5 consecutive days weekly schedule (Schedule B).

- One cycle will be 28 days, and subjects may continue cycles in the absence of
progressive disease or unacceptable treatment-related toxicity to a total of 24 cycles.

- After determining MTD of RO4929097, an evaluation of RO4929097 plus concomitant
dexamethasone (Part 2) in at least one of the schedules tested in Part 1, will be
undertaken.

- After the MTD of RO4929097 plus dexamethasone has been identified, enrollment of
subjects with relapsed/refractory T-ALL (Part 3) will be undertaken to obtain initial
efficacy data in this patient population.