Gamma-Secretase Inhibitor RO4929097 in Treating Young Patients With Relapsed or Refractory Solid Tumors, CNS Tumors, Lymphoma, or T-Cell Leukemia

OBJECTIVES:

Primary

- To estimate the maximum-tolerated dose (MTD) and recommend a phase II dose of
gamma-secretase inhibitor RO4929097 administered orally to children with relapsed or
refractory solid tumors or lymphoma on two schedules: once daily orally on a 3-day
on/4-day off weekly schedule (schedule A) or once daily for 5 consecutive days weekly
schedule (schedule B).

- To define and describe the toxicities of this drug administered on these schedules to
children with relapsed or refractory solid tumors, lymphoma, or T-cell leukemia.

- To estimate the MTD and recommended phase II dose of gamma-secretase inhibitor
RO4929097 administered with dexamethasone.

- To define and describe the toxicities of gamma-secretase inhibitor RO4929097
administered with dexamethasone.

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

Secondary

- To preliminarily define the antitumor activity of gamma-secretase inhibitor RO4929097
in children with solid or CNS tumors and lymphoma within the confines of a phase I
study.

- To obtain initial efficacy data on the antitumor activity of gamma-secretase inhibitor
RO4929097 when combined with dexamethasone in children with relapsed-refractory T-cell
leukemia (T-acute lymphoblastic leukemia [ALL]).

- To study the effect of gamma-secretase inhibitor RO4929097 on Hes1 (hairy/enhancer of
split) and other components of the Notch signaling pathway in peripheral blood
mononuclear cells and/or T-ALL blasts. (exploratory)

- To examine archival tumor samples for expression of JAGGED1, JAGGED2, cleaved NOTCH1,
and HES1, and HES5 by IHC and for amplification of NOTCH1 or NOTCH2 using FISH
analysis. (exploratory)

- To preliminarily assess changes following treatment with gamma-secretase inhibitor
RO4929097 using FDG PET imaging. (exploratory)

OUTLINE: This is a multicenter, phase I, dose-escalation study of gamma-secretase inhibitor
RO4929097 followed by a phase II study. Patients are enrolled sequentially to group A or B.

- Group A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days
1-3, 8-10, 15-17, and 22-24. Treatment repeats every 28 days for up to 24 courses in
the absence of disease progression or unacceptable toxicity.

- Group B: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days
1-5, 8-12, 15-19, and 22-26. Treatment repeats every 28 days for up to 24 courses in
the absence of disease progression or unacceptable toxicity.

Patients may also receive concurrent oral dexamethasone twice daily on the days of
gamma-secretase inhibitor RO4929097 administration.

Once the MTD or recommended phase II dose of RO4929097 plus dexamethasone in children with
solid tumors, including CNS tumors, or lymphoma has been identified, this dose is used for
patients with relapsed-refractory T-ALL (phase 2 portion of the study) to evaluate RO4929097
in combination with dexamethasone using one of the studied schedules.

Blood, plasma, bone marrow, and tumor tissue samples may be collected at baseline and
periodically during the first course for correlative lab and tumor studies, including
pharmacokinetics.

After completion of study treatment, patients are followed up for up to 30 days.