Biomarkers of RO4929097and Other Drugs in Treating Patients With Metastatic or Unresectable Solid Tumors

OBJECTIVES:

Primary

- To evaluate the extent that gamma-secretase inhibitor RO4929097 (RO4929097) induces its
own metabolism by comparing plasma pharmacokinetic parameters of a lower-dose versus a
higher-dose of RO4929097 on days 1 and 10 of course 1.

Secondary

- To evaluate the effect of ketoconazole, a strong inhibitor of CYP3A4, on RO4929097
plasma pharmacokinetics.

- To evaluate the effect of rifampin, a strong inducer of CYP3A4, 2D6 and 2C9, on
RO4929097 plasma pharmacokinetics.

- To evaluate the effect of RO4929097 on the plasma pharmacokinetics of CYP450
substrates; midazolam hydrochloride (CYP3A4), omeprazole (CYP2C19), tolbutamide
(CYP2C9), and dextromethorphan (CYP2D6) after single-dose and chronic administration.

- To assess the influence of polymorphisms in CYP3A4, 3A5, 2C9, ABCB1, and 2D6 on
RO4929097 plasma pharmacokinetics.

- To assess any evidence of clinical activity (CR, PR, SD) in patients with advanced
solid tumors treated with RO4929097.

OUTLINE: Patients are randomized to 1 of 2 treatment regimens.

- Regimen I (low-dose of oral gamma-secretase inhibitor RO4929097 [RO4929097]): Patients
receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17 and midazolam
hydrochloride IV, oral omeprazole, oral tolbutamide, and oral dextromethorphan
hydrobromide on days 1 and 10. After completion of course 1, patients are randomized to
1 of 2 treatment arms.

- Arm I: Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and 15-17
and oral ketoconazole once daily on days 1-10 for course 2 only.

- Arm II: Patients receive low-dose RO4929097 once daily on days 1-3, 8-10, and
15-17 and oral rifampin once daily on days 1-10 for course 2 only.

- Regimen II (high-dose of RO4929097): Patients receive high-dose RO4929097 once daily on
days 1-3, 8-10, and 15-17 and midazolam hydrochloride IV, oral omeprazole, oral
tolbutamide, and oral dextromethorphan hydrobromide on days 1 and 10. After completion
of course 1, patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and
15-17 and oral ketoconazole once daily on days 1-10 for course 2 only.

- Arm II: Patients receive high-dose RO4929097 once daily on days 1-3, 8-10, and
15-17 and oral rifampin once daily on days 1-10 for course 2 only.

- In all arms, treatment with RO4929097 repeats every 21 days for ≥ 3 courses in the
absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetics studies and evaluation of SNPs in CYP2D6, CYP2C9, ABCB1, and CYP3A4/5.

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