A Phase I Study of Various Administration Schedules of RO4929097 With Multi-parameter Assessment (Biomarkers, Pharmacokinetics, Pharmacodynamics) in Patients With Advanced Solid Cancers
I. To determine the safety profile of 6 different administration schedules of
gamma-secretase inhibitor RO4929097 in patients with advanced solid malignancies.
I. To determine pharmacokinetic (PK) parameters of gamma-secretase inhibitor RO4929097
administered using 6 different administration schedules.
II. To assess the preliminary antitumor activity of gamma-secretase inhibitor RO4929097 in
I. To assess the pharmacodynamic (PD) effects of gamma-secretase inhibitor RO4929097 on
Notch signaling pathway in tumor and surrogate tissues, as well as soluble markers of
angiogenesis in plasma, when administered using 6 different dosing schedules. (Exploratory)
II. To evaluate the relationship between PK and PD effects in an attempt to define the
optimal biological dosing schedule (OBDS) that can provide a sustained inhibition of Notch
signaling pathway over time with a tolerable toxicity profile. (Exploratory) III. To
correlate inhibition of Notch signaling pathway measured in tumor and surrogate tissues with
preliminary antitumor activity and assess the potential clinical predictive value of OBDS as
defined above. (Exploratory) IV. To assess the effect of the various pharmacogenomic
polymorphisms of the cytochrome P450 pathway on PK and PD parameters. (Exploratory)
OUTLINE: This is a multicenter, dose-escalation study. Patients are assigned to 1 of 6 dose
GROUP A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3
GROUP B: Patients receive oral RO4929097 once daily on days 1-7.
GROUP C: Patients receive oral RO4929097 once daily on days 1, 3, 5, 7, 9, 11, 13, 15, 17,
19, and 21.
GROUP D: Patients receive oral RO4929097 once daily on days 1, 8, and 15.
GROUP E: Patients receive oral RO4929097 once daily on days 1, 4, 8, 11, 15, and 18.
GROUP F: Patients receive oral RO4929097 once daily days 1-5, 8-12, and 15-19.
Treatment in all groups repeats every 3 weeks in the absence of disease progression or
unacceptable toxicity. Patients undergo tumor biopsies at baseline and between days 15 and
22 in the first course of treatment. Plasma samples are collected periodically for
pharmacokinetic, pharmacodynamic, and pharmacogenomic analysis and to assess levels of
adipsin and markers of angiogenesis.
After completion of study treatment, patients are followed up for 4 weeks.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety profile of six different administration schedules of RO4929097
Up to 4 weeks
University Health Network-Princess Margaret Hospital
United States: Food and Drug Administration