Titre officiel
A Phase I Study of Various Administration Schedules of RO4929097 With Multi-parameter Assessment (Biomarkers, Pharmacokinetics, Pharmacodynamics) in Patients With Advanced Solid Cancers
Sommaire:
JUSTIFICATION : Les inhibiteurs enzymatiques, par exemple l’inhibiteur de la
gamma-sécrétase RO4929097, pourraient stopper la multiplication des cellules
tumorales en inhibant certaines des enzymes nécessaires à la croissance
cellulaire.
BUT : Cet essai de phase I vise à déterminer les effets
secondaires ainsi que la dose et le mode d’administration optimaux de
l’inhibiteur de la gamma-sécrétase RO4929097 pour le traitement des patients
atteints d’une tumeur maligne solide métastatique ou non résécable.
Description de l'essai
Primary Outcome:
- Safety profile of six different administration schedules of RO4929097
Secondary Outcome:
- Determination of pharmacokinetic profiles of various administration schedules
- Preliminary antitumour activity of RO4929097 assessed using RECIST 1.1 criteria
- Pharmacokinetic (PK) parameters of RO4929097 administered using six different dosing schedules
PRIMARY OBJECTIVES:
I. To determine the safety profile of 6 different administration schedules of
gamma-secretase inhibitor RO4929097 in patients with advanced solid malignancies.
SECONDARY OBJECTIVES:
I. To determine pharmacokinetic (PK) parameters of gamma-secretase inhibitor RO4929097
administered using 6 different administration schedules.
II. To assess the preliminary antitumour activity of gamma-secretase inhibitor RO4929097 in
these patients.
TERTIARY OBJECTIVES:
I. To assess the pharmacodynamic (PD) effects of gamma-secretase inhibitor RO4929097 on
Notch signaling pathway in tumour 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 tumour and surrogate tissues with
preliminary antitumour 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 multicentre, dose-escalation study. Patients are assigned to 1 of 6 dose
schedules.
GROUP A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3
and 8-10.
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 tumour 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.
Voir cet essai sur ClinicalTrials.gov
