Gastrointestinal Stromal Tumor Clinical Trial
Official title:
A Phase 1B/II Study of GDC-0449 (NSC 747691) in Combination With RO4929097, a Gamma-Secretase Inhibitor (GSI) in Advanced/Metastatic Sarcomas
This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
PRIMARY OBJECTIVES:
I. To determine the maximum-tolerated dose (MTD) of gamma-secretase inhibitor RO4929097
(RO4929097) when given in combination with fixed-dose Hedgehog antagonist GDC-0449 (GDC-0449)
which will become the recommended dose for the phase II portion of this study. (Phase Ib) II.
To assess the progression-free survival (PFS) of the combination of RO4929097 with and
without GDC-0449 in two arms of patients with advanced sarcoma. (Phase II)
SECONDARY OBJECTIVES:
I. To describe the tolerability and adverse event profile of daily GDC-0449 administered
orally in combination with daily RO4929097 administered orally for 21 consecutive days.
(Phase Ib) II. To describe the pharmacokinetics of the combination of the combination of
GDC-0449 and RO4929097. (Phase Ib) III. To assess Response Evaluation Criteria In Solid
Tumors (RECIST) 1.1 overall response rates (complete and partial response [CR+PR]) for
combination therapy. (Phase Ib and II) IV. To conduct pharmacodynamic studies in tissue
biopsies (pre- and post-study) for explorative and hypothesis-generating studies. (Phase Ib
and II) V. To assess overall survival. (Phase II) VI. To further describe the
pharmacokinetics and pharmacodynamics of the combination of GDC-0449 and RO4929097 at the
phase II dose at the continuous schedule. (Phase II) V. To conduct pharmacodynamic studies in
tissue biopsies (pre- and post- study drug[s]) for explorative and hypothesis generating
studies. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of gamma-secretase/notch signalling pathway
inhibitor RO4929097 followed by a phase II study.
PHASE IB:
PART A: Patients receive vismodegib orally (PO) once daily (QD) on days 1-21.
PART B: Beginning within 7 days of finishing part A, patients receive vismodegib PO and
gamma-secretase/notch signalling pathway inhibitor RO4929097 PO QD on days 1-21. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive gamma-secretase/notch signalling pathway inhibitor RO4929097 PO QD on
days 1-21.
ARM II: Patients receive vismodegib PO and gamma-secretase/notch signalling pathway inhibitor
RO4929097 PO QD on days 1-21.
In both arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up for 4 weeks.
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