Stage IV Breast Cancer Clinical Trial
Official title:
A Phase I Study of the Hedgehog Smoothened Antagonist GDC-0449 (NSC # 747691) Plus Pan-Notch Inhibitor RO4929097 (NSC # 749225) Administered in Patients With Advanced Breast Cancer
This phase I trial studies the side effects and best dose of RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) when given together with vismodegib in treating patients with breast cancer that is metastatic or cannot be removed by surgery. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as vismodegib, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving RO4929097 and vismodegib together may slow the growth of tumor cells and may be a more active treatment for advanced breast cancer.
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of continuous daily administration of 150 mg/day
of GDC0449 (vismodegib) in combination with escalating doses of RO4929097
(gamma-secretase/Notch signalling pathway inhibitor RO4929097) administered on a repeated
schedule of days 1-3, 8-10 every 21 days (for a total of 6 days of RO4929097 administration
per 21 day cycle) in patients with advanced breast cancer.
II. To determine the dose limiting toxicity (DLT) and identify the maximum tolerated dose
(MTD) and/or recommended phase 2 dose (RP2D) for this administration schedule.
SECONDARY OBJECTIVES:
I. To determine the pharmacokinetics (PK) and pharmacogenetics (PG) of GDC0449 and
RO4929097, each alone and in combination.
II. To attempt to evaluate select pharmacodynamic (PD) stem cell differentiation biomarkers
in the hedgehog and notch signaling pathways (e.g. GLI family zinc finger [Gli]1/2/3,
patched [Ptch] 1/2, hairy and enhancer of split 1, [Drosophila] [Hes1], huntingtin
interacting protein 1 [Hip1], hairy/enhancer-of-split related with YRPW motif 1 [Hey1],
Notch4, Jagged1, numb homolog [Drosophila] [numb], BMI1 polycomb ring finger oncogene
[Bmi-1], cluster of differentiation [CD]44/CD24, aldehyde dehydrogenase [ALDH]
proto-oncogene tyrosine-protein kinase [Src] family kinases) and the percentage of breast
cancer stem cell (BCSC) in serial breast tumor biopsies before and after GDC0449 or
RO4929097 alone and after 1 cycle of treatment with the combination of GDC0449 and
RO4929097.
III. To determine tumor response in patients with measurable disease as assessed by the
Response Evaluation Criteria in Solid Tumors (RECIST).
IV. To perform molecular profiling of the tumor cell and BCSC populations before and after
GDC0449 or RO4929097 alone and after 1 cycle of treatment with the combination of GDC0449
and RO4929097 at the MTD.
OUTLINE: This is a dose-escalation study of gamma-secretase/Notch signalling pathway
inhibitor RO4929097.
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) on
day 1 or days -2, -1, and 1 of course 1 and days 1-3 and 8-10 of course 2 and all subsequent
courses. Patients also receive vismodegib PO once daily (QD) beginning day 8 of course 1.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
;
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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