RO4929097 and Vismodegib in Treating Patients With Breast Cancer That is Metastatic or Cannot Be Removed By Surgery
This phase I trial studies the side effects and best dose of RO4929097 when given together with vismodegib in treating patients with breast cancer that is metastatic or cannot be removed by surgery. RO4929097 and vismodegib may slow the growth of tumor cells and may be an effective treatment for advanced breast cancer
HER2-negative Breast Cancer
Recurrent Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Other: laboratory biomarker analysis
Other: pharmacological study
Other: pharmacogenomic studies
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Dose-Escalation Study of the Hedgehog Smoothened Antagonist GDC-0449 (NSC # 747691) Plus Pan-Notch Inhibitor RO4929097 (NSC # 749225) Administered in Patients With Advanced Breast Cancer|
- Occurrence of adverse events and the associated NCI CTCAE grade [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
- Occurrence of DLTs and the associated National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
- MTD and/or RP2D of gamma-secretase/Notch signalling pathway inhibitor RO4929097, determined according to incidence of DLT, graded using the NCI CTCAE [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
- Max concentration (Cmax), time to Cmax (tmax), terminal half-life (t1/2), area under curve 0-infinity (AUC0-inf), AUC 0-next dose (AUCtlast), accumulation index (AI), Cmax steady state (Css, max), and min concentration steady state (Css, min) [ Time Frame: Course 1 days 1-3 or days -2, -1, and 1; course 1 days 17 and 21; and course 2 days 1, 7, 10, and 11 ] [ Designated as safety issue: No ]Single and multiple-dose PK parameters summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and the 90% confidence interval for the mean).
- PG parameters, including, but not limited to, metabolizing enzymes (e.g., CYP3A5, 2C9, and UGT1A1) and transporters (e.g., ABCG2 and ABCB1) [ Time Frame: Baseline ] [ Designated as safety issue: No ]Summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and the 90% confidence interval for the mean).
- Measurement of tumor response using RECIST criteria before and after treatment [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]Will be described by point estimates and exact 90% confidence intervals for proportions using Wilson's method.
|Study Start Date:||August 2011|
|Estimated Primary Completion Date:||September 2013 (Final data collection date for primary outcome measure)|
Experimental: Treatment (RO4929097 and vismodegib)
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 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 QD beginning day 8 of course 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Other Names:Drug: vismodegib
Other Names:Other: laboratory biomarker analysis
Correlative studiesOther: pharmacological study
Other Name: pharmacological studiesOther: pharmacogenomic studies
Other Name: Pharmacogenomic Study
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.
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]) 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.
|United States, Maryland|
|Johns Hopkins University||Recruiting|
|Baltimore, Maryland, United States, 21287-8936|
|Contact: Vered Stearns 443-287-6489 firstname.lastname@example.org|
|Principal Investigator: Vered Stearns|
|United States, Massachusetts|
|Dana-Farber Harvard Cancer Center||Recruiting|
|Boston, Massachusetts, United States, 02115|
|Contact: Ian E. Krop IKROP@PARTNERS.ORG|
|Principal Investigator: Ian E. Krop|
|United States, Michigan|
|University of Michigan Comprehensive Cancer Center||Recruiting|
|Ann Arbor, Michigan, United States, 48109-0944|
|Contact: Max S. Wicha 734-936-1831 email@example.com|
|Principal Investigator: Max S. Wicha|
|Barbara Ann Karmanos Cancer Institute||Recruiting|
|Detroit, Michigan, United States, 48201|
|Contact: Patricia M. LoRusso 313-576-8716 firstname.lastname@example.org|
|Principal Investigator: Patricia M. LoRusso|
|Principal Investigator:||Patricia LoRusso||Barbara Ann Karmanos Cancer Institute|