RO4929097 and Vismodegib in Treating Patients With Breast Cancer That is Metastatic or Cannot Be Removed By Surgery
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|ClinicalTrials.gov Identifier: NCT01071564|
Recruitment Status : Terminated
First Posted : February 19, 2010
Last Update Posted : April 15, 2015
|Condition or disease||Intervention/treatment||Phase|
|Estrogen Receptor Negative HER2/Neu Negative Progesterone Receptor Negative Recurrent Breast Carcinoma Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Triple-Negative Breast Carcinoma||Drug: Gamma-Secretase Inhibitor RO4929097 Other: Laboratory Biomarker Analysis Other: Pharmacogenomic Study Other: Pharmacological Study Drug: Vismodegib||Phase 1|
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] 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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||13 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Study Start Date :||November 2009|
|Actual Primary Completion Date :||June 2014|
|Actual Study Completion Date :||June 2014|
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 Inhibitor RO4929097
Other Name: RO4929097
Other: Laboratory Biomarker Analysis
Other: Pharmacogenomic Study
Other Name: PHARMACOGENOMIC
Other: Pharmacological Study
- 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 ]
- Occurrence of adverse events and the associated National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade [ Time Frame: Up to 30 days after completion of study treatment ]
- Occurrence of DLTs and the associated NCI CTCAE grade [ Time Frame: 6 weeks ]
- Change in gene expression levels [ Time Frame: Baseline to up to 30 days ]Will be summarized with descriptive statistics appropriate to such distributions.
- Change in percentage of select BCSC biomarkers in the Hh and Notch signaling pathways [ Time Frame: Baseline to 2 weeks of intervention ]Will be summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and the 90% confidence interval for the mean).
- 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 ]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).
- Measurement of tumor response using RECIST criteria before and after treatment [ Time Frame: Up to 30 days after completion of study treatment ]Will be described by point estimates and exact 90% confidence intervals for proportions using Wilson's method.
- Pharmacogenetics (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 ]Summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and the 90% confidence interval for the mean).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01071564
|United States, Maryland|
|Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center|
|Baltimore, Maryland, United States, 21287|
|United States, Michigan|
|University of Michigan University Hospital|
|Ann Arbor, Michigan, United States, 48109|
|Barbara Ann Karmanos Cancer Institute|
|Detroit, Michigan, United States, 48201|
|Principal Investigator:||Patricia LoRusso||Barbara Ann Karmanos Cancer Institute|