This phase I trial studies the side effects and the best dose of gamma-secretase inhibitor RO4929097 when given together with paclitaxel and carboplatin in patients with stage II or stage III triple-negative breast cancer. Gamma-secretase inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs use in chemotherapy, such as paclitaxel and carboplatin, 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 gamma-secretase inhibitor RO4929097 together with paclitaxel and carboplatin before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
PRIMARY OBJECTIVES: I. To determine the maximum-tolerated dose (MTD) and dose limiting toxicity (DLT) of RO4929097 (gamma-secretase inhibitor RO4929097) given 3 days on, 4 days off in combination with weekly paclitaxel and every 3 weeks carboplatin that will not cause a 30% or more decrease in paclitaxel area under the plasma-concentration time curve (AUC)0-24hr on day 15 compared to day -1 in patients with clinical stage II-III triple negative breast cancer (TNBC). SECONDARY OBJECTIVES: I. To measure real-time pharmacokinetics of RO4929097 when administered in combination with weekly paclitaxel and every 3 weeks carboplatin in patients with stage II-III TNBC. II. To measure real-time pharmacokinetics of paclitaxel when administered in combination with RO4929097 (3 days on, 4 days off) and every 3 weeks carboplatin in patients with stage II-III TNBC. III. To evaluate the rate of pathologic and clinical complete response to the treatment with combination of RO492097, paclitaxel, and carboplatin in patients with clinical stage II-III TNBC. OUTLINE: This is a dose-escalation study of gamma secretase inhibitor RO4929097 (RO4929097). Patients receive gamma-secretase inhibitor RO4929097 orally (PO) once daily (QD) on days 1-3, 8-10, and 15-17, paclitaxel intravenously (IV) over 60 minutes on days 1, 8, and 15 (day -1 of course one), and carboplatin IV over 60 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Within 4 weeks after completion of neoadjuvant therapy, patients undergo definitive breast surgery. After completion of study treatment, patients are followed up for 1 year.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Given IV
Given PO
Correlative studies
Given IV
Ancillary studies
Undergo surgery
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Incidence of adverse events of gamma-secretase inhibitor RO4929097 as assessed by CTCAE v 4.0
Time frame: Up to 1 year
MTD of gamma-secretase inhibitor RO4929097 based on DLT as assessed by CTCAE version (v) 4.0
Analysis will consist of descriptive statistics only. Frequency will be computed for discrete variables with 95% confidence intervals for the proportion.
Time frame: 21 days
Pharmacokinetic parameters of gamma-secretase inhibitor RO4929097 and paclitaxel
AUC0-24hrs, clearance, maximum concentration, and maximum time (for gamma-secretase inhibitor RO4929097 only) when each drug is administered alone versus when they are co-administered will be compared. Only descriptive statistics will be provided.
Time frame: At baseline, at 30, 55, 70 and 90 minutes, and 2, 3, 4, 6, 8 and 24 hours of days 1, 8, 15, and 17 of course 1
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