This phase Ib trial studies the side effects and best dose onalespib when given together with paclitaxel in treating patients with triple negative breast cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Onalespib works by blocking proper processing of proteins that are important for cancer growth. This results in inability of these proteins to work properly. Paclitaxel kills breast cancer cells by interfering with their ability to divide. Giving onalespib together with paclitaxel may be better than giving either one alone in treating patients with breast cancer.
PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) of onalespib (AT13387) in combination with paclitaxel in patients with advanced triple negative breast cancer (TNBC). II. To determine the toxicity profile (based on Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v.\]5.0) of the combination of AT13387 in combination with paclitaxel in patients with advanced TNBC. SECONDARY OBJECTIVES: I. To determine the effect of AT13387 on pharmacokinetics of paclitaxel in the study patient population. II. To determine the effect of paclitaxel on pharmacokinetics of AT13387 in the study patient population. III. To observe anti-tumor activity determining the overall response rate (partial response + complete response), response duration and progression-free survival. OUTLINE: This is a dose-escalation study of onalespib. SAFETY RUN-IN: Patients receive onalespib intravenously (IV) over 1 hour on day -7. TREATMENT: Patients receive paclitaxel IV over 60 minutes on day 1, 8, and 15. Patients also receive onalespib IV over 1 hour beginning on days 8 and 15 of cycle 1 and on days 1, 8, and 15 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
31
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
Recommended phase 2 dose (R2PD)
Defined as level at which no more than 1 of 6 patients experience a dose limiting toxicity (maximum tolerated dose or \[MTD\]); or doses of the combination below MTD, if in the opinion of the investigators, lower doses are better tolerated and safer.
Time frame: Up to 28 days
Toxicity profile of onalespib in combination with paclitaxel
Will be based on the Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5.0.
Time frame: Up to 2 years
Pharmacokinetic (PK) parameters of onalespib
A descriptive analysis will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Time frame: Pre-dose, immediately prior to end of infusion, 0.5, 1, 2, 4, 6, 8, and 24 hours after end of infusion on day -7 of course 1 and day 8 (and prior to starting paclitaxel, and immediately prior to end of infusion of paclitaxel on day 8)
Pharmacokinetic (PK) parameters of paclitaxel
A descriptive analysis will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Time frame: Pre-dose, immediately prior to end of infusion, 0.5, 1, 2, 4, 6, 8, and 24 hours after end of infusion on days 1 and 8 of course 1 (and immediately prior to end of infusion of onalespib, prior to starting paclitaxel on day 8)
Overall response rate (partial response [PR]+ complete response [CR])
Will be assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Overall response will be assessed in all patients in an exploratory manner, using summary statistics, by dose level. Will also calculate corresponding 95% binomial confidence intervals for these response rates.
Time frame: Up to 6 months
Response duration
Will be based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Time frame: From the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years
Progression-free survival
Progression free survival will be summarized using Kaplan and Meier methods, where patients who are event-free at the time of their last evaluation will be censored at that time point.
Time frame: From study enrollment to first documented disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause (whichever occurs first), assessed up to 2 years
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