This phase I clinical trial studies the side effects and the best dose of dinaciclib when given together with epirubicin hydrochloride (epirubicin) in patients with metastatic (cancer that has spread to other parts of the body) triple-negative breast cancer. Dinaciclib is designed to stop cancer cells from dividing into new cancer cells. Epirubicin is designed to block the way cancer cells grow and divide and may slow or stop cancer cells from spreading throughout the body. Researchers want to find out what is the highest tolerable dose of the experimental drug dinaciclib that can be given in combination with epirubicin in patients with metastatic triple negative breast cancer.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of dinaciclib given in combination with epirubicin in patients with metastatic triple negative breast cancer. SECONDARY OBJECTIVES: I. To determine the predictive value of myeloid cell leukemia sequence 1 protein (MCL-1), low molecular weight cyclin E (LMW-E), and tumor grade as predictors of biologic response (i.e. induction of apoptosis) in tumors treated with therapy. II. To evaluate the efficacy of combination therapy. III. To determine the effects of therapy on proliferation as measured by proliferation-related Ki-67 antigen (Ki67) and apoptosis as measured by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling assay (TUNEL). OUTLINE: This is a dose-escalation study of dinaciclib. Patients receive dinaciclib intravenously (IV) over 2 hours on day 1 and epirubicin hydrochloride IV over 30 minutes on day 2. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
M D Anderson Cancer Center
Houston, Texas, United States
MTD of dinaciclib given in combination with epirubicin hydrochloride, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4
The number (%) of DLTs will tabulate by dose level of dinaciclib.
Time frame: 21 days
Predictive value of MCL-1, LMW-E, and tumor grade as predictors of biologic response (i.e. induction of apoptosis) in tumors treated with therapy
A logistic regression model will be used to assess whether the expression level of LMW-E can predict clinical benefit, adjusted for dose level and other potential prognostic factors: visceral organ involvement (present vs. absent), number of prior therapies for metastatic breast cancer (0-2 or \> 2), age (\< 60 vs. \> 60) and ECOG performance status (0-1 vs. 2).
Time frame: Up to 30 days after completion of study treatment
Clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD]), assessed using Response Evaluation Criteria in Solid Tumors (RECIST)
The overall clinical benefit rate for patients treated at the MTD will be estimated with a 90% credible interval.
Time frame: At 6 months
Changes in proliferation as measured by Ki67 and apoptosis as measured by TUNEL
For the patients with pre- and post- treatment biopsies, summary statistics used to describe change in apoptotic index pre- to post-treatment, and boxplots to illustrate distribution pre- and post-treatment, as well as distribution of change. Mean change estimated with 95% confidence interval. MCL-1, LMW-E, and Ki67 similarly analyzed. Analyses also performed stratified by tumor grade. Correlation between changes in MCL-1 and LMW-E pre- to post-treatment estimated with 95% confidence interval. Number of tumors in 4 categories (negative, low, medium, high) tabulated by % of TUNEL+ tumor cells.
Time frame: From baseline to 2 weeks
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