This phase II trial studies how well radium-223 dichloride and paclitaxel work in treating patients with advanced breast cancer that has spread to the bones. Radium-223 dichloride is a radioactive drug that behaves in a similar way to calcium and collects in cancer that has spread to the bones (bone metastases). The radioactive particles in radium-223 dichloride act on bone metastases, killing the tumor cells and reducing the pain that they can cause. Drugs used in chemotherapy, such as paclitaxel, 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 radium-223 dichloride and paclitaxel may work better in treating patients with metastatic breast cancer compared to paclitaxel alone.
PRIMARY OBJECTIVE: I. To determine if the combination of radium-23 dichloride (radium Ra 223 dichloride) and paclitaxel improves progression-free survival (PFS) compared to paclitaxel alone. SECONDARY OBJECTIVES: I. To determine the time to the first symptomatic skeletal event (SSE) (defined as 1st use of radiation therapy to relieve skeletal symptoms, new symptomatic pathologic vertebral or non-vertebral bone fractures, spinal cord compression, or tumor-related orthopedic surgical intervention). II. To measure the objective response rate (ORR). III. To determine the safety of radium-223 dichloride with paclitaxel. IV. To measure overall survival (OS). EXPLORATORY OBJECTIVES: I. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES) and messenger ribonucleic acid (RNA) sequencing (RNAseq), in order to: Ia. Investigate if molecular alterations in deoxyribonucleic acid (DNA) repair genes are associated with response to radium-223 dichloride, and; Ib. Investigate if loss of heterozygosity in triple negative tumors is associated with response to radium-223 dichloride. II. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome. III. To correlate change in level of total alkaline phosphatase, bone-specific alkaline phosphatase, and serum osteocalcin to response to radium-223 dichloride therapy. IV. To examine the radium-223 dichloride bio-distribution and absorbed dose in each bone metastatic lesions as well as elsewhere in the body including critical organs using dosimetry. V. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood, and nucleic acids obtained from patients at the Experimental Therapeutics Clinical Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital. VI. To explore the symptomatic adverse events (AE) for tolerability of each treatment arm. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15 and radium Ra 223 dichloride IV over 1 minute on day 1 of each cycle. Treatment with radium Ra 223 dichloride repeats every 28 days for 6 cycles and treatment with paclitaxel repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) scan, bone scan and/or magnetic resonance imaging (MRI), as well as collection of blood samples throughout trial. Patients may optionally undergo single photon emission computed tomography (SPECT) on trial. ARM II: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan, bone scan, and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial. After completion of study treatment, patients are followed up at 30 days, then every 3 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
70
Correlative studies
Undergo bone scan
Undergo CT scan
Ancillary studies
Undergo MRI
Given IV
Given IV
Undergo SPECT
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, United States
Progression-free survival (PFS)
Tumor progression will be determined from radiographic scans performed every 8 weeks (computed tomography and bone scan) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The log-rank test will be used to analyze PFS for comparison of treatment effects, i.e., the only covariate that will be used is the treatment arm. Distributions of PFS times will be estimated using the Kaplan-Meier product-limit method.
Time frame: From randomization to the first documented tumor progression or death due to any cause, whichever occurred first, assessed up to 2 years
PFS
Treatment comparison in PFS will be conducted in pre-defined subgroups, including hormone receptor status and presence/absence of visceral metastases and two-sided 80% confidence intervals (CIs) will be provided for each subgroup.
Time frame: From randomization to the first documented tumor progression or death due to any cause, whichever occurred first, assessed up to 2 years
Time to first symptomatic skeletal event (SSE)
Will be defined as the first use of radiation therapy to relieve skeletal symptoms, new symptomatic pathologic vertebral or non-vertebral bone fractures, spinal cord compression, or tumor-related orthopedic surgical intervention. Distributions of time to SSE will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
Time frame: From randomization to the occurrence of the first SSE, assessed up to 2 years
Objective response rate
Will be defined as the proportion of all subjects with confirmed partial response or complete response according to RECIST 1.1.
Time frame: From start of treatment until disease progression, assessed up to 2 years
Overall survival (OS)
The log-rank test will be used as the primary analysis for comparison of treatment effects, i.e., the only covariate that will be used is the treatment arm. Distributions of OS times will be estimated using the Kaplan-Meier product-limit method. The median OS times with two-sided 95% CIs will be estimated for each treatment group.
Time frame: From randomization to death due to any cause, assessed up to 2 years
Incidence of adverse events (AEs)
Will be assessed by grading all treatment-related AEs and events of clinical interest according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Grade 3 or higher diarrhea or constipation are ECI for the proposed trial. Adverse events will be summarized according to grade, overall and by treatment arm, as number and percentage of participants. All adverse events resulting in discontinuation, dose modification, and/or dosing interruption, and/or treatment delay of drug will also be summarized by treatment arm.
Time frame: Up to 30 days after end of study treatment
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, United States
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States
...and 20 more locations