Phase II Trial of Radium-223 Dichloride in Combination With Paclitaxel in Patients With Bone Metastatic Breast Cancer
Overview
- Phase
- Phase 2
- Intervention
- Biospecimen Collection
- Conditions
- Anatomic Stage IV Breast Cancer AJCC v8
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 70
- Locations
- 30
- Primary Endpoint
- Progression-free survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Women or men with metastatic breast cancer with two or more bone metastases identified by technetium Tc-99m (99mTc) bone scintigraphy and/or CT, at least one of these bone lesions must not have been treated with prior radiation therapy
- •A diagnosis of breast cancer must have been histologically or cytologically confirmed at any time point
- •Patients with non-bone metastases (in addition to bone metastases) are permitted if:
- •Five or less visceral metastasis (=\< 4 cm in size) and asymptomatic (not including lymph nodes)
- •Enlarged lymph nodes =\< 4 cm
- •Patients with HER2 negative disease (HER2 negativity by immunohistochemistry \[IHC\] or fluorescent in situ hybridization \[FISH\] ratio according to the American Society of Clinical Oncology-College of American Pathologists guideline criteria) (Hammond et al., 2010; Wolff et al., 2013). Hormone-receptor positive (estrogen receptor \[ER\]-positive and/or progesterone receptor \[PR\]-positive) as well as triple-negative (ER-negative, PR-negative and no overexpression of HER2) breast cancer may be enrolled. Hormone receptor status will be determined at the local institution. ER and PR negativity will be defined as \< 1% tumor staining by IHC
- •Patient must be eligible to receive therapy with paclitaxel for the treatment of their breast cancer. Patients with hormone-receptor positive disease should have progressed on at least one prior line of hormone therapy and a CDK4/6 inhibitor in the metastatic setting to be eligible (except if patient had a contraindication or intolerable toxicity with the use of these agents). Previous radiation and chemotherapy for the treatment of metastatic breast cancer is allowed
- •Age \>= 18 years
- •Because no dosing or AE data are currently available on the use of radium-223 dichloride in combination with paclitaxel in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
Exclusion Criteria
- •Patients with peripheral neuropathy \> grade 1
- •Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia
- •Patients who have had chemotherapy or immunotherapy with checkpoint inhibitor within 4 weeks prior to treatment. Patient who receives radiation therapy or hormone therapy within 2 weeks prior to treatment are excluded. For patients on trial therapy prior to study enrollment, washout period of 6 times the half-life of previously administered investigational agents prior to starting radium-223 dichloride is required
- •Prior therapy with radionuclides (e.g., strontium, samarium, rhenium, radium)
- •Patients who are receiving any other investigational agents. Vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is allowed as well as any therapy as required for the treatment of active coronavirus disease 2019 (COVID-19) infection
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to radium-223 dichloride or other agents used in study
- •Patients with psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant women are excluded from this study because radium-223 dichloride is an alpha particle-emitting radiopharmaceutical agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with radium-223 dichloride, breastfeeding should be discontinued if the mother is treated with radium-223 dichloride. These potential risks may also apply to other agents used in this study
- •Imminent/established spinal cord compression, pathological fracture in weight bearing bones or bone lesion with soft tissue component unless treated as appropriate with radiation and/or surgery before starting on trial
- •Prior hemibody external radiotherapy
Arms & Interventions
Arm I (paclitaxel, radium Ra 223 dichloride)
Patients receive paclitaxel 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 CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.
Intervention: Biospecimen Collection
Arm I (paclitaxel, radium Ra 223 dichloride)
Patients receive paclitaxel 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 CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.
Intervention: Magnetic Resonance Imaging
Arm I (paclitaxel, radium Ra 223 dichloride)
Patients receive paclitaxel 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 CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.
Intervention: Paclitaxel
Arm II (paclitaxel)
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.
Intervention: Biospecimen Collection
Arm II (paclitaxel)
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.
Intervention: Computed Tomography
Arm II (paclitaxel)
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.
Intervention: Paclitaxel
Arm I (paclitaxel, radium Ra 223 dichloride)
Patients receive paclitaxel 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 CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.
Intervention: Bone Scan
Arm I (paclitaxel, radium Ra 223 dichloride)
Patients receive paclitaxel 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 CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.
Intervention: Electronic Health Record Review
Arm I (paclitaxel, radium Ra 223 dichloride)
Patients receive paclitaxel 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 CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.
Intervention: Radium Ra 223 Dichloride
Arm II (paclitaxel)
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.
Intervention: Electronic Health Record Review
Arm II (paclitaxel)
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.
Intervention: Magnetic Resonance Imaging
Arm I (paclitaxel, radium Ra 223 dichloride)
Patients receive paclitaxel 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 CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.
Intervention: Computed Tomography
Arm II (paclitaxel)
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.
Intervention: Single Photon Emission Computed Tomography
Arm II (paclitaxel)
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.
Intervention: Bone Scan
Arm I (paclitaxel, radium Ra 223 dichloride)
Patients receive paclitaxel 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 CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.
Intervention: Single Photon Emission Computed Tomography
Outcomes
Primary Outcomes
Progression-free survival (PFS)
Time Frame: From randomization to the first documented tumor progression or death due to any cause, whichever occurred first, assessed up to 2 years
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.
Secondary Outcomes
- Objective response rate(From start of treatment until disease progression, assessed up to 2 years)
- PFS(From randomization to the first documented tumor progression or death due to any cause, whichever occurred first, assessed up to 2 years)
- Overall survival (OS)(From randomization to death due to any cause, assessed up to 2 years)
- Incidence of adverse events (AEs)(Up to 30 days after end of study treatment)
- Time to first symptomatic skeletal event (SSE)(From randomization to the occurrence of the first SSE, assessed up to 2 years)