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Testing the Addition of Radium Therapy (Radium-223 Dichloride) to the Usual Chemotherapy Treatment (Paclitaxel) for Advanced Breast Cancer That Has Spread to the Bones

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04090398
Recruitment Status : Recruiting
First Posted : September 16, 2019
Last Update Posted : October 5, 2021
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
Anatomic Stage IV Breast Cancer AJCC v8 Hormone Receptor-Positive Breast Carcinoma Metastatic Breast Carcinoma Metastatic HER2-Negative Breast Carcinoma Metastatic Malignant Neoplasm in the Bone Metastatic Triple-Negative Breast Carcinoma Prognostic Stage IV Breast Cancer AJCC v8 Drug: Paclitaxel Radiation: Radium Ra 223 Dichloride Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Radium-223 Dichloride in Combination With Paclitaxel in Patients With Bone Metastatic Breast Cancer
Actual Study Start Date : December 27, 2019
Estimated Primary Completion Date : June 30, 2022
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: 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. 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.
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Radiation: Radium Ra 223 Dichloride
Given IV
Other Names:
  • Alpharadin
  • BAY 88-8223
  • BAY88-8223
  • Radium 223 Dichloride
  • Radium-223 Dichloride
  • Xofigo

Active Comparator: Arm II (paclitaxel)
Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. 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 ]
    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.

  2. Time to first symptomatic skeletal event (SSE) [ Time Frame: Time from randomization to the occurrence of the first SSE, assessed up to 2 years ]
    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.

  3. Objective response rate [ Time Frame: From start of treatment until disease progression, assessed up to 2 years ]
    Will be defined as the proportion of all subjects with confirmed partial response or complete response according to RECIST 1.1.

  4. Overall survival (OS) [ Time Frame: Time from randomization to death due to any cause, assessed up to 2 years ]
    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.

  5. Incidence of adverse events (AEs) [ Time Frame: Up to 30 days after end of study treatment ]
    Will be assessed by grading all treatment-related AEs and events of clinical interest (ECI) according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 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.

  6. Fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET)/computed tomography (CT) response [ Time Frame: Up to day 1 of cycle 4 (each cycle = 28 days) ]
    Will be measured by PET Response Criteria in Solid Tumors at baseline and after cycle 3 (between treatments on cycle 3, day 15 and cycle 4, day 1). The peak SUL of hottest single tumor lesion with maximal 1.2 - cm diameter volume region of interest (ROI) (SULpeak) will be measured. The longest diameters and SULpeak of target lesions (up to 5 of the hottest lesions) on the PET/CT images before and after treatment will be measured (Wahl et al., 2009). Tumor response by PERCIST will be summarized as number and percentage of participants with complete response, partial response, stable disease, and progressive disease by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.

Other Outcome Measures:
  1. Qualitative or semi-quantitative 18F-FDG PET/CT reporting of standardized uptake value (SUV) [ Time Frame: Up to 2 years ]
    Quantitative imaging biomarkers will be used for 18F-FDG-PET scan analysis as recommended. Two levels of SUV analysis will be performed: lesion level, in which SUV metrics will be extracted from each lesion ROI, and patient level, in which all lesions for a single patient will be grouped into a patient ROI before SUV analysis. Uptake will be quantified with maximal uptake (SUVmax), mean uptake (SUVmean), and total uptake (SUVtotal). For both ROI levels, SUVmax will be defined as the maximum SUV of the ROI and SUVtotal will be defined as the total summed SUV of the ROI normalized to voxel volume. SUVmean will be defined as the mean SUV within the lesion ROI or the mean of the SUVmean of all lesions within the patient ROI. For each SUV metric, response will be calculated as percent change from baseline to mid-treatment scans.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 computed tomography (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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (with the exception of < 3 mg/dL for patients with Gilbert's disease)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN (=< 5 ULN for patients with liver metastasis)
  • Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2
  • Hemoglobin > 10 g/dL
  • Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Patients with asymptomatic, treated brain metastases are permitted if there is no evidence of progression for at least 4 weeks after central nervous system (CNS)-directed treatment, as ascertained by clinical examination or brain imaging (magnetic resonance imaging [MRI] or CT scan) during the screening period
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. History of other active malignancy requiring treatment within the last 3 years or bone marrow dysplasia such as myelodysplastic syndrome (MDS) is not allowed
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this study, patients should be class 2B or better
  • Concomitant use of bisphosphonates or denosumab is required (except if medical contraindication such as hypocalcemia or concern for osteonecrosis of the jaw). If not already on bone modifying agents, patient must initiate such therapy within one month before start of study treatment
  • The effects of radium-223 dichloride on the developing human fetus are unknown. For this reason and because alpha particle-emitting radiopharmaceutical agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 6 months after the last dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Pre-menopausal subjects as well as subjects with ovarian radiation or concomitant treatment with an LH-RH agonist/antagonist must have a negative pregnancy test and agree to use an adequate method of contraception as recommended by their treating physicians. Subjects of child-bearing potential who are sexually active and their male partners must agree to utilize, during the treatment period and for 6 months after last dose of radium-223 dichloride, 2 reliable and acceptable methods of contraception used simultaneously: a) barrier method such as a) condoms (male or female) with spermicidal agent or b) diaphragm or cervical cap with spermicide, combined with a highly effective non-hormonal birth control method such as an intra-uterine device. Men treated or enrolled on this protocol must also agree to use adequate contraception and not donate sperm prior to the study, for the duration of study participation, and 6 months after completion of Radium-223 dichloride
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
  • No prior paclitaxel in metastatic setting within 2 years prior to Radium-223 dichloride start. No prior paclitaxel in adjuvant or neoadjuvant setting within 6 months prior to Radium-223 dichloride start

Exclusion Criteria:

  • Patients with peripheral neuropathy > grade 1
  • Patients who have not recovered from adverse events (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
  • Patients must not have an active infection requiring systemic treatment
  • Patients must not use immunosuppressive medication =< 7 days of registration, EXCEPT for the following:

    • Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
    • Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent
    • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) is allowed
  • Patients with Crohn's disease or ulcerative colitis
  • Patients with a marked baseline prolongation of QT/corrected QT interval (QTc) interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds [ms]) (CTCAE grade 1) using Fridericia's QT correction formula
  • Patients with a history of additional risk factors for Torsades de Pointes (TdP) (e.g. heart failure, hypokalemia, family history of long QT syndrome)
  • The use of concomitant medications that prolong the QT/QTc interval
  • Life expectancy < 6 months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04090398

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Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Jyoti Malhotra University Health Network Princess Margaret Cancer Center LAO
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Responsible Party: National Cancer Institute (NCI) Identifier: NCT04090398    
Other Study ID Numbers: NCI-2019-06088
NCI-2019-06088 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10302 ( Other Identifier: University Health Network Princess Margaret Cancer Center LAO )
10302 ( Other Identifier: CTEP )
UM1CA186644 ( U.S. NIH Grant/Contract )
UM1CA186716 ( U.S. NIH Grant/Contract )
First Posted: September 16, 2019    Key Record Dates
Last Update Posted: October 5, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms by Site
Breast Diseases
Skin Diseases
Albumin-Bound Paclitaxel
Radium Ra 223 dichloride
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action