Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical Trial 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.
Phase
Phase 2
Funding Agency/Sponsor
National Cooperative Group
Disease
Breast Cancer
Enrollment Eligibility
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