Clinical Trials /

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

NCT04090398

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of Radium Therapy (Radium-223 Dichloride) to the Usual Chemotherapy Treatment (Paclitaxel) for Advanced Breast Cancer Spread to the Bones
  • Official Title: Phase II Trial of Radium-223 Dichloride in Combination With Paclitaxel in Patients With Bone Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-06088
  • SECONDARY ID: NCI-2019-06088
  • SECONDARY ID: 10302
  • SECONDARY ID: 10302
  • SECONDARY ID: UM1CA186716
  • NCT ID: NCT04090398

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • Breast Carcinoma Metastatic in the Bone
  • Metastatic Breast Carcinoma
  • Metastatic Triple-Negative Breast Carcinoma
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm I (paclitaxel, radium Ra 223 dichloride)

Purpose

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 Ra 223 dichloride (radium-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 (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. 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.

      ARM II: 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.

      After completion of study treatment, patients are followed up at 30 days, then every 3 months
      for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (paclitaxel, radium Ra 223 dichloride)ExperimentalPatients 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.
  • Paclitaxel
Arm II (paclitaxel)Active ComparatorPatients 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.
  • Paclitaxel

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 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 are permitted if:

               -  Three or less visceral metastases (=< 2 cm in size) and asymptomatic (not
                  including lymph nodes).

               -  Enlarged lymph nodes =< 3 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 received at
             least one line of hormone therapy in the metastatic setting to be eligible. Previous
             radiation and chemotherapy for the treatment of metastatic breast cancer is allowed.
             However, patient must not have received more than three lines of chemotherapy in the
             metastatic setting

          -  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 > 9 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 and 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 physiological corticosteroids is allowed. Concomitant use of
             bisphosphonates or denosumab is required. Patient must have been on such therapy with
             bone modifying agent for at least 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

        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. No radiation therapy for 2 weeks prior to treatment. 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

          -  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 Fredericia'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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description: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.
Measure:Time to first symptomatic skeletal event (SSE)
Time Frame:Time from randomization to the occurrence of the first SSE, assessed up to 2 years
Safety Issue:
Description: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.
Measure:Objective response rate
Time Frame:From start of treatment until disease progression, assessed up to 2 years
Safety Issue:
Description:Will be defined as the proportion of all subjects with confirmed partial response or complete response according to RECIST 1.1.
Measure:Overall survival (OS)
Time Frame:Time from randomization to death due to any cause, assessed up to 2 years
Safety Issue:
Description: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.
Measure:Incidence of adverse events (AEs)
Time Frame:Up to 30 days after end of study treatment
Safety Issue:
Description: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.
Measure:Fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET)/computed tomography (CT) response
Time Frame:Up to day 1 of cycle 4
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 9, 2020