Clinical Trials /

Radiation Therapy, Palbociclib, and Hormone Therapy in Treating Breast Cancer Patients With Bone Metastasis

NCT03691493

Description:

This phase II trial studies how well radiation therapy given with standard care palbociclib and hormone therapy work in treating patients with breast cancer that has spread from one part of the body to the bone. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Antihormone therapy, such as fulvestrant, letrozole, anastrozole, exemestane, or tamoxifen, may lessen the amount of estrogen made by the body. Giving radiation therapy, palbociclib, and hormone therapy may work better in treating breast cancer patients with bone metastasis.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Radiation Therapy, Palbociclib, and Hormone Therapy in Treating Breast Cancer Patients With Bone Metastasis
  • Official Title: A Phase II Multi-Institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone Therapy for Treatment of Bone Metastasis in Breast Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: IRB00105944
  • SECONDARY ID: NCI-2018-02000
  • SECONDARY ID: Winship4472-18
  • NCT ID: NCT03691493

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • Estrogen Receptor Positive
  • HER2/Neu Negative
  • Metastatic Breast Carcinoma
  • Metastatic Malignant Neoplasm in the Bone
  • Progesterone Receptor Positive
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
AnastrozoleArimidex, ICI D1033, ZD-1033Radiation, palbociclib, hormone therapy
ExemestaneAromasin, FCE-24304Radiation, palbociclib, hormone therapy
FulvestrantFaslodex, ICI 182,780, ZD9238Radiation, palbociclib, hormone therapy
LetrozoleCGS 20267, FemaraRadiation, palbociclib, hormone therapy
PalbociclibIbrance, PD-0332991Radiation, palbociclib, hormone therapy
TamoxifenSoltamox, NolvadexRadiation, palbociclib, hormone therapy

Purpose

This phase II trial studies how well radiation therapy given with standard care palbociclib and hormone therapy work in treating patients with breast cancer that has spread from one part of the body to the bone. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Antihormone therapy, such as fulvestrant, letrozole, anastrozole, exemestane, or tamoxifen, may lessen the amount of estrogen made by the body. Giving radiation therapy, palbociclib, and hormone therapy may work better in treating breast cancer patients with bone metastasis.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the response rate three months post-conventionally fractionated radiotherapy,
      relative to baseline, for bone metastases in breast cancer patients receiving concurrent
      palbociclib and hormone therapy treatment.

      SECONDARY OBJECTIVES:

      I. To determine whether conventionally fractionated radiotherapy in combination with
      palbociclib and hormone therapy in breast cancer patients with bone metastases adversely
      increases the frequency and severity of palbociclib toxicities including grade 3 neutropenia.

      II. To determine whether radiotherapy in combination with palbociclib in breast cancer
      patients with bone metastases adversely increases the frequency and severity of radiotherapy
      toxicities including neurological and bone injury.

      III. To assess fatigue, quality of life, and depression before and after radiotherapy for
      bone metastases in metastatic breast cancer patients treated with palbociclib.

      IV. To determine progression free survival (PFS) and overall survival (OS) in breast cancer
      patients treated with palbociclib and concurrent radiotherapy to bone metastases.

      V. To evaluate the relationship between volume of irradiated bone and side effects of
      treatment, including leukopenia and neutropenia.

      TRANSLATIONAL RESEARCH OBJECTIVES:

      I. To collect, store, and analyze circulating tumor-derived deoxyribonucleic acid (ctDNA) in
      metastatic breast cancer patients treated with palbociclib and radiotherapy to bone
      metastases and to determine the relationship between ctDNA and responders versus
      non-responders, PFS, and OS.

      II. To collect, store, and analyze plasma for inflammatory cytokine measurements and
      determine their relationship with fatigue, depression, and quality of life before and after
      radiotherapy for bone metastases in metastatic breast cancer patients treated with
      palbociclib.

      III. To collect, store, and analyze ribonucleic acid (RNA) for gene expression to identify
      functional biology processes over-represented in genes differentially regulated among
      patients who develop toxicities versus those who do not and those who are responders versus
      those who are not and to identify transcriptional regulatory pathways driving observed
      differences in gene expression.

      OUTLINE:

      Patients undergo radiation therapy over 5-10 days and receive palbociclib orally (PO) once
      daily (QD) on days 1-21. At the discretion of treating physician, patients also receive
      letrozole, anastrozole, exemestane, or tamoxifen PO QD on days 1-28, or fulvestrant
      intramuscularly (IM) on days 1 and 15 of course 1 and on day 1 of subsequent courses. Courses
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 1 and 3 months.
    

Trial Arms

NameTypeDescriptionInterventions
Radiation, palbociclib, hormone therapyExperimentalPatients undergo radiation therapy over 5-10 days and receive palbociclib PO QD on days 1-21. At the discretion of treating physician, patients also receive letrozole, anastrozole, exemestane, or tamoxifen PO QD on days 1-28, or fulvestrant IM on days 1 and 15 of course 1 and on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Anastrozole
  • Exemestane
  • Fulvestrant
  • Letrozole
  • Palbociclib
  • Tamoxifen

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed metastatic breast cancer

          -  Known estrogen, progesterone, and human epidermal growth factor receptor 2 (Her2)
             status of either primary tumor or metastasis

          -  Metastatic estrogen receptor positive (ER+) or progesterone receptor positive (PR+),
             Her2/neu negative breast cancer patients with imaging confirming bone metastasis
             within 60 days of radiation simulation

          -  Must be actively receiving palbociclib (125 or 100 mg PO daily for 3 weeks followed by
             a week off during 28-day cycles) plus one of the following hormone therapies for at
             least 28 days:

               -  Fulvestrant (500 mg IM injection on days 1 and 15 cycle one and then on day one
                  of each subsequent cycle (28 days) -or-

               -  Letrozole (2.5 mg PO daily) -or-

               -  Anastrozole (1 mg PO daily) -or-

               -  Exemestane (25 mg PO daily) -or-

               -  Tamoxifen (20 mg PO daily)

          -  Patients must be willing and able to provide written informed consent/assent for the
             trial

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Karnofsky performance status (KPS) ≥ 60% within 60 days prior to registration

          -  Must have bone disease that is either symptomatic (i.e. pain) or has a lytic or mixed
             lytic disease that can be assessed by computed tomography (CT), magnetic resonance
             imaging (MRI), bone scan or positron emission tomography (PET)/CT within 60 days prior
             to radiotherapy on this study

          -  One previous line of chemotherapy in advanced disease is allowed

          -  Appropriate stage for study entry based on the following diagnostic workup:

               -  History and physical examination within 60 days prior to registration

               -  Clinical grade CT scans of the chest, abdomen, and pelvis with radionuclide bone
                  scan OR whole body PET/CT documenting metastatic disease prior to radiotherapy on
                  this protocol or MRI documenting site of metastatic disease to be treated on
                  protocol

          -  Patient must be eligible for palliative radiotherapy (conventional radiation either 30
             Gy in 10 fractions or 20 Gy in 5 fractions) for up to 4 separate anatomic regions
             containing bone metastases defined by 4 separate and not overlapping radiation plans

          -  Absolute neutrophil count ≥ 1000/mcl (obtained within 60 days prior to registration on
             study)

          -  Platelets ≥ 75,000 mm³ (obtained within 60 days prior to registration on study)

          -  Hemoglobin ≥ 8.0 g/dl (obtained within 60 days prior to registration on study) (Note:
             The use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8.0g/dl is
             acceptable) (obtained within 60 days prior to registration on study)

          -  For females of child-bearing potential, negative serum or urine pregnancy test within
             14 days prior to radiation simulation

          -  The patient or a legally authorized representative must provide study-specific
             informed consent prior to study entry

          -  Prior Treatment:

               -  Patients may or may not have received radiotherapy or neoadjuvant or adjuvant
                  chemotherapy in the treatment of their initial, non-metastatic breast cancer, but
                  must be entered on study after their last dose of radiotherapy, last cycle of
                  chemotherapy and biologic therapy (if applicable) and have sufficient resolution
                  of side effects per physician assessment at time of radiotherapy

               -  Patients must have not active wound healing issues from surgery and sufficient
                  resolution of surgical side effects, per physician assessment, at time of
                  radiotherapy

               -  If patients have one line of chemotherapy for advanced disease, patients must be
                  entered on study after their last dose of chemotherapy and have sufficient
                  resolution of side effects per physician assessment at time of radiotherapy

               -  Patients must have already initiated palbociclib (3 weeks on, 1 week off) and
                  hormone therapy for at least 28 days prior to radiotherapy

               -  During radiotherapy, no other investigation or commercial agents or therapy for
                  cancer other than palbociclib, bisphosphonates, rank ligand inhibitors, and
                  hormone therapy should be administered

               -  Patients may have received bisphosphonates or rank ligand inhibitors prior to
                  enrollment on study

        Exclusion Criteria:

          -  Co-existing or prior invasive non-breast malignancy (except non-melanomatous skin
             cancer), unless disease free for a minimum of 3 years

          -  Previous radiation dose, date, fraction size, must be reported for prior invasive
             malignancy must be reported

          -  Previous palliative radiation to the disease to be treated on protocol (including
             radiopharmaceuticals)

          -  Patients prescribed stereotactic body radiation therapy (SBRT) for bone metastasis to
             be treated on this protocol will be excluded

          -  Grade 4 neutropenia

          -  Metastases to be treated on protocol located within 2 cm from a previously irradiated
             structure:

               -  Spinal cord previously irradiated to > 40 Gy (delivered in ≤ 3 Gy/fraction)

               -  Brachial plexus previously irradiated to > 50 Gy (delivered in ≤ 3 Gy/fraction)

               -  Small intestine, large intestine, or stomach previously irradiated to > 45 Gy
                  (delivered in ≤ 3 Gy/fraction)

               -  Brainstem previously irradiated to > 50 Gy (delivered in ≤ 3 Gy/fraction)

               -  Whole lung previously irradiated with prior V20 Gy > 35% (delivered in ≤ 3
                  Gy/fraction)

          -  Untreated brain metastases or unstable/progressive brain metastases (imaging of
             treated brain metastases must be performed within 28 days of registration for this
             protocol to confirm brain metastases stability)

          -  Severe, active co-morbidity such as congestive heart failure (CHF) or unstable angina
             within last 6 months, transmural myocardial infarction within the last 6 months. Acute
             bacterial or fungal infection requiring intravenous (IV) antibiotics at time of
             registration, chronic obstructive pulmonary disease (COPD) or other respiratory
             illness requiring hospitalization at time of registration

          -  Lactating females must cease expression of milk prior to registration

          -  Temperature above 100.4° Fahrenheit

          -  Human immunodeficiency virus (HIV) positive with cluster of differentiation 4 (CD4)
             count < 200 cells/ microliter. HIV positive patients are eligible, provided they are
             receiving treatment with highly active antiretroviral therapy (HAART) and have a CD4
             count > 200 cells/microliter within 28 days prior to registration. HIV testing is not
             required for eligibility for this protocol. This exclusion criteria is necessary
             because the treatments involved in this protocol may be significantly
             immunosuppressive

          -  Previous chemotherapy or radiotherapy within 2 weeks prior to registration or patients
             who have not recovered from adverse events due to previous chemotherapy and
             radiotherapy

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy. Indolent cancers (such as low
             risk prostate or In-Situ cancers) that are not being treated are acceptable

          -  Has active autoimmune disease that has required continued systemic treatment in the
             past 2 years (i.e. with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
             physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
             etc.) is not considered a form of systemic treatment

          -  Has an active infection requiring systemic therapy

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Cannot receive concurrent cytotoxic chemotherapy (e.g. taxanes, cytoxan,
             anthracyclines, platinum based aged, capecitabine) at time of registration or during
             radiation treatment on this study

          -  Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 90 days after the last dose of trial treatment

          -  Absolute neutrophil count < 1000/microliter (mcl)

          -  Platelets < 75,000 mm

          -  Hemoglobin < 8.0 g/dl

          -  Concurrent therapy with other investigational products is not allowed

          -  Receiving medications or substances that are potent inhibitors or inducers of
             cytochrome P450, family 3, subfamily A (CYP3A) isoenzymes, as palbociclib is primarily
             metabolized by CYP3A4 enzymes, within 7 days of randomization:

               -  Inhibitors - boceprevir, clarithromycin, indinavir, delavirdine, conivaptan,
                  itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone,
                  nelfinavir, posaconazole, ritonavir, saquinavir, suboxone, telaprevir,
                  telithromycin, voriconazole, amprenavir, atazanavir, diltiazem, erythromycin,
                  fosamprenavir, verapamil, and grapefruit, grapefruit juice or any product
                  containing grapefruit

               -  Inducers - carbamazepine, phenytoin, primidone, rifampin, rifapentine, St. John's
                  wort, felbamate, nevirapine, phenobarbital, rifabutin

          -  Receiving hormone replacement therapy (e.g. topical estrogens, but not intra-vaginal
             preparations, raloxifene, megestrol acetate)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:At 3 months post-radiation
Safety Issue:
Description:Response rate will be estimated as the number of responders divided by the number of patients evaluated for response. Among patients who present with pain, responders will be considered those patients who have a 2 point decrease in the Brief Pain Inventory (BPI), and among those who do not present with pain (radiotherapy due to risk of unstable fracture or cord compression), responders will be considered those without development of a pathologic fracture or neurologic compromise (cord compression) due to cancer on imaging.

Secondary Outcome Measures

Measure:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame:Up to 3 months post-radiation
Safety Issue:
Description:Adverse events, such as bone fracture following radiotherapy, any grade 3 toxicity (except neutropenia or leukopenia), grade 4 neutropenia, grade 4 leukopenia, grade 3 febrile neutropenia, or grade 3 brachial plexopathy or spinal cord injury, will be summarized descriptively.
Measure:Progression-free survival (PFS)
Time Frame:Time from registration to death or progression, assessed up to 3 months post-radiation
Safety Issue:
Description:PFS will be estimated using the Kaplan-Meier method.
Measure:Overall survival (OS)
Time Frame:Time from registration to death, assessed up to 3 months post-radiation
Safety Issue:
Description:OS will be estimated using the Kaplan-Meier method.
Measure:Fatigue as measured by The Multidimensional Fatigue Inventory (MFI)
Time Frame:Up to 3 months post-radiation
Safety Issue:
Description:Fatigue will be assessed before and after radiotherapy.
Measure:Quality of life as measured by Short Form Health Survey (SF-36)
Time Frame:Up to 3 months post-radiation
Safety Issue:
Description:Quality of life will be assessed before and after radiotherapy.
Measure:Depression as measured by Hospital Anxiety and Depression Scale (HADS)
Time Frame:Up to 3 months post-radiation
Safety Issue:
Description:Depression will be assessed before and after radiotherapy.
Measure:Adherence as measured by drug diary
Time Frame:Up to 3 months post-radiation
Safety Issue:
Description:Adherence will be determined by number of days drug taken divided by number of days drug should have been taken over the time period of the study.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

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