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

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 conventional 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.

Patient Selection Guidelines:

- Patients must have the psychological ability and general health that permits
completion of the study requirements and required follow up

- Women of childbearing potential who are sexually active should be willing and able to
use medically acceptable forms of contraception during protocol treatment

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 14 days prior to registration on
study)

- Platelets ≥ 75,000 mm³ (obtained within 14 days prior to registration on study)

- Hemoglobin ≥ 8.0 g/dl (obtained within 14 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

- 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

- 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)

- Patients with clinical signs of cord compression, patients with radiographic evidence
of cord compression are eligible for enrollment but cannot have clinical signs of cord
compression