Clinical trial NCT03691493: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: Pfizer
name: National Cancer Institute (NCI)
name: National Institutes of Health (NIH)
First posted: 2018-10-01
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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 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 cycles 1 and on day 1 of subsequent cycles. Cycles 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.

Eligibility criteria: 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 registration:

  * 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

Primary outcomes:
measure: Response Rate
timeFrame: Up to 3 months post radiation
Secondary outcomes:
measure: Response Rate Incorporating BPI and Analgesic Measures According to International Bone Consensus Guideline Criteria
timeFrame: Up to 3 months post radiation
measure: Number of Participants With Adverse Events Graded According to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
timeFrame: Up to 3 months post radiation
measure: Progression-free Survival (PFS)
timeFrame: Up to 44 months post radiation
measure: Overall Survival (OS)
timeFrame: Up to 44 months post radiation
measure: Fatigue as Measured by The Multidimensional Fatigue Inventory (MFI)
timeFrame: Pre-radiation on day 1, Last Day of radiation (5-10 days), 1 month post radiation, and 3 months post radiation, change last day of radiation, change 1 month post radiation, change 3 months post radiation
measure: Quality of Life as Measured by Short Form Health Survey (SF-36)
timeFrame: Pre-radiation on day 1, Last Day of radiation (5-10 days), 1 month post radiation, and 3 months post radiation, change last day of radiation, change 1 month post radiation, change 3 months post radiation
measure: Quality of Life as Measured by European Organization for Research and Treatment of Cancer Metastases Module (EORTC QLQ-BM22)
timeFrame: Pre-radiation on day 1, Last Day of radiation (5-10 days), 1 month post radiation, and 3 months post radiation, change last day of radiation, change 1 month post radiation, change 3 months post radiation
measure: Quality of Life as Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 for Palliative Care (EORTC QLQ-C15-PAL)
timeFrame: Pre-radiation on day 1, Last Day of radiation (5-10 days), 1 month post radiation, and 3 months post radiation, change last day of radiation, change 1 month post radiation, change 3 months post radiation
measure: Depression as Measured by Hospital Anxiety and Depression Scale (HADS)
timeFrame: Pre-radiation on day 1, Last Day of radiation (5-10 days), 1 month post radiation, and 3 months post radiation, change last day of radiation, change 1 month post radiation, change 3 months post radiation
measure: Number of Participants With Adherence as Measured by Drug Diary
timeFrame: Pre-radiation on day 1, Last Day of radiation (5-10 days), 1 month post radiation, and 3 months post radiation, change last day of radiation, change 1 month post radiation, change 3 months post radiation
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Grady Health System
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Augusta
country: United States
facility: Augusta University Medical Center
state: Georgia
city: Columbus
country: United States
facility: John B. Amos Cancer Center
state: Georgia
city: Savannah
country: United States
facility: Lewis Cancer and Research Pavilion at Saint Joseph's/Candler
state: Georgia
city: Portland
country: United States
facility: Maine Medical Center-Bramhall Campus
state: Maine
Study officials:
affiliation: Emory University
name: Mylin Torres, MD
role: PRINCIPAL_INVESTIGATOR
References: