PRIMARY OBJECTIVES:
I. To determine the dose limiting toxicities and maximum tolerated dose of olaparib given in
combination with chest wall hyperthermia in patients with locally advanced or metastatic
breast cancer with chest wall recurrences who have wild-type BRCA status (patients with
germline BRCA mutations are excluded from this study).
SECONDARY OBJECTIVES:
I. To determine the local progression free survival (in months) for patients with chest wall
recurrences defined as time to progression of disease on chest wall with olaparib with
hyperthermia.
II. To determine the 1-year progression free survival (in months) for patients with chest
wall recurrences treated with olaparib with hyperthermia.
III. To determine the best local overall response rate of chest wall after the combination of
hyperthermia and olaparib.
IV. To determine the quality of life and pain scores before, during and after treatment as
measured by the Edmonton Symptom Assessment System which includes a pain score and 8 other
subjective measures of wellness for cancer patients (0 to 10).
EXPLORATORY OBJECTIVES:
I. To evaluate BRCA1/2 levels by immunohistochemistry and explore if hyperthermia induced
BRCA1/2 expression.
II. To evaluate HR (homologous recombination) competency by RAD51 foci and explore if
hyperthermia induces homologous recombination in breast tissue.
III. To explore deoxyribonucleic acid (DNA) damage as measured by gammaH2AX and comet assay
in cells dissociated from biopsy tissues.
OUTLINE: This is a dose-escalation study of olaparib.
Patients receive olaparib orally (PO) twice daily (BID). Treatment continues for 4 weeks in
the absence of disease progression and unacceptable toxicity. Beginning week 2, patients also
undergo hyperthermia treatment over 1 hour twice weekly for 3 weeks in the absence of disease
progression and unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 12 months.
Inclusion Criteria:
- Patients regardless of estrogen receptor (ER)/progesterone receptor (PR)/HER2 status
and have breast cancer recurrence on the chest wall
- Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol
- Provision of signed and dated, written informed consent form prior to any mandatory
study specific procedures, sampling, and analyses
- Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days
prior to administration of study treatment)
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 28 days prior
administration of study treatment)
- Platelet count >= 100 x 10^9/L (measured within 28 days prior to administration of
study treatment)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 28
days prior to administration of study treatment)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) /
alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x
institutional upper limit of normal unless liver metastases are present in which case
they must be =< 5x ULN (measured within 28 days prior to administration of study
treatment)
- Patients must have creatinine clearance estimated of >= 51 mL/min using the
Cockcroft-Gault equation or based on a 24 hour urine test (measured within 28 days
prior to administration of study treatment)
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Patients must have a life expectancy >= 16 weeks
- Breast cancer with chest wall disease that is at least 2 cm in size at the greatest
dimension
- Patients will be eligible for this trial regardless of number of lines of therapy and
after adjuvant chemotherapy with recurrence on the chest wall
- Patients with hormone receptor positive disease who discontinue endocrine therapy two
weeks prior to initiating study treatment are eligible
- Body mass index (BMI): 15 to 50 at the time of consent
- Postmenopausal or evidence of non-childbearing status for women of childbearing
potential: negative urine or serum pregnancy test within 28 days of initiating study
treatment and confirmed prior to treatment on day 1 and willingness to use effective
contraception during study treatment and for at least 30 days after last dose of study
drug. Postmenopausal is defined as:
- Amenorrhea for 1 year or more following cessation of exogenous hormonal
treatments
- Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
post menopausal range for women under 50
- Radiation-induced oophorectomy with last menses > 1 year ago
- Chemotherapy-induced menopause with > 1 year interval since last menses
- Surgical sterilization (bilateral oophorectomy or hysterectomy)
Exclusion Criteria:
- As judged by the investigator, any evidence of non-compliance which in the
investigator's opinion makes it undesirable for the patient to participate in the
trial
- Patients with rapidly progressing disease
- Metastatic disease should not be progressing so as to require systemic treatment
within 4 weeks of enrollment based on clinical assessment by the investigator
- Metastatic disease should not be progressing so as to require palliative treatment
within 4 weeks of enrollment based on clinical assessment by the investigator
- Other malignancy unless curatively treated with no evidence of disease for >= 5 years
except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer
of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma
- Resting electrocardiogram (EKG) indicating uncontrolled, potentially reversible
cardiac conditions, as judged by the investigator (e.g. unstable ischemia,
uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval
by Fridericia [QTcF] prolongation > 500 ms, electrolyte disturbances, etc.), or
patients with congenital long QT syndrome
- Persistent toxicities caused by previous cancer therapy >= grade 2, excluding alopecia
and neuropathy
- Patients with current or previous diagnosis of myelodysplastic syndrome/acute myeloid
leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid
leukemia (AML)
- Patients with symptomatic uncontrolled brain metastases or spinal cord metastases. A
scan to confirm the absence of brain metastases is not required. The patient can
receive a stable dose of corticosteroids before and during the study as long as these
were started at least 4 weeks prior to treatment. Patients with spinal cord
compression unless considered to have received definitive treatment for this and
evidence of clinically stable disease for 28 days
- Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder
that prohibits obtaining informed consent
- Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication
- Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV)
- Any previous treatment with PARP inhibitor, including olaparib
- Subjects with a known hypersensitivity to olaparib or any of the excipients of the
product
- Patients with a known hypersensitivity to hyperthermia
- Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 3 weeks prior to study treatment
- Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting olaparib is 2 weeks
- Concomitant use of known strong CYP3A inducers (eg. phenobarbital, enzalutamide,
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's
wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required
washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital
and 3 weeks for other agents
- Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of surgery
- Patients with known active hepatitis B or C
- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable outside of 28 days prior to
enrollment)
- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)
- Any patient with a known germline BRCA1 or 2 mutation
- Participation in another clinical study with an investigational product administered
in the last 2 months
- Previous enrollment in the present study
- Breast feeding women
- Involvement in the planning and/or conduct of the study
- No radiotherapy, treatment with cytotoxic agents, biologic agents within 3 weeks prior
to beginning treatment on this study. Patients must have recovered from the acute
toxicities of any prior treatment with cytotoxic drugs to =< grade 1 (allowance for
grade 2 alopecia and neuropathy) in order to be eligible. Patients who underwent
post-mastectomy radiation will not be excluded from this study
