A Phase 2 Study of Olaparib Monotherapy in Metastatic Breast Cancer Patients with Germline or Somatic Mutations in DNA Repair Genes (Olaparib Expanded)

Protocol # :
Metastatic Breast Cancer
Invasive Breast Cancer
Somatic Mutation Breast Cancer (BRCA1)
Somatic Mutation Breast Cancer (BRCA2)
CHEK2 Gene Mutation
ATM Gene Mutation
PALB2 Gene Mutation
RAD51 Gene Mutation
BRIP1 Gene Mutation
NBN Gene Mutation
Disease Sites
Principal Investigator
Tung, Nadine
Site Investigator
Garber, Judy, E.
Site Research Nurses
Bowers, Jordan
Casella, Allison
Cung, Connie
Germon, Victoria
Jeon, Maryangel, H.
Kasparian, Elizabeth
Lehnus, Jaclyn
Livesey, Megan
Macauley, Colleen
Marchetti, Kelly
O'Brien, Joanne
Orechia, Meghan
Patel, Nikita
Roche, Kathleen, A.
Sheehan, Susan
Wong, Christine

Trial Description

This research study is for patients with metastatic breast cancer.

- Metastatic means that the cancer has spread beyond the breast. In addition, through
genetic testing of the blood or tumor, an altered gene has been found that suggests the
tumor may not be able to repair its genetic material (DNA) when it becomes damaged.

- This aspect of the cancer may cause it to be more sensitive - that is, more effectively
killed by certain types of drugs such as the study agent being evaluated in this trial,

- Olaparib is a type of drug known as a PARP inhibitor. Some types of breast cancer
and ovarian cancer share some basic features that make them sensitive to similar
treatments. Information from those other research studies suggests that this drug
may help to treat metastatic breast cancer.

- This study will evaluate whether olaparib is effective in breast cancer
patients whose tumor has a mutation in one of the other genes that function
with BRCA1 and BRCA2 to repair damaged DNA .This mutation may have been
inherited from a parent, or may have developed only in the tumor.

- This study will also evaluate whether olaparib is effective in breast cancer
patients whose tumor has a mutation in BRCA1 or BRCA2 that was acquired by the
tumor, but not inherited.

Eligibility Requirements

Inclusion Criteria:

- Patients must have histologically confirmed invasive breast cancer with stage IV
disease, either biopsy proven or with unequivocal evidence of metastatic disease by
physical examination or radiological study.

- Cohorts 1 and 2: Documented germline (Cohort 1) or somatic mutation or homozygous
deletion (Cohort 2) in one of the DNA repair genes listed below that is deleterious or
suspected to be deleterious, and no germline BRCA1 or BRCA2 mutation. The mutation may
be identified through any CLIA approved NGS panel.

FANCM, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, plus other HR-related genes at
the discretion of Dr. Tung with the key study collaborators (see details below in
italics). (Cohorts 1 or 2)

--- OR

- Documented somatic mutation (deleterious or suspected deleterious) in BRCA1 or
BRCA2 through any CLIA approved lab only if in addition to the lack of a germline
BRCA1/2 mutation is demonstrated through a CLIA approved lab. Patients with
germline mutations in BRCA1/2 are NOT eligible for this study. (Cohort 2 only)

- Cohort 1a: germline PALB2 mutation

-- The mutation must be identified through a CLIA-approved NGS panel. Mutations must
be reviewed and confirmed by Dr. Tung to meet eligibility prior to registration.

- Cohort 2a: somatic mutation of BRCA 1 or BRCA 2

-- The mutation must be identified through a CLIA-approved NGS panel. Mutations must
be reviewed and confirmed by Dr. Tung to meet eligibility prior to registration.
Documentation of absence of germline mutation in BRCA 1/2 is required.

- All deep (homozygous) deletions, frameshift mutations and truncating mutations in the
genes listed above are eligible as well as missense variants in these genes that have
previously been reported as pathogenic or likely pathogenic. If there is a discrepancy
between two labs regarding the pathogenicity of a particular variant, the final
decision regarding eligibility will be determined by the study steering committee.

- At least one measurable lesion that can be accurately assessed at baseline by CT (MRI
where CT is contraindicated) and is suitable for repeated assessment as per RECIST

-- NOTE: If the only site of measurable of disease has been previously irradiated,
there must be evidence of post-radiation progression. For a lesion to be considered as
measurable, it must be one that can be accurately measured at baseline as ≥ 10 mm in
the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with
computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for
accurate repeated measurements

- Patients may not have progressed on more than two chemotherapy regimens in the
metastatic setting.

- The following will NOT be counted as a prior line of cytotoxic chemotherapy:

- If a patient discontinued a cytotoxic regimen due to toxicity (e.g.,
hypersensitivity or neuropathy) but had not progressed on that regimen, or if a
prior chemotherapy regimen was discontinued after response achieved, it will not
be counted in the number of prior chemotherapy regimens allowed.

- Prior hormonal therapy and non-hormonal targeted therapy; including the
combination of an aromatase inhibitor and everolimus.

- Targeted and biologic therapies.

- The patient can receive a stable dose of bisphosphonates or denosumab for bone
metastases, before and during the study as long as this was started at least 5
days prior to study treatment.

- The most recent cytotoxic, biologic or targeted therapy received must have been
completed at least 21 days prior to study treatment; hormonal therapy must have been
completed at least 7 days prior, unless otherwise noted.

- Prior therapy is allowed as follows:

- Platinum chemotherapy in the adjuvant setting is allowed, if the last platinum
dose was > 12 months before identification of metastatic disease. Platinum-based
chemotherapy in the metastatic setting is not permitted.

- History of prior anthracycline (e.g. doxorubicin, epirubicin) and taxane-based
(e.g. paclitaxel, docetaxel) chemotherapy in the neo-adjuvant / adjuvant or
metastatic setting is preferred, but not required.

- Patients with hormone receptor-positive (estrogen and/or progesterone
receptor-positive) disease must have received and progressed on at least one
endocrine therapy (adjuvant or metastatic), or have disease that the treating
physician believes to be inappropriate for endocrine therapy. Endocrine therapy
must have been completed at least 7 days before study treatment.

- Prior radiation is allowed; radiation therapy must have been completed at least
21 days before study treatment.

- Prior treatment with FDA approved or investigational biologics (other than PARP
inhibitors) and novel molecularly targeted therapies, including oral or IV
formulations, shall not exclude patients from participation.

- For agents with ambiguous categorization, final determination of patient
eligibility will be made by the Protocol Chair prior to enrollment.

- Prior PARP inhibitor use is not allowed for this study

- Age ≥ 18 years.

- ECOG performance status 0-1 (Karnofsky ≥60%, see Appendix A) Life expectancy ≥16 weeks

- Participants must have normal organ and bone marrow function measured within 28 days
prior to registration as defined below:

- absolute neutrophil count ≥1,500/mcL

- white blood cells > 3,000/mcL

- platelets ≥100,000/mcL

- hemoglobin ≥ 10.0 g/dL with no blood transfusions (packed red blood cells in the
past 28 days is permitted)

- total bilirubin ≤ 1.5 x institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- Serum or plasma creatinine ≤ 1.5 x institutional upper limit of normal (ULN)

--- OR

- creatinine clearance ≥51 mL/min/1.73 m2 for participants

- Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum
creatinine (mg/dL) x 72 ---- a where F=0.85 for females and F=1 for males.

- Willingness to undergo biopsy.

- Patients with a history of treated CNS metastases are eligible, provided they meet all
of the following criteria: Disease outside the CNS is present; no clinical evidence of
progression since completion of CNS-directed therapy; minimum of 2 weeks between
completion of radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥3)
acute toxicity with no ongoing requirement for > 10mg of prednisone per day or an
equivalent dose of other corticosteroid. NOTE: 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.

- Both men and women are eligible for this study

- Postmenopausal or evidence of non-childbearing status for women of childbearing
potential. For women who are not post-menopausal, a negative urine or serum pregnancy
test is required within 28 days of study treatment and confirmed prior to treatment on
day 1.

- Post-menopausal is defined as one of the following:

- > 60 years old

- Amenorrheic for 1 year or more following cessation of exogenous hormonal

- 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

- surgical sterilisation (bilateral oophorectomy or hysterectomy)

- Men and women of reproductive potential need to employ two highly effective and
acceptable forms of contraception throughout their participation in the study and for
30 days (for women) or 90 days (for men) after the last dose of study medication
because the effects of olaparib on the developing human fetus are unknown. 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.

- Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations.

- Ability to understand and the willingness to sign a written informed consent document.
Informed consent must be provided prior to any study specific procedures

Exclusion Criteria:

- Any previous treatment with a PARP inhibitor, including olaparib.

- Germline BRCA1 or BRCA2 mutation

- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
suggestive of MDS/AML.

- Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence
of brain metastases is not required. Patients with spinal cord compression unless
considered to have received definitive treatment for this and evidence of clinically
stable disease for 28 days.

- Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.

- Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) and grapefruit, grapefruit juice or
any product containing grapefruit,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 (e.g., phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout
period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
weeks for other agents.

- 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

- Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding

- Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV).

- Patients with prior myelodysplastic syndrome or acute myeloid leukemia.

- Other malignancy within the last 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; or, other solid tumors including
lymphomas (without bone marrow involvement) curatively treated with no evidence of
disease for ≥5 years

- Resting EKG with QTc > 470 msec or family history of long QT syndrome. If EKG
demonstrates QTc >470 msec, patient will be eligible only if repeat EKG demonstrates
QTc ≤470 msec.

- Pregnant or breast feeding women.

- Patients with a known hypersensitivity to olaparib or any of the excipients of the

- Major surgery within 2 weeks of starting study treatment: patients must have recovered
from any effects of any major surgery.

- Patients with known active hepatitis (i.e., Hepatitis B or C)

- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)

- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable).

- Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication