Olaparib and Durvalumab to Treat Patients With Metastatic Triple Negative Breast Cancer

PRIMARY OBJECTIVES:

I. Assess overall response to treatment

SECONDARY OBJECTIVES:

I. Assess participant benefit from treatment

II. Determine the time to disease progression following response to study therapy

III. Determine time to first disease progression or death of participants enrolled on the
study

IV. Determine survival of participants enrolled on the study

V. Assess safety and tolerability of the proposed therapy

EXPLORATORY OBJECTIVES:

I. Examine response rates depending on tumor characteristics

II. Identify predictive biomarkers of sensitivity to therapy

III. Identify emerging mechanism of resistance to therapy

IV. Determine changes in tumor cells induced by PARP inhibitors

OUTLINE: This is an open-label, single-arm phase II study of olaparib and durvalumab.

Participants with biopsy proven TNBC will undergo a pre-treatment biopsy, after which they
will receive a 4 week, single cycle, induction treatment of olaparib (oral, twice a day). At
the 4 week mark, participants will then undergo a repeat on-treatment biopsy, following which
durvalumab will be administered (IV over 1 hr) every 4 weeks, in addition to olaparib.
Treatment courses repeat every 28 days for 12 cycles.

At the completion of all on-study procedures, participants will be considered off-treatment
and will be followed every 6 months for disease and survival outcomes up to 1 year.
Participants will be asked to submit an optional tumor biopsy in the event of disease
progression.

Inclusion Criteria:

- Ability to understand and the willingness to sign a written informed consent document.

- Participants are >= 18 years old at time of informed consent.

- Metastatic TNBC, as defined by:

1. ER and PR negative as defined as ER < 10% and PR < 10% by immunohistochemistry
according to American Society of Clinical Oncology (ASCO)/College of American
Pathologists (CAP) guidelines for hormone receptor testing

2. HER2 non-amplified per ASCO/CAP guidelines, defined as:

1. IHC score 0/1+

2. IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to
CEP17 < 2.0, and if reported, average HER2 gene copy number <4
signals/cells; or

3. ISH non-amplified with a ratio of HER2 to CEP17 <2.0, and if reported,
average HER2 gene copy number < 4 signals/cells

- Participants must have at least one measurable site of disease as defined by RECIST
v1.1 that is amendable to biopsy.

- Prior therapies for metastatic breast cancer

1. Frontline patients who have not received prior systemic therapy for metastatic
breast cancer are eligible.

2. Patients who have received <= 2 prior chemotherapy regimens for metastatic breast
cancer are eligible.

- Participants must have fully recovered from the acute toxic effects of all prior
treatment to grade 1 or less, except alopecia and <= Grade 2 neuropathy which are
allowed

- Participants must have a life expectancy >=16 weeks.

- Participant must have Eastern Cooperative Oncology Group (ECOG) performance status <=1

- Participant must consent to undergo a pre-treatment screening biopsy for enrollment
and subsequent biomarker analyses.

- Participants must consent to undergo one mandatory on-study tumor biopsy following a 4
week, single cycle induction treatment of olaparib. A second on-study biopsy at time
of disease progression is optional, but not mandatory.

- Participants must not have had prior immunotherapy with anti-PD-L1, including
durvalumab anti-PD-1, anti-CTLA4 or similar drugs.

- Participants must not have received previous treatment with PARP inhibitors, including
olaparib.

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

1. Haemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days

2. Absolute neutrophil count (ANC) >= 1.5 x 109/L

3. Platelet count >= 100 x 109/L

4. Total bilirubin <= 1.5 x institutional upper limit of normal (ULN)

5. 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

6. Participants must have creatinine clearance estimated of >= 51 mL/min using the
Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine
clearance = (140-age [years]) x weight (kg) (x F) serum creatinine (mg/dL) x 72;
where F=0.85 for females and F=1 for males.

- Female participants of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.

- Female participants of childbearing potential agree to use adequate methods of
contraception starting with the first dose of study therapy through 60 days after the
last dose of study therapy. Participants of childbearing potential are those who are
not proven postmenopausal. Postmenopausal is defined as:

1. Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments

2. Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
post menopausal range for women under 50

3. Radiation-induced oophorectomy with last menses > 1 year ago

4. Chemotherapy-induced menopause with > 1 year interval since last menses

5. Surgical sterilisation (bilateral oophorectomy or hysterectomy)

- Male participants must agree to use an adequate method of contraception starting with
the first dose of study therapy through 60 days after the last dose of study therapy.

- Participants must not have received live vaccines within 30 days prior to the first
dose of immunotherapy. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG,
and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,
Flu-Mist®) are live attenuated vaccines, and are not allowed. Patients, if enrolled,
should not receive live vaccine whilst receiving immunotherapy and up to 30 days after
the last dose of immunotherapy

Exclusion Criteria:

- Currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigation device
within 4 weeks of first dose of treatment.

a. Individuals in the follow-up phase of a prior investigational study may participate
as long as it has been 4 weeks since last dose of the previous investigational agent
of device.

- Participants with germline BRCA mutated TNBC will be excluded

- 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. Participants with a history of localized triple negative breast cancer may
be eligible, provided they completed their adjuvant chemotherapy more than three years
prior to registration, and that the participant remains free of recurrent or
metastatic disease

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

- Participant received prior chemotherapy or any other targeted therapies within the
past 28, or radiation (except for palliative reasons) within the past 3 weeks, prior
to going on-study.

- Participants with known active central nervous system (CNS) metastases and/or
carcinomatous meningitis.

- Participants with previously treated brain metastases may participate provided they
are stable [without evidence of progression by imaging (confirmed by CT scan if CT
used at prior imaging, or confirmed by MRI if MRI was used at prior imaging) for at
least four weeks prior to the first dose of trial treatment and any neurologic
symptoms have returned to baseline], have no evidence of new or enlarging brain
metastases, and are not using steroids for at least 7 days prior to trial treatment.
This exception does not include carcinomatous meningitis which is excluded regardless
of clinical stability.

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

- Participants with visceral crisis defined as severe organ dysfunction as assessed by
signs and symptoms, laboratory studies, and rapid progression of disease.

- Active infection requiring systemic antibiotic therapy. Participants requiring
systemic antibiotics for infection must have completed therapy before treatment is
initiated.

- Participants 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
illness/social situation that prohibits obtaining informed consent.

- Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic
arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte
disturbances, etc.), or participants with congenital long QT syndrome

- Participants with a history of hypersensitivity reactions to study agent or their
excipients.

- Participant is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the trial, starting with the screening visit through
120 days after the last dose of trial treatment.

- Involvement in the planning and/or conduct of the study

- Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and
requirements.

DRUG-SPECIFIC EXCLUSION CRITERIA: Durvalumab

- Participant has evidence of interstitial lung disease or active non-infectious
pneumonitis.

- Major surgery within 2 weeks of starting study treatment and participants must have
recovered from any effects of any major surgery Note: Local surgery of isolated
lesions for palliative intent is acceptable per investigator discretion.

- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies).
Participants with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction
is negative for HCV RNA.

- History of active primary immunodeficiency

- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. The following are exceptions to this
criterion:

1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)

2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent

3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)

- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
criterion:

1. Participants with vitiligo or alopecia

2. Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement

3. Any chronic skin condition that does not require systemic therapy

4. Participants without active disease in the last 5 years may be included but only
after consultation with the study physician

5. Participants with celiac disease controlled by diet alone

- History of allogenic bone marrow transplant or double umbilical cord blood
transplantation