This is a randomized, international, multicenter, Phase II study designed to explore the
efficacy of olaparib or olaparib in combination with durvalumab in platinum-treated mTNBC.
The primary objectives are to explore olaparib or olaparib in combination with durvalumab as
maintenance therapy following clinical benefit with platinum-based therapy in subjects with
mTNBC.
Subjects suitable for enrollment into this trial are adult subjects with histologically
documented triple negative adenocarcinoma of the breast that is inoperable, locally advanced,
or metastatic, and is not amenable to resection with curative intent, and who have received
at least 4 cycles of platinum-based chemotherapy in the 1st or 2nd line setting AND derived
clinical benefit (CR / PR / SD) per RECIST 1.1 with platinum-based therapy as determined by
the treating physician.
Eligible subjects will be randomized to either olaparib or olaparib in combination with
durvalumab. Study treatment will continue until disease progression, intolerable toxicity,
elective withdrawal from the study, or study completion or termination. Upon treatment
discontinuation, subjects will be followed every 2 months for survival.
Although randomization will be used to allocate subjects to either the olaparib or olaparib
in combination with durvalumab arm, no comparisons between treatment regimens are planned.
The purpose of randomization was to reduce bias due to subject selection into either
treatment arm.
Inclusion Criteria:
1. Age ≥ 21 years of age
2. ECOG performance status 0-2
3. Inoperable locally advanced or metastatic breast cancer not amenable to resection with
curative intent and histologically confirmed to be estrogen receptor (ER) negative,
progesterone receptor (PR) negative, and HER2 negative:
- ER negative status is defined as < 1% tumor cells positive for ER by
immunohistochemistry (IHC), irrespective of staining intensity
- PR negative status is defined as < 1% tumor cells positive for PR by IHC,
irrespective of staining intensity
NOTE: Enrollment is permitted for ER/PR low-expression subjects (defined as ≤ 10%) who
are expected to benefit from this trial at the investigator's discretion.
- HER2 negative status is determined by:
- IHC 1+, as defined by incomplete membrane staining that is faint/barely
perceptible and within > 10% of invasive tumor cells, or
- IHC 0, as defined by no staining observed or membrane staining that is incomplete
and is faint/barely perceptible and within ≤ 10% of the invasive tumor cells, or
- FISH negative based on:
- Single-probe average HER2 copy number < 4.0 signals / cell, or
- Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals
/ cell
4. Minimum six 1-weekly doses or three 3-weekly doses of platinum chemotherapy
(monotherapy or combination therapy at investigator's discretion) with stable disease
(SD), partial response (PR) or complete response (CR) to the platinum therapy as
assessed by investigator.
5. Has received no more than 2 prior chemotherapy regimens for metastatic breast cancer
including current platinum based chemotherapy.
6. Able to provide a representative formalin-fixed, paraffin embedded tumour specimen
archival or fresh tissue for correlative studies and biomarker analysis.
7. Hemoglobin ≥ 9.0 g/dL and no blood transfusions in the 28 days prior to study entry.
Absolute neutrophil count ≥1,500/mm3. Platelet count ≥100 x 10^9/L.
8. Total bilirubin <1.5 x the upper limit of normal (ULN) with the following exception:
subjects with known Gilbert's disease who have serum bilirubin <3 x ULN may be
enrolled.
9. Aspartate transaminase (AST) and alanine transaminase (ALT) <2.5 x ULN with the
following exceptions: subjects with documented liver or bone metastases may have AST
and ALT <5 x ULN.
10. Alkaline phosphatase (ALP) <2 x ULN (<5 x ULN in subjects with known liver involvement
and <7 ULN in subjects with known bone involvement).
11. Serum creatinine <1.5 x ULN or creatinine clearance >51 mL/min by the Cockcroft-Gault
formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of
creatinine clearance.
12. For subjects of childbearing potential, agreement (by both subject and partner) to use
two effective forms of contraception, including surgical sterilization, reliable
barrier method, birth control pills, contraceptive hormone implants, or true
abstinence and to continue its use for the duration of the study and for 3 months
after last dose of study treatment.
13. Subjects of childbearing potential should have a negative urine or serum pregnancy
test during their screening visit. If the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required.
14. Subjects willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examination.
15. For inclusion in genetic research, subjects must provide informed consent for genetic
research collection of specimens to be stored at repository for future research.
Exclusion Criteria:
1. 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. Subjects who have entered the follow-up
phase of an investigational study may participate as long as it has been 4 weeks since
last dose of the previous investigational agent or device.
2. Concurrent enrollment in another clinical study, unless it is an observational (non
interventional) clinical study or the follow-up period of an interventional study.
3. Active autoimmune disease that has required systemic treatment in past 2 years (ie,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, or similar treatment) is not
considered a form of systemic treatment.
4. Is taking chronic systemic steroids in doses > 10mg of prednisolone or equivalent
within 7 days prior to the first dose of trial treatment.
5. Previous treatment with PARP inhibitors including olaparib.
6. Patients that have required discontinuation of treatment due to treatment-related
toxicities from prior therapy with PD-1, PDL-1 or CTLA-4 inhibitors or previous
history of immune-related grade 3 or 4 adverse event.
7. Known active central nervous system metastasis and / or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate, provided they have:
1. Stable brain metastases [without evidence of progression by imaging (confirmed by
computerized tomography {CT} scan if CT used at prior imaging) for at least four
weeks prior to the first dose of trial treatment**,
2. No evidence of new or enlarging brain metastases; any neurologic symptoms should
have returned to baseline,
3. Not used steroids for brain metastases in the 7 days prior to trial initiation.
Taking chronic systemic steroids in doses ≤ 10mg of prednisolone is allowed.
- This exception does not include carcinomatous meningitis, as subjects with
carcinomatous meningitis are excluded regardless of clinical stability.
8. History and/or confirmed pneumonitis, or extensive bilateral lung disease on high
resolution/spiral CT scan.
9. Patients with suspected or confirmed myelodysplastic syndrome/acute myeloid leukemia.
10. History of another primary malignancy except for:
1. Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of study drug and of low potential risk for recurrence.
2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
3. Adequately treated carcinoma in situ without evidence of disease eg, cervical
cancer in situ.
11. Major surgery within 2 weeks of starting the study, and subjects must have recovered
from any effects of any major surgery.
12. Receipt of radiation therapy within 4 weeks prior to starting study drug(s). Limited
field of radiation for palliation within 2 weeks of the first dose of study treatment
is allowed provided:
1. The lung is not in the radiation field
2. Irradiated lesion(s) cannot be used as target lesions
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease, active bleeding
diatheses including any subjects known to have evidence of acute or chronic hepatitis
B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness / social
situations that would limit compliance with study requirements or compromise the
ability of the subject to give written informed consent.
14. Subjects unable to swallow orally administered medication, and subjects with
gastrointestinal disorders likely to interfere with absorption of the study
medication.
15. Subjects requiring treatment with potent inhibitors or inducers of CYP3A4.
16. Pregnant or breast-feeding women. If breastfeeding can be stopped prior to study
enrollment until 1 month after the last study dose, then the patient could be allowed
to enter the study.
17. Immunodeficient subjects, eg, subjects who are known to be serologically positive for
human immunodeficiency virus (HIV).
18. Received a live vaccine within 30 days of planned start of study therapy.
19. Subjects with a known hypersensitivity to olaparib or durvalumab, or any of the
excipients of the product.
20. Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative
colitis)
21. History of allogeneic organ transplant
22. Active bleeding diatheses
23. Patients with known active hepatic disease (ie, Hepatitis B or C)
24. Known history of previous clinical diagnosis of tuberculosis.
