Metastatic Triple Negative Breast Cancer

Study objectives are defined for the following patient populations:  “Breast cancer susceptible gene mutation (BRCAm)” = patients from stratum A  “Homologous Recombination Repair gene mutation (HRRm)” = patients from stratum A and patients from stratum B  “Non BRCAm HRRm” = patients from stratum B  “All” = patients from any stratum  “Non HRRm” = patients from stratum C

Olaparib (AZD2281), AZD6738 and AZD1775

AZD1775
AZD6738
Olaparib (AZD2281)

film-coated tablet
film-coated tablet
dry-filled capsules

100 or 150
20, 80 or 100
25 or 100

Primary Outcome Measures :
Progression-Free Survival (PFS) assessment to evaluate the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy compared to olaparib monotherapy in BRCAm, Non BRCAm HRRm, Non HRRm patient population. [ Time Frame: From data of randomization until date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. ]
PFS was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomized therapy or another anti-cancer therapy prior to progression. Patients who did not progress or die at the time of analysis would be censored at the time of the latest date of assessment from their last evaluable RECIST using BICR. Sensitivity analysis of PFS using investigator assessment according to RECIST 1.1.


Secondary Outcome Measures :
PFS assessment to evaluate the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy compared to olaparib monotherapy in HRRM and in All patient population. [ Time Frame: From data of randomization until date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. ]
PFS was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomized therapy or receives another anti-cancer therapy prior to progression. Patients who did not progress or die at the time of analysis would be censored at the time of the latest date of assessment from their last evaluable RECIST according to BICR. Sensitivity analysis of PFS using investigator assessment according to RECIST 1.1.

Objective response rate (ORR) assessment to evaluate the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy compared to olaparib monotherapy. [ Time Frame: From date of randomisation until progression, or last evaluable assessment in the absence of progression, assessed up to 24 months. ]
The ORR was defined using the BICR data to define a visit response of CR or PR, with the denominator defined as subset of all randomised patients with measurable disease at baseline per BICR. ORR will be assessed by using BICR according to RECIST 1.1. For sensitivity analysis, ORR was defined as the percentage of patients with at least one Investigator-assessed visit response of CR or PR and will be based on a subset of all randomised patients with measurable disease at baseline per the site Investigator.

ORR will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm patient population.


Duration of response (DoR) assessment to evaluate the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy compared to olaparib monotherapy. [ Time Frame: The time from the date of first documented response until date of documented progression according to BICR data or death in the absence of disease progression, assessed up to 24 months. ]
The DoR was defined as the time from the date of first documented response according to BICR data until date of documented progression according to BICR data or death in the absence of disease progression (ie, date of PFS event or censoring - date of first response + 1). DoR will be assessed by using BICR according to RECIST 1.1. For sensitivity analysis, DoR was defined as the time from the date of first documented response according to Investigator assessment until date of documented progression according to Investigator assessment or death in the absence of disease progression (ie, date of PFS event or censoring - date of first response + 1). DoR will be assessed in BRCAm, Non BRCAm HRRm and Non HRRm patient population.

Tumour change assessment to evaluate the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy compared to olaparib monotherapy. [ Time Frame: At week 16. ]
Absolute change and percentage change from baseline in tumor lesions tumour size, at 16 weeks. Tumour change will be assessed in BRCAm, Non BRCAm HRRm and Non HRRm patient population.

Overall survival (OS) assessment to evaluate the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy compared to olaparib monotherapy. [ Time Frame: From the date of randomisation until death due to any cause, assessed up to 42 months. ]
OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis would be censored based on the last recorded date on which the patient was known to be alive. OS will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm patient population.

PFS assessment to compare the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy. [ Time Frame: From data of randomization until date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. ]
PFS will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm patient population. Sensitivity analysis of PFS using Investigator assessments according to RECIST 1.1.

ORR assessment to compare the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy. [ Time Frame: From date of randomisation until progression, or last evaluable assessment in the absence of progression, assessed up to 24 months. ]
ORR will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All, Non HRRm patient population. ORR will be assessed by using BICR according to RECIST 1.1. Sensitivity analysis of objective response using Investigator assessments according to RECIST 1.1.

DoR assessment to compare the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy. [ Time Frame: The time from the date of first documented response until date of documented progression according to BICR data or death in the absence of disease progression, assessed up to 24 months. ]
DoR will be assessed in BRCAm, Non BRCAm HRRm, Non HRRm patient population. DoR will be assessed by using BICR according to RECIST 1.1.Sensitivity analysis of DoR using Investigator assessments according to RECIST 1.1.

Tumour change assessment to compare the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy. [ Time Frame: At week 16. ]
Absolute change and percentage change from baseline in TLs tumour size at 16 weeks will be based on RECIST. Tumour change will be assessed in BRCAm, Non BRCAm HRRm, Non HRRm patient population. Sensitivity analysis of tumour change using Investigator assessments according to RECIST 1.1.

Overall survival (OS) assessment to compare the efficacy of Ceralasertib+olaparib and adavosertib+olaparib combination therapy. [ Time Frame: From the date of randomisation until death due to any cause, assessed up to 42 months. ]
Time to death for any cause. OS will be assessed in BRCAm, HRRm, Non BRCAm HRRm, All,Non HRRm patient population.

Minimum steady-state plasma drug concentration during a dosage interval (Cmin ss). [ Time Frame: At Day 1 and Day 10 of cycle 1 (each cycle is 21 days) for olaparib and adavosertib. At Day 1 and Day 7 of Cycle 1 (each cycle is 28 days) for olaparib and Ceralasertib. ]
To assess Cmin ss in olaparib, Ceralasertib and adavosertib treatments. At Cycle 1 Day 1: 2 hours, 4.5 hours and 9 hours; Cycle 1 Day 7: pre-dose, 0.5 hour, 2 hours, 4.5 hours and 9 hours for olaparib arm. At Cycle 1 Day 1: 3. Cycle 1 Day 1: 2 hours (±1 hour), 4.5 hours (±1.5 hour) and 9 hours, (±3 hours), Cycle 1 Day 7: pre-dose, 0.5hour (±0.5 -1 hour, 2 hours and (±1 hour), 4.5 hours. (±1.5 hours) and 9 hours (±3 hour) for olaparib and Ceralasertib. At Cycle 1 Day 1: 2 hours, 4.5 hours and 9 hours; Cycle 1 Day 10: pre-dose, 0.5 hour, 2 hours, 4.5 hours and 9 hours for olaparib arm and adavosertib.

Number of participants with adverse events (AEs) [ Time Frame: Adverse events collected from informed consent until 30-day follow-up period after last dose of study medication. ]
AEs (severity graded by Common Terminology Criteria for Adverse Event [CTCAE] v4). Safety and tolerability of the combination of AZD6738+olaparib and the combination of adavosertib+olaparib compared with olaparib monotherapy by assessment of adverse events (AEs).

Assessment of twelve lead safety electrocardiography (ECG). [ Time Frame: At baseline, cycle 1 [On Day 1, 7, 15 for olaparib monotherapy and Ceralasertib+olaparib; on Day 1, 10, 15 for adavosertib+Olaparib], at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
ECG assessment to be done in triplicate on Day 1 of every cycle, within 1-2 hours of dosing. The patients will rest for at least 10 minutes before the start of each recording and they must be in the same supine body position (maximum 30 degrees flexion in the hip and feet not in contact with the footboard) at the recording time point.

Assessment of Eastern Cooperative Oncology Group performance status (ECOG). [ Time Frame: At baseline, Day 1 of cycle 1 and subsequent cycles/ treatment visits (each cycle is 21 days for olaparib and adavosertib and and 28 days for olaparib and Ceralasertib), and at treatment discontinuation (an average of 1 year). ]
A performance status using scales and criteria to assess how a patient's disease is Progressing. The cycle length for olaparib monotherapy and Ceralasertib+olaparib treatment arms will be 28 days. The cycle length for adavosertib+olaparib treatment arm is 21 days.

Laboratory assessments of urinalysis. [ Time Frame: At screening Part 2 (visit 1; from day -28 to 0). ]
To assess the urinalysis (Hemoglobin/erythrocytes/blood, protein/albumin, and glucose) as a criteria of safety and tolerability of the combination of Ceralasertib+olaparib and the combination of adavosertib +olaparib compared with olaparib monotherapy. After screening, urinalysis will only be required if clinically indicated.

Frequency of tumour HRR mutations [ Time Frame: At Screening (up to Day-28) ]
To explore the frequency of HRR (including BRCA) mutation(s) in tumour samples in All patient population.

Nature of tumour HRR mutations [ Time Frame: At Screening (up to Day-28) ]
To describe the nature of HRR (including BRCA) mutation(s) in tumour samples in the All patient population.

To compare the frequency and nature of tumour HRR mutations to germline mutational status [ Time Frame: At Screening (up to Day-28) ]
To compare the frequency and nature of tumour HRR to germline mutational status in All patient population.

Number of participants with abnormal laboratory assessments of clinical chemistry- Ceralasertib+olaparib [ Time Frame: At baseline, Cycle 1 (On Day 1, 7, 15 [each cycle is 28 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
To assess the clinical chemistry (creatinine, bilirubin total, alkaline phosphatase, aspartate transaminase, alanine transaminase, albumin, potassium, sodium, calcium, blood urea nitrogen, C-reactive protein, and total protein) as a criterion of safety and tolerability of Ceralasertib+olaparib.

Number of participants with abnormal laboratory assessments of clinical chemistry- adavosertib +olaparib [ Time Frame: At baseline, Cycle 1 (Day 1, 8, 10, 15 [each cycle is 21 days]), Cycle 2 (Day 1, 8, 15), Day 1 on next visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
To assess the clinical chemistry (creatinine, bilirubin total, alkaline phosphatase, aspartate transaminase, alanine transaminase, albumin, potassium, sodium, calcium, blood urea nitrogen, C-reactive protein, and total protein) as a criterion of safety and tolerability of adavosertib +olaparib.

Number of participants with abnormal laboratory assessments of clinical chemistry- olaparib monotherapy [ Time Frame: At baseline, Cycle 1 (On Day 1, 7, 15 [each cycle is 28 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
To assess the clinical chemistry (creatinine, bilirubin total, alkaline phosphatase, aspartate transaminase, alanine transaminase, albumin, potassium, sodium, calcium, blood urea nitrogen, C-reactive protein, and total protein) as a criterion of safety and tolerability of olaparib monotherapy.

Laboratory assessments of Haematology - Ceralasertib+olaparib [ Time Frame: At baseline, Cycle 1 (On Day 1, 7, 15 [each cycle is 28 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
To assess the hematology (haemoglobin, leukocyte count, absolute neutrophil count, absolute lymphocyte count, platelet count, and mean cell volume (MCV)) as a criterion of safety and tolerability of Ceralasertib+olaparib.

Laboratory assessments of Haematology- adavosertib +olaparib [ Time Frame: At baseline, Cycle 1 (Day 1, 8, 10, 15 [each cycle is 21 days]), Cycle 2 (Day 1, 8, 15), Day 1 on next visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
To assess the hematology (haemoglobin, leukocyte count, absolute neutrophil count, absolute lymphocyte count, platelet count, and mean cell volume (MCV)) as a criterion of safety and tolerability of adavosertib +olaparib.

Laboratory assessments of Haematology - olaparib monotherapy [ Time Frame: At baseline, Cycle 1 (On Day 1, 7, 15 [each cycle is 28 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
To assess the hematology (haemoglobin, leukocyte count, absolute neutrophil count, absolute lymphocyte count, platelet count, and mean cell volume (MCV)) as a criterion of safety and tolerability of olaparib monotherapy.

Assessments of blood pressure- Ceralasertib+olaparib [ Time Frame: At baseline, Cycle 1 (On Day 1 [each cycle is 28 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
Blood pressure (systolic and diastolic) will be measured as a criterion of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.

Assessments of blood pressure- adavosertib +olaparib [ Time Frame: At baseline, Cycle 1 and 2 (Day 1, 8, 15 [each cycle is 21 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
Blood pressure (systolic and diastolic) will be measured as a criterion of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.

Assessments of blood pressure- olaparib monotherapy [ Time Frame: At baseline, Cycle 1 (On Day 1 [each cycle is 28 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
Blood pressure (systolic and diastolic) will be measured as a criterion of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.

Assessments of pulse- Ceralasertib+olaparib [ Time Frame: At baseline, Cycle 1 (On Day 1 [each cycle is 28 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
Pulse rate will be measured as a criterion of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.

Assessments of pulse- adavosertib +olaparib [ Time Frame: At baseline, Cycle 1 and 2 (Day 1, 8, 15 [each cycle is 21 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
Pulse rate will be measured as a criterion of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.

Assessments of pulse- olaparib monotherapy [ Time Frame: At baseline, Cycle 1 (On Day 1 [each cycle is 28 days]), Day 1 on subsequent treatment visits, at treatment discontinuation (an average of 1 year), and 30 day follow-up period after last dose of study medication. ]
Pulse rate will be measured as a criterion of safety and tolerability preferably using a semi-automatic BP recording device with an appropriate cuff size after 10 minutes rest.

Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1. * Provision of informed consent prior to any study specific procedures
2. * Patients must be male or female ≥18 years of age
3. * Progressive cancer at the time of study entry
4. * Histologically or cytologically confirmed TNBC with evidence of metastatic
disease (defined as ER and PgR negative [IHC nuclear staining <1% positive] and
HER2 negative [IHC 0, 1+ or IHC 2+ with corresponding ISH non-amplified of
ratio less than 2.0 or ISH non-amplified ratio less than 2.0] as per ASCO-CAP
HER2 guideline recommendations 2013 (ASCO-CAP)
5. * Patients must have received at least 1 and no more than 2 prior lines of treatment
for metastatic disease with an anthracycline (eg, doxorubicin, epirubicin) and/or a
taxane (eg, paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant,
adjuvant or metastatic setting..
* Patients who have received platinum (cisplatin or carboplatin, either as
monotherapy or in combination) for advanced breast cancer are eligible to enter the
study provided there has been no evidence of disease progression during the
platinum chemotherapy.
* Patients who have received prior platinum based chemotherapy are eligible if
platinum was given either as potentially curative treatment for a prior non breast
cancer (eg, ovarian cancer) with no evidence of disease for ≥5 years prior to study
entry or as adjuvant/neoadjuvant treatment for breast cancer provided at least
12 months have elapsed between the last dose of platinum-based treatment and
randomisation
6. Confirmed presence of qualifying HRR mutation or absence of any HRR mutation
in tumour tissue by the Lynparza HRR assay.
 FFPE tumour tissue blocks are required for each patient, but if not
available, tissue sections are accepted. At least twenty (20) (thirty [30]
preferable) unstained sections without cover slips must be submitted to
ensure sufficient material for the prospective Lynparza HRR testing to
determine study eligibility and research that will aid understanding of the
patient population relative to treatment with DDR and other cancer agents.
 If a patient has a previously known qualifying BRCA1/2 mutation (in blood
or tumour tissue), then the patient can be invited to consent to the full
study. The patient will need to consent to provide an archival tumour
block or tissue sections for central assessment of the HRR mutation status.
 If patients have a mutation in one of the 13 other non BRCA HRR genes
based on prior breast cancer tissue specimen testing by the commercially
available FoundationOne® assay, they must have the mutation confirmed
as a qualifying mutation by FMI. Similarly, if patients have no detected
mutation in any of the 15 HRR genes based on prior breast cancer tissue
specimen testing by the FoundationOne®
assay, they must have the lack of
HRR mutation confirmed by FMI. The patient will need to consent to provide an archival tumour sample (tissue block or sections) and a blood
sample.
7. *At least one measurable lesion that can be accurately assessed at baseline by
computed tomography (CT) (magnetic resonance imaging [MRI] where CT is
contraindicated) and is suitable for repeated assessment as per RECIST 1.1.
8. Patients must have normal organ and bone marrow function measured within
28 days prior to randomisation as defined below:
(a) Haemoglobin (Hb) ≥10.0 g/dL with no blood transfusions (packed red
blood cells) in the past 28 days
(b) Absolute neutrophil count (ANC) ≥ 1.5 x 109
/L
(c) Platelet count ≥100 x 109
/L with no platelet transfusions in the
past 28 days
(d) Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) unless
the patient has documented Gilbert’s Syndrome
(e) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT)
≤2.5 x institutional ULN unless liver metastases are present in which case
they must be ≤5 x ULN
(f) Patients must have creatinine clearance (CrCl) estimated using the
Cockcroft-Gault equation of ≥51 mL/min:
9. * ECOG PS 0-1 within 28 days of randomisation.
10. * Postmenopausal or evidence of non childbearing status for women of childbearing
potential: negative urine or serum pregnancy test within 28 days of study treatment
and confirmed prior to treatment on Day 1.
Postmenopausal is defined as:
 Amenorrheic for 1 year or more following cessation of exogenous
hormonal treatments
 Luteinizing hormone and Follicle stimulating hormone levels in the
postmenopausal 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 sterilisation (bilateral oophorectomy or hysterectomy).
11. Women of childbearing potential and their partners, who are sexually active, must
agree to the use of 2 highly effective forms of contraception in combination (as
described in Appendix E) from the signing of the informed consent, throughout the
period of taking study treatment and for at least 1 month after last dose of study
drug(s), or they must totally/truly abstain from any form of sexual intercourse (as
described in Appendix E).
12. Male patients must use a condom during treatment and for 6 months after the last
dose of study drug(s) when having sexual intercourse with a pregnant woman or
with a woman of childbearing potential. Female partners of male patients should
also use a highly effective form of contraception (see Appendix E for acceptable
methods) for 6 months after the last dose of study drug(s) if they are of childbearing
potential.
13. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations.
14. * Patients must have a life expectancy of ≥16 weeks.

Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. * Involvement in the planning and/or conduct of the study (applies to AstraZeneca
staff and/or staff at the study site).
2. Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within
21 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been
completed 21 or more days before Cycle 1 Day 1. The patient can receive a stable
dose of bisphosphonates or denosumab for bone metastases, before and during the
study as long as these were started at least 5 days prior to study treatment.
3. * More than 2 prior lines of cytotoxic chemotherapy for metastatic disease.
 Prior treatments with hormonal therapy and non hormonal targeted therapy
are allowed and not counted as a prior line of cytotoxic chemotherapy.
 For the purposes of this protocol, the combination of an aromatase
inhibitor and everolimus is not considered cytotoxic chemotherapy.
 Treatment with biologics will not be considered as prior line of therapy.
4. * Previous randomisation in the present study.
5. * Previous treatment with a PARP inhibitor (including olaparib) or other DDR
inhibitor (unless treatment was for less than 3 weeks duration and at least 12 months
have elapsed between the last dose and randomisation. Patients that did not tolerate
prior treatment are excluded).
6. * Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is
longer) prior to randomisation. The minimum washout period for immunotherapy
shall be 42 days.
7. * Patients with MDS/AML or with features suggestive of MDS/AML.
8. * Patients with second primary cancer, EXCEPTIONS: 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
tumours curatively treated with no evidence of disease for ≥ 5 years prior to study
entry (including lymphomas [without bone marrow involvement]).
9. Mean resting corrected QTc interval using the Fridericia formula (QTcF)
>470 msec/female patients and >450 msec for male patients (as calculated per
institutional standards) obtained from 3 ECGs performed 2-5 minutes apart at study
entry, or congenital long QT syndrome.
AZD1775 should not be given to patients who have a history of Torsades de pointes
unless all risk factors that contributed to Torsades have been corrected. AZD1775
has not been studied in patients with ventricular arrhythmias or recent myocardial
infarction.
10. Any of the following cardiac diseases currently or within the last 6 months defined
by New York Heart Association (NYHA) ≥ Class 2:
 Unstable angina pectoris
 Congestive heart failure
 Acute myocardial infarction
 Conduction abnormality not controlled with pacemaker or medication
 Significant ventricular or supraventricular arrhythmias (patients with
chronic rate-controlled atrial fibrillation in the absence of other cardiac
abnormalities are eligible)
11. Concomitant use of known strong cytochrome P (CYP) 3A inhibitors (eg.
itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with
ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or
moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem,
fluconazole, verapamil). The required washout period prior to starting study
treatment is 2 weeks.
Patient has had prescription or non-prescription drugs or other products known to be
sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic
index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be
discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study
until 2 weeks after the last dose of study drug (see Appendix H).
Transporter studies (in vitro) have shown that AZD1775 is an inhibitor of breast
cancer resistance protein (BCRP). Please refer to Appendix H for use with BCRP
substrates.
Patients should stop using herbal medications 7 days prior to first dose of study
treatment. Please see Appendix H for further details.
12. Concomitant use of known strong (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 study treatment is 5 weeks for enzalutamide or
phenobarbital and 3 weeks for other agents.
13. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy,
excluding alopecia and CTCAE grade 2 peripheral neuropathy.
14. Major surgery within 2 weeks of starting study treatment: patients must have
recovered from any effects of any major surgery.
15. * Immunocompromised patients, eg, patients who are known to be serologically
positive for human immunodeficiency virus (HIV).
16. * Patients with known active hepatitis (ie, hepatitis B or C).
17. * 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 CT scan or any psychiatric disorder that prohibits obtaining informed consent, and any other medical condition that, in the opinion of
the Investigator, places the patient at unacceptable risk of toxicity.
18. * 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 (SD) for
28 days.
 * Patients with a history of treated central nervous system (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 3 weeks between
completion of radiotherapy and Cycle 1 Day 1 and recovery from
significant (Grade ≥3) acute toxicity with no ongoing requirement for
>10 mg of prednisone per day or an equivalent dose of other
corticosteroid. If on corticosteroids, the patient should be receiving a
stable dose of corticosteroids, started at least 4 weeks prior to treatment.
19. * Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication.
20. * Patients with a known hypersensitivity to olaparib, AZD1775, AZD6738, or any
of the excipients of the products.
21. Pregnant or breast feeding women.