| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple negative Breast Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
For BRCAm, Non BRCAm HRRm, Non HRRm subject population
- To assess the efficacy of the combination of ceralasertib+olaparib and the combination of AZD1775+olaparib compared with olaparib monotherapy by assessment of PFS |
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| E.2.2 | Secondary objectives of the trial |
-To assess the efficacy of combination of ceralasertib+olaparib and combination of AZD1775+olaparib compared with olaparib monotherapy by assessment of PFS for HRRm and all subject populations
-To assess the efficacy of combination of ceralasertib+olaparib and combination of AZD1775+olaparib compared with olaparib monotherapy in terms of ORR, DOR, tumour change and OS
- To compare the efficacy of combination of ceralasertib+olaparib with combination of AZD1775+olaparib in terms of PFS, ORR, DOR, tumour change and OS
-To explore the frequency of and describe the nature of tumour HRR (including BRCA) mutation(s) in tumour samples and to compare this with germline HRR (including BRCA) mutation status
-To assess exposure to olaparib, ceralasertib and AZD1775 in all patients
-To assess the safety and tolerability of combination of ceralasertib+olaparib and combination of AZD1775+olaparib compared with olaparib monotherapy |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion 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 at initial diagnosis with evidence of metastatic or incurable advanced locoregional 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).
Note: An Allred score of 0-2 is acceptable however for a score of 2 the Proportion score must be checked to make sure it is 1 (≤1% cells are ER positive)
5. Patients must have received at least 1 and no more than 2 prior lines of treatment for metastatic or incurable advanced locoregional disease with an anthracycline (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 (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 (thirty 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 or other HRR mutation, 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
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 ≥10.0 g/dL with no blood transfusions (packed red blood cells) in the past 28 days
b) Absolute neutrophil count ≥ 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 unless the patient has documented Gilbert’s Syndrome
e) Aspartate aminotransferase /alanine aminotransferase ≤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 of ≥51 mL/min estimated or measured using standard methodology at the investigating centre (Cockcroft-Gault, MDRD, CK-EPI, EDTA or 24 hr urine):
Estimated CrCl = (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
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 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)
Please see protocol for further details |
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| E.4 | Principal exclusion criteria |
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. No longer applicable from CSPv6.0 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
- Unstable angina pectoris
- Congestive heart failure ≥ Class 2 as defined by the New York Heart Association
- Acute myocardial infarction
- Conduction abnormality not controlled with pacemaker or medication (patients with a conduction abnormality controlled with pacemaker or medication at the time of screening are eligible)
- 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
NAP from CSPv7.0 - 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
NAP from CSPv7.0 - Transporter studies (in vitro) have shown that AZD1775 is an inhibitor of breast cancer resistance protein (BCRP) Patients should stop using herbal medications 7 days prior to first dose of study treatment
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)
Please see protocol for further details |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Study end points are defined for the following patient populations: BRCAm, Non BRCAm HRRm, Non HRRm
- PFS using BICR according to RECIST 1.1
- Sensitivity analysis of PFS using Investigator assessments according to RECIST 1.1 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Study end points are defined per the patient populations
- PFS and objective response using BICR according to RECIST 1.1
- Sensitivity analysis of PFS and objective response using Investigator assessments according to RECIST 1.1
- DoR and tumour change using BICR according to RECIST 1.1
- Sensitivity analysis of DoR, and tumour change using Investigator assessments according to RECIST 1.1
- Time to death for any cause
- Mutation status of HRR pathway genes
- Cmin ss
Safety
- AEs (severity graded by CTCAE v4)
- laboratory tests (clinical chemistry, haematology and urinalysis)
- vital signs (pulse and BP)
- ECG data
- ECOG PS |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 117 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Korea, Republic of |
| Taiwan |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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