| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To determine the efficacy of single agent olaparib vs physician’s choice chemotherapy (capecitabine, vinorelbine or eribulin) by progression-free survival (PFS) using blinded independent central review (BICR) data assessed by Response Evaluation Criteria in Solid Tumours (RECIST 1.1). |
|
| E.2.2 | Secondary objectives of the trial |
1.Efficacy of single agent olaparib vs physician's choice chemotherapy (capecitabine, vinorelbine or eribulin) by assessment of overall survival (OS).
2.Efficacy of single agent olaparib vs physician's choice chemotherapy (capecitabine, vinorelbine or eribulin) by assessment of time to second progression, defined as objective radiological or symptomatic progression, or death (PFS2).
3.Efficacy of single agent olaparib vs physician's choice chemotherapy (capecitabine, vinorelbine or eribulin) by assessment of objective response rate (ORR) using BICR data assessed by RECIST 1.1.
4.Assessment of the effect of olaparib on the Health-related Quality of Life (HRQoL)measured by EORTC QLQ-C30 global QoL scale.
5.Assessment of adverse events (AEs), graded by CTCAE (v4.0)
6.Assessment of physical examination.
7.Assessment of vital signs including blood pressure (BP), pulse and electrocardiogram (ECG).
8.Assessment of laboratory parameters including clinical chemistry and haematology
|
|
| 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. *Histologically or cytologically confirmed breast cancer with evidence of metastatic disease
4. Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)
5.*Patients must have received treatment with an anthracycline (e.g.
doxorubicin, epirubicin) unless contraindicated and a taxane (e.g.
paclitaxel, docetaxel) in either an neoadjuvant/adjuvant or metastatic setting.
6. *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
7.Patients who have received prior platinum based chemotherapy are
eligible if platinum was
given EITHER a) 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 b) as
adjuvant/neoadjuvant treatment for breast cancer provided at least 12
months have elapsed between the last dose of platinum-based treatment
and randomization.
8. Patients with 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
9. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT (MRI where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.
10. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
. Haemoglobin ≥ 10.0 g/dL with no blood transfusions (packed red blood cells and platelet transfusions) in the past 28 days
. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
. Platelet count ≥ 100 x 109/L
. Total bilirubin ≤ 1.5 x institutional upper limit of normal
. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN
. Serum or plasma creatinine ≤ 1.5 x institutional upper limit of normal
(ULN)
11. *ECOG performance status 0-1 within 21 days of randomisation
12. *Postmenopausal or evidence of non-childbearing status for women
of childbearing potential: negative urine or serum pregnancy test
9. Postmenopausal is defined as any of the following :
. Age >/= 60 yrs
. Age < 60 and amenorrheic for 1 year or more in the absence of
chemotherapy and/or hormonal treatment
. LH, FSH and plasma oestradiol levels in the post menopausal range for
women under 60 years of age
. radiation-induced oophorectomy with last menses >1 year ago
. or surgical sterilisation (bilateral oophorectomy or hysterectomy)
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. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary tumour if available For inclusion in
a) the optional exploratory genetic research and/or
b) the optional tumour biopsy research, patients must fulfil the following criteria:
. Provision of informed consent for genetic research
. Provision of informed consent for tumour biopsy research
If a patient declines to participate in the optional exploratory genetic research or the optional tumour biopsy research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study. |
|
| E.4 | Principal exclusion criteria |
1.*Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff/BCA staff and/or staff at the study site).
2. BRCA1 and/or BRCA2 mutations that are considered to be non detrimental (e.g., “Variants of uncertain clinical significance” or “Variant of unknown significance” or “Variant, favour polymorphism” or “benign polymorphism” etc.).
3. Cytotoxic chemotherapy or non-hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Endocrine therapy must have been discontinued 7 or more days before Cycle 1 Day 1. Palliative radiotherapy must have been completed 14 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 2 weeks prior to study treatment.
4. *Patients with HER2-positive disease (3+ by IHC or ISH amplified > 2.0).
5. *Previous randomisation in the present study.
6. Exposure to an investigational product within 30 days or 5 half lives (whichever is longer) prior to randomisation
7. *Any previous treatment with a PARP inhibitor, including olaparib.
8. *Patients with second primary cancer, EXCEPTIONS: adequately treated nonmelanoma 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 including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for . 5 years prior to study entry.
9. Resting ECG with QTc > 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome. If ECG demonstrates QTc >470 msec, patient will be eligible only if repeat ECG demonstrates QTc .470
msec.
10. *Patients cannot have received 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.
*Concomitant use of known potent CYP3A inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
12. Persistent toxicities (.CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
13. *Patients with myelodysplastic syndrome/treatment related acute myeloid leukaemia.
14. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
15. *Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
16. *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 bilateral lung disease on High Resolution Computed Tomography scan or any psychiatric disorder that would limit ability to comply with study procedures, and any other medical condition that, in the opinion of the investigator, places the patient at unacceptable risk of toxicity.
17. *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.
18. *Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
19. Pregnant or breast feeding women.
20. *Previous allogeneic bone marrow transplant.
21. *Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
22. *Whole blood transfusions in the last 120 days prior to enrolment to the study which may interfere with gBRCA testing (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no.10) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assessed when approx 75% patients have experienced objective disease progression by RECIST. RECIST assessments performed at baseline, every 6 wks for the first 24 weeks, then every 12 wks until progression. Data collection will last up to approx 7 years |
|
| E.5.2 | Secondary end point(s) |
1.Overall Survival
2.Time from randomisation to second progression or death (PFS2).
3.Objective Response Rate by BICR using RECIST 1.1
4.Adjusted mean change from baseline in global QoL score from the EORTC-QLQ-C30 questionnaire.
5.Safety and tolerability of olaparib by assessment of adverse events
6.Safety and tolerability of olaparib by assessment of physical examination.
7.Safety and tolerability of olaparib by assessment of vital signs.
8.Safety and tolerability of olaparib by assessment of laboratory parameters.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.At PFS analysis & at approx 60% deaths, every 8 wks after objective
progression. 2. At PFS analysis & final OS. After 1st objective
progression, every 8 wks. 3. At time of PFS analysis. Baseline, every 6
wks for first 24 weeks, then every 12 wks until objective progression. 4.
EORTC QLQ-C30 questionnaires to be completed at baseline & every 6
wks until disease progression. 5.AEs collected from informed consent
until post treatment 30-day f/u period. 6. Baseline & until study
treatment d/c & at the post treatment 30-day f/u visit. 7.Baseline &
until study treatment d/c & at the post treatment 30-day f-u visit.
8.Baseline & until study treatment d/c & at the post treatment 30-day fu
visit.
Study data collection for all endpoints is expected to last up to
approximately 7 years. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Bulgaria |
| China |
| Czech Republic |
| France |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Switzerland |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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