| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Breast Cancer |
|
| 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 | 14.1 |
| 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 compare Progression Free Survival (PFS) in patients treated with AZD8931 given in combination with anastrozole versus anastrozole alone. |
|
| E.2.2 | Secondary objectives of the trial |
1. To investigate the safety and tolerability of AZD8931 given in combination with anastrozole
2. To compare the objective response rate (ORR) (as evaluated by response evaluation criteria in solid tumours version 1.1 (RECIST 1.1) criteria) in patients treated with AZD8931 given in combination with anastrozole versus anastrozole alone
3. To compare the overall survival (OS) in patients treated with AZD8931 given in combination with anastrozole versus anastrozole alone
4. To investigate the population PK of AZD8931 and O-desmethyl AZD8931in combination with anastrozole
5. To investigate the effect of AZD8931 in combination with anastrozole on Health Related Quality of Life (HRQoL) versus anastrozole alone.
6. To explore the association between quantitative ER expression (using standardised central testing) and patient clinical outcomes by PFS |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of signed, written informed consent prior to any study specific procedures
2. Post menopausal females defined as: natural menopause with menses > 1 year ago; or radiation-induced oophorectomy with last menses >1 year ago; or chemotherapy induced menopause with 1 year interval since last menses; or serum FSH and LH and plasma oestradiol levels in the post menopausal range for the institution; or bilateral oophorectomy
3. Patients with histologic or cytologic diagnosis of breast cancer with evidence of locally advanced or metastatic disease. Lesions should not be amenable to surgery or radiation of curative intent
4. Documented ER- and/or PgR positive breast cancer
5. Patients must be endocrine therapy naive i.e. they have never received endocrine therapy (e.g. tamoxifen, aromatase inhibitors etc.) for their breast cancer.
6. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by computed tomography (CT), magnetic resonance imaging (MRI) or plain x ray and is suitable for repeat assessment
7. World Health Organisation (WHO) performance status 0 or 1
8. Estimated life expectancy of more than 12 weeks.
For inclusion in the optional PGx, patients must also fulfil the following criterion:
9. Patients receiving bisphosphonate therapy for skeletal related events must have been on their current dose for at least 5 days prior to randomisation. If they are expected to require bisphosphonate therapy at any time during the study it must be commenced at least 5 days prior to randomisation.
10. Patients receiving ongoing treatment with angiotensin converting enzyme (ACE) inibitors, postassium sparing diuretics or potassium supplements must have been on therapy for at least 2 weeks with no changes in dose in that time. Similarly, patients receiving a stable or decreasing dose regime of steroids or systemic (oral) anit-cholinergic (anti-muscarinic) medication are allowed.
11. Consent to the provision of tumour from both diagnostic and/or re biopsy samples where available. |
|
| E.4 | Principal exclusion criteria |
1. Patients must not have received more than 1 prior chemotherapy regimen for their breast cancer.
2. Trastuzumab or lapatinib eligible (as confirmed by local testing practices or treatment availability)
3. Any prior therapy with an inhibitor of ErbB1 (EGFR) or ErbB2 (HER2) (eg, lapatinib)
4. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count <1.5 x 109/L or platelet count <100 x 109/L
5. Inadequate renal function as demonstrated by serum creatinine >1.5 x upper limit of normal (ULN), or creatinine clearance <50mL/min
6. Haemoglobin < 9g/dL (5.59 mmol/L), any blood transfusion must be >14 days prior to the determination of the haemoglobin levels
7. Inadequate liver function defined as;
- serum bilirubin >2 x ULN,
- and ALT or AST >2.5 x ULN in the absence of noted liver metastases,
- and ALP >2.5 x ULN in the absence of noted liver metastases,
- or ALP, AST and ALT >5.0 x ULN if judged by the investigator to be related to liver metastases. Elevated ALP is not exclusionary if due to the presence of bone metastasis and liver function is otherwise considered adequate in the investigator’s judgment.
8. Resting ECG with measurable QTc interval of >450msec at 2 or more time points within a 24 hour period
9. Cardiac ejection fraction outside institutional range of normal or ≤50% (whichever is higher) as measured by echocardiogram (or multiple uptake gated acquisition scan (MUGA) if an echocardiogram cannot be performed or is inconclusive)
10. Known uncontrolled or symptomatic angina, arrythmias or congestive heart failure; evidence of transmural infarction on ECG, poorly controlled hypertension (systolic >180 mmHg or diastolic >100 mmHg), significant valvular disease or history of high risk dysrrhythmia (such as ventricular fibrillation or ventricular tachycardia [includes ventricular triplets])
11. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
12. Active or uncontrolled systemic disease which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol
13. History or repeated unexplained episodes of syncope/dizziness
14. Medical diagnosis of acne rosacea, psoriasis, severe atopic eczema
15. Concurrent second primary malignancy (except in situ carcinoma of the cervix). Patients with a prior cancer are eligible if they are disease-free with no evidence of recurrence or relapse in the past 5 years.
16. Unresolved toxicity >CTC grade 2 (except alopecia) from previous anti-cancer therapy
17. Prior exposure to anthracyclines or mitoxantrone with cumulative exposure in excess of 360 mg/m2 for doxorubicin, 720 mg/m2 for epirubicin, or 72 mg/m2 for mitoxantrone
18. Unable to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation. Guidance on medicines to avoid and on washout periods is given in Appendix E to this protocol
19. Unable to discontinue any medication or herbal supplement with know moderate or potent inhibitory effect on CYP3A4 or CYP2D6, or potent inducing effects on CYP3A4 or CYP2D6. Such drugs must have been discontinued for an appropriate period prior to starting AZD8931. Guidance on medicines to avoid and on washout periods is given in appendix E to this protocol
20. Known hypersensitivity to AZD8931, its excipients, or drugs in its class (including oral tyrosine kinase inhibitors)
21. Currently receiving (and are unwilling to discontinue) oestrogen replacement therapy (last dose ≤7 days prior to randomisation)
22. Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or staff at the study site)
23. Receipt of investigational drug within 30 days or five half lives, whichever is longer, of the first dose of IP (AZD8931 or matching placebo)
25. Prior diagnosis of dry eye syndrome, eyelid or eyelash abnormalities |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - PFS as evaluated by RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Estimated as September 2013 |
|
| E.5.2 | Secondary end point(s) |
1. Adverse Events (AE), laboratory findings, physical examination, vital signs, cardiac monitoring (including 12 lead electrocardiograms [ECGs] and echocardiography / MUGA)
2. OS
3. Time to deterioration of functional assessment of cancer therapy breast (FACT B) Trial Outcomes Index (TOI) and functional assessment of cancer therapy endocrine symptoms (FACT ES) total score as evaluated by FACT B and FACT ES
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Time Frame: Routine safety monitoring at four weekly visits until week 24 and then 12 weekly visits up to treatment discontinuation or withdrawal.
2. Following progression, patients will be contacted at 12 weekly intervals to determine survival status.
3. Quality of life questionnaires to be completed at four weekly visits until week 24 and then 12 weekly thereafter.
|
|
| 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 | 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Brazil |
| Canada |
| India |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Philippines |
| South Africa |
| Thailand |
| United States |
|
| 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
|
| The point at which no patient will be exposed to study related procedures. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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