| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple negative (ER-negative, PR-negative/unknown, HER2-negative) advanced or metastatic breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
The main aim of this study in all treated patients and in patients with and without aberrant activation of the PI3K/AKT pathway is:
Progression-free survival, defined as the time from the date of randomisation to the date of first documented tumour progression (using RECIST1.1) or death from any cause, whichever occurs first. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary aims of the study in all treated patients and in patients with and without aberrant activation of the PI3K/AKT pathway are:
• Objective response, defined as a complete or partial response (as assessed by the site radiologist and/or investigator, using RECIST 1.1)
• Average change (%) in tumour size at 8 weeks compared to baseline, as assessed by RECIST 1.1); tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions
• Clinical Benefit (CB), defined as number of patients with complete or partial response or stable disease maintained ≥24 weeks (as assessed by the site radiologist and/or investigator, using RECIST 1.1).
• Overall survival, defined as the time from date of randomisation to the date of death due to any cause
• Duration of response, defined as the time from first documentation of complete or partial response to disease progression (as assessed by the site radiologist and/or investigator, using RECIST 1.1)
• |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Written informed consent prior to admission to this study
2. Women, age ≥ 18 years
3. Histologically confirmed breast cancer
4. Metastatic or locally recurrent disease; locally recurrent disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible).
5. Patients must have
• at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, or
• lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable disease as defined above; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible
6. Radiological or clinical evidence of recurrence or progression
7. Triple-negative disease, defined as tumour cells being
• negative for ER with <1% of tumour cells positive for ER on IHC or IHC score (Allred) of ≤2
• negative for PR with <1% of tumour cells positive for PR on IHC or IHC score (Allred) of ≤2 or PR unknown, and
• negative for HER2 with 0,1+ or 2+ intensity on IHC and no evidence of amplification on ISH.
8. Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing
9. Patients must be able to swallow and retain oral medication
10. Haematologic and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to randomisation
• ANC ≥ 1.5x 109/L, and platelet count ≥ 100 x 109/L
• Serum creatinine < 1.5 times the upper limit of normal (ULN)
• Bilirubin level < 1.5 x ULN
• AST or ALT <2.5 x ULN or <5 x ULN in the presence of liver metastases
11. ECOG performance status 0-2
12. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had a hysterectomy, bilateral oopheroctemy, bilateral tubular ligation or is post-menopausal (total cessation of menses for ≥ 1 year; if the patient is of childbearing potential, she must have a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception (for example, intrauterine device [IUD], birth control pills unless clinically contraindicated, or barrier device) beginning 2 weeks before the first dose of investigational product and for at least 1 month after AZD5363/placebo treatment discontinuation or for at least 6 months after paclitaxel treatment discontinuation, whichever is longer.
13. Willing and able to provide written informed consent |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Patients with confirmed brain metastases or a history of primary central nervous system tumors or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases. Patients with treated brain metastases that are asymptomatic and have been clinically stable for 3 months will be eligible for protocol participation
2. Prior chemotherapy for metastatic breast cancer
3. Radiotherapy with a wide field of radiation (greater than or equal to 30% marrow or whole pelvis or spine) within 4 weeks before the first dose of study medication (AZD5363/placebo)
4. Prior treatment with PI3K inhibitors, AKT inhibitors or mTOR inhibitors.
5. Prior treatment with paclitaxel or docetaxel in the (neo)adjuvant setting within 12 months from the end of paclitaxel or docetaxel treatment and inclusion into this study
6. Preexisting sensory or motor polyneuropathy ≥ Grade 2 according to NCI CTC
7. Malabsorption syndrome or other condition that would interfere with enteral absorption
8. Clinically significant pulmonary dysfunction
9. QTc Prolongation defined as a QTc interval >470 msecs or other significant abnormalities in rhythm, conduction or morphology of resting ECG including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate <50 beats/min)
10. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval.
11. Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure NYHA Grade ≥2, or Cardiac ejection fraction outside institutional range of normal or <50%
12. Clinically significant abnormalities of glucose metabolism as defined by any of the following
• Diagnosis of diabetes mellitus type I or II (irrespective of management).
• Glycosylated haemoglobin (HbA1C) ≥8.0% at screening (64 mmol/mol) (conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C (%) – 2.15] x 10.929)
• Fasting Plasma Glucose ≥ 7.0mmol/L (126 mg/dL) at screening. Fasting is defined as no caloric intake for at least 8 hours.
13. Patients with proteinuria (3+ on dipstick analysis or > 500mg/24 hours) or creatinine > 1.5 x ULN concurrent with creatinine clearance <50 mL/min
14. Exposure to potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort) (for details please refer to Appendix 2).
15. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study entry.
16. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
17. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
18. Detained persons or prisoners
19. Pregnant or nursing women |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure for this study is progression-free survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Progression free survival is defined as the time from the date of randomisation to the date of first documented tumour progression based on investigator assessment (using RECIST 1.1) or death from any cause, whichever occurs first.
Tumour assessments of progression will be performed at screening, weeks 8, 16 and 24, and every 12 weeks thereafter, at the end of treatment and at follow-up. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
The secondary outcome measures in all treated patients and in patients with and without aberrant activation of the PI3K/AKT pathway are:
1. Objective response, defined as a complete or partial response (as assessed by the site radiologist and/or investigator, using RECIST 1.1)
2. Average change (%) in tumour size at 8 weeks compared to baseline, as assessed by RECIST 1.1); tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions
3. Clinical Benefit (CB), defined as number of patients with complete or partial response or stable disease maintained ≥24 weeks (as assessed by the site radiologist and/or investigator, using RECIST 1.1).
4. Overall survival, defined as the time from date of randomisation to the date of death due to any cause
5. Duration of response, defined as the time from first documentation of complete or partial response to disease progression (as assessed by the site radiologist and/or investigator, using RECIST 1.1)
6. Duration of clinical benefit, defined as the time from randomisation to disease progression (as assessed by the site radiologist and/or investigator, using RECIST1.1) in patients with CB
7. 8-week progression-free survival and 24-week progression-free survival, respectively, defined as the percentage of patients with an 8 or 24 week visit response of CR, PR or SD (as defined by RECIST 1.1) with no evidence of previous progression.
8. Patient reported outcomes, as assessed by the Functional Assessment of Cancer Therapy-General (FACT-G) scale, the Functional Assessment of Cancer Therapy-Diarrhoea (FACT-D) subscale, the Functional Assessment of Cancer Therapy – EGFRI (FACT-EGFRI) subscale, and the Euro-QOL 5D (EQ-5D)
Safety Outcome Measures
The safety outcome measures for this study are as follows:
• Incidence of serious adverse events
• Incidence of grade 3 and 4 adverse events (CTCAE, version 4.03)
• Incidence of all adverse events of all grades
• Incidence of the following selected adverse events - any grade (Hyperglycaemia, Diarrhoea, Rash, Interstitial pneumonitis)
• Adverse events leading to discontinuation of the study medication
• Changes in vital signs and clinical laboratory results during and following study drug administration
Exploratory Outcome Measures
• Alterations in DNA and RNA, including mutational status, RNA expression levels, DNA copy number, and protein expression |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy
1. Assessed at the end of the study by an independent review facility (IRF).
2. Assessed at the end of patient treatment (Investigator) and at the end of the study (IRF).
3. Assessed at ≥24 weeks and at the end of the trial.
4. Assessed at ≥24 weeks (investigator) and at the end of the study (IRF).
5&6. Assessed at disease progression (investigator) and at the end of the study (IRF).
7. Assessed at disease progression (investigator) and at the end of the study (IRF).
8. Assessed when the last patient has submitted their last FACT questionnaire.
Safety
Assessed at all study visits and analysed at the end of the study.
Exploratory
When final patients submits last sample. |
|
| 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 | Yes |
| 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) | 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 35 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| France |
| Georgia |
| Hungary |
| Korea, Republic of |
| Romania |
| United Kingdom |
|
| 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
|
| For the purposes of Clinical Trial Authorisation (CTA) under the European Union Directive 2001/20/EC, the study is deemed to have ended 30 days after the last patient receives the last dose of the investigational medicinal product (IMP). For all other purposes, the study end date is deemed to be the date of last data capture. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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