| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Estrogen receptor positive advanced or metastatic breast cancer. |
|
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Estimate the clinical benefit of fulvestrant (FV)+ AZD2014 (AZD) (continuous daily schedule) relative to fulvestrant alone, as measured by investigator-assessed progression-free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
Estimate the clinical benefit (investigator assessed PFS) of:
1)FV+AZD2014(continuous schedule) vs FV+everolimus(E)
2)FV+AZD(intermittent) vs FV+E vs FV alone
3)FV+AZD(continuous) vs FV+AZD(intermittent)
Estimate the clinical benefit (independent review facility PFS) of: FV+AZD vs FV+E or FV alone
Assess the clinical activity of FV+AZD vs FV+E or FV alone
Establish the safety:
1)and tolerability of FV+AZD vs FV+E or FV alone;
2)of the intermittent schedule of AZD vs continuous one
Estimate overall survival benefit of FV+AZD vs FV+E or FV alone
Investigate the:
1)effects of FV+/- AZD or E on bone-turnover biomarkers
2)PK of AZD in patients co-administrated with FV;
Compare the differences in patient reported outcomes (FACT-G, FACTAnti-A-ES subscales)
Determine the minimum plasma concentration (steady state) in patients of FV alone and when administered in combination with AZD4 or E |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent prior to admission to this study.
2. Women, age ≥ 18 years.
3. Histologically confirmed breast cancer.
4. Metastatic and/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 downstaging with study treatment are not eligible).
5. Patients must have:
a. at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, or
b. 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. ER positive disease, defined as tumour cells being positive for ER with ≥1% of tumour cells positive for ER on IHCor IHC score (Allred) of ≥3
8. HER2 negative disease with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH.
9. Formalin fixed, paraffin embedded tumour sample from the primary and/or recurrent cancer must be available for central testing
10. Postmenopausal women. Women will be considered postmenopausal if they meet one of the following criteria:
a. Age ≥50 years and 1 year or more of amenorrhea
b. Age <50 years and 1 year or more of amenorrhea, with an estradiol assay <20pg/mL
c. Age <50 with prior hysterectomy but intact ovaries with an estradiol assay <20pg/mL
d. Status after bilateral oophorectomy (≥28 days prior to first study treatment)
Note: Ovarian radiation or treatment with a luteinizing hormonereleasing
hormone (LHRH) agonist (goserelin acetate
or leuprolide acetate) is not permitted for induction of ovarian suppression.
11. Disease refractory to aromatase inhibitors (AI), defined as
a. Disease recurrence while on, or within 12 months of end of adjuvant treatment with letrozole, anastrozole, or exemestane or
b. Progression while on, or within one month of end of letrozole, anastrozole or exemestane treatment for locally advanced or metastatic Breast Cancer.
Note: Any number of lines of hormonal therapy before or after AI therapy is allowed.
Note: Letrozole, anastrozole or exemestane do not have to be the last treatment prior to randomisation.
12. Haematologic and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to randomisation
a. ANC ≥ 1500 cells/μl, haemoglobin ≥ 9g/dl, and platelet count ≥100000/μl
b. Serum Creatinine < 1.5 times ULN or > 1.5 times ULN concurrent with creatinine clearance ≥ 50ml/min (measured or calculated by Cockcroft and Gault equation), confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN.
c. Bilirubin level < 1.5 x ULN if no demonstrable liver metastases or < 3 times ULN in the presence of liver metastases
d. AST or ALT <2.5 x ULN
e. International normalized ratio (INR) <1.5 and activated partial thromboplastin time (aPTT) <1.5 x ULN; for patients requiring therapeutic anticoagulation therapy, a stable INR ≤2.5 x ULN is required to mitigate potential bleeding
f. No Clinically relevant and treatment resistant abnormalities in potassium, sodium, calcium (corrected for plasma albumin) or magnesium
g. Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 ×ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved
13. ECOG performance status 0-2
14. 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 |
|
| E.4 | Principal exclusion criteria |
1.Presence of life-threatening metastatic visceral disease
2.>1 line of prior chemotherapy for MBC.
3.Prior chemotherapy, biological therapy, androgens, thalidomide, immunotherapy, other anticancer agents or any IMPs within 14days prior to receiving study drug (not inc. palliative radiotherapy at focal sites), radiotherapy with a wide field of radiation (greater than or equal to 30% marrow or whole pelvis or spine) within 4weeks of starting study drugs, or strontium-90 (or other radiopharmaceuticals) within the past 3months or major surgery within 4weeks prior to entry into the study (excluding the placement of vascular access). With the exception of alopecia, all unresolved toxicities from prior treatment should be ≤grade 1 CTCAE at start of treatment.
4.Prior treatment with fulvestrant or everolimus.
5.Prior treatment with PI3K inhibitors, Akt inhibitors or mTOR inhibitors.
6.Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids (≥10mg prednisolone or an equivalent dose of other antiinflammatory corticosteroids) use for ≥28 days at the time of study entry except in cases outlined below:
Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intraarticular) are allowed. Patients on stable low dose of corticosteroids for at least 2weeks prior to randomisation are allowed.
7.Current refractory nausea/vomiting, chronic gastrointestinal disease, inability to swallow the formulated product or previous significant bowel resection that precludes adequate absorption of the study drugs.
8.Clinically significant pulmonary dysfunction.
9.Significant cardiovascular disease; patients who have experienced any of the following procedures or conditions currently or in the preceding 12months:
a.Myocardial infarction, acute coronary syndromes (inc. unstable angina), or coronary angioplasty/stenting/bypass grafting.
b.Symptomatic congestive heart failure (CHF) New York Heart Association Classes IIIV or LVEF <50% by either ECHO or MUGA.
c.Severe cardiac arrhythmia requiring medication or severe conduction abnormalities.
d.Poorly controlled hypertension (resting diastolic blood pressure >100 mmHg).
e.Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy.
10.QTc prolongation defined as a QTc interval >470 msecs or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate <50 beats/min).
11.Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40years of age).
12.Clinically significant abnormalities of glucose metabolism as defined by any of the following
a.Diagnosis of diabetes mellitus type I (irrespective of management) or uncontrolled diabetes mellitus type II.
b.Glycosylated haemoglobin (HbA1C) ≥8.0% at screening (64mmol/mol) (conversion equation for HbA1C [IFCCHbA1C (mmol/mol) = [DCCTHbA1C (%) – 2.15] x 10.929)
13.Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 within the following wash-out periods before the first dose of study treatment.
14.Exposure to sensitive or narrow therapeutic range substrates of the drug metabolizing enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1, BCRP, OATP1B1, OATP1B3, OCT1 and OCT2) within the appropriate wash-out period before the first dose of study treatment
15.Application of haemopoietic growth factors within 2weeks prior to receiving study drug.
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/condition that contraindicates the use of an IMP, may affect the interpretation of the results, renders the patient at high risk from treatment complications or interferes with obtaining informed consent.
17.History of hypersensitivity to any excipients of AZD2014, everolimus or drugs with a similar chemical structure or class to AZD2014 or everolimus.
18.History of hypersensitivity to any excipients of fulvestrant and/or castor oil.
19. Patients presenting with anaemia symptoms (anaemia classed as haemoglobin ≥90g/L).
20.Currently receiving (and unwilling to discontinue) oestrogen replacement therapy (last dose ≤7 days prior to randomisation).
21.Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
22.Detained persons or prisoners
23. Pregnant or nursing women (inc. no breast feeding from 2weeks prior to receiving study drug untill 8 weeks after the last dose of IMP |
|
| 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 followup.
|
|
| E.5.2 | Secondary end point(s) |
The secondary outcome measures for this study are as follows:
Efficacy
1. Progression free survival, defined as the time from the date of randomisation to the date of first documented tumour progression as assessed by an independent review facility [IRF] (using RECIST 1.1) or death from any cause, whichever occurs first.
2. Objective response, defined as a complete or partial response, based on investigator and IRF assessment using RECIST 1.1.
3. Average change (%) in tumour size at 16 weeks compared to baseline, based on investigator and IRF assessment using RECIST 1.1; tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions.
4. Clinical Benefit, defined as number of patients with complete or partial response or stable disease maintained ≥24 weeks, based on investigator and IRF assessment using RECIST 1.1).
5. Overall survival, defined as the time from date of randomisation to the date of death due to any cause.
6. Duration of response, defined as the time from first documentation of complete or partial response to disease progression based on investigator and IRF assessment using RECIST 1.1.
7. Duration of clinical benefit, defined as the time from randomisation to disease progression based on investigator and IRF assessment using RECIST 1.1 in patients with CB.
8. Percentage change in serum of serum beta Cterminal crosslinking telopeptide of Type I collagen (βCTx) and Nterminal propeptide of Type I procollagen (PINP) from screening/baseline to each time that samples are collected.
9. Patient reported outcomes, as assessed by the Functional Assessment of Cancer Therapy General (FACTG) scale together with the BreastAntiA and Endocrine Symptom (FACTB and AntiAES) subscales.
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)
o Hyperglycaemia
o Diarrhoea
o Stomatitis
o Rash
o Interstitial pneumonitis
o Fatigue
o T-Wave changes
• Adverse events leading to discontinuation of the study medication.
• Changes in vital signs and clinical laboratory results during and following study drug administration.
Pharmacokinetics Outcome Measures
The PK outcome measures for this study are as follows:
• Plasma drug clearance (CL/F), estimated maximum drug concentration (Cmax), elimination halflife (t1/2) and volume of distribution (Vss/F) for AZD2014.
• Cssmin for fulvestrant.
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 week 16 and at the end of the trial.
4. Assessed at ≥24 weeks (investigator) and at the end of the study (IRF).
5. Assessed on patient death.
6&7. Assessed at disease progression (investigator) and at the end of the study (IRF).
8. Assessed at when the last patient has given their last sample for analysis.
9. 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.
Pharmacokinetics
Analysed when final patient submits last sample.
Exploratory
When final patients submits last sample. |
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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 | Yes |
| 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 | 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 | 4 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 83 |
| 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 |
| Germany |
| Hungary |
| Korea, Republic of |
| Portugal |
| Romania |
| Spain |
| United Kingdom |
|
| 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
|
| 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. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
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