This is an open-label, multicentre, 4-arm randomised phase II trial of fulvestrant + AZD2014
versus fulvestrant + everolimus versus fulvestrant alone in patients with ER-positive,
HER2-negative advanced or metastatic breast cancer, whose disease relapsed during treatment
with (or within 12 months after discontinuation of) an AI in the adjuvant setting or
progressed during treatment with an AI in the metastatic setting. Patients will be randomised
(2:3:3:2) to one of the four treatment arms:
- Fulvestrant
- Fulvestrant + AZD2014 (continuous daily schedule)
- Fulvestrant + AZD2014 (intermittent schedule - 2 days on, 5 days off)
- Fulvestrant + everolimus
Randomization will be stratified by the following criteria:
- Measurable disease (vs. non-measurable).
- Sensitivity to prior endocrine therapy (sensitive versus resistant) Sensitivity to prior
endocrine therapy is defined as (i) at least 24 months of endocrine therapy before
recurrence in the adjuvant setting or (ii) a complete or partial response to prior
metastatic endocrine treatment, or (iii) stabilization for at least 24 weeks of
endocrine therapy for advanced disease.
Treatment will be continued until disease progression unless there is evidence of
unacceptable toxicity or if the patient requests to be withdrawn from the study. If one of
the treatments (fulvestrant or mTOR inhibitor) is discontinued prior to disease progression,
patients should be continued on single agent treatment until progression, evidence of
unacceptable toxicity or if the patient requests to be withdrawn from the study.
At the time of documented disease progression (using RECIST 1.1), patients randomised to
receive fulvestrant + everolimus who still meet eligibility criteria may be permitted to
receive open-label crossover treatment with fulvestrant + AZD2014. Crossover therapy must
begin no later than 28 days after the clinic visit at which progression was determined.
Patients will receive crossover therapy until progression, intolerable toxicity, elective
withdrawal from the study, or until the completion or termination of the study, whichever
occurs first.
Tumour evaluations will be performed before the initiation of treatment, every 8 weeks during
the first 40 weeks and every 12 weeks thereafter until disease progression.
The study will also assess the relationship between the anticipated anti-tumour activity of
the treatment regimen and biological characteristics of patients' tumour at baseline
Inclusion criteria:
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:
1. 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
2. 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
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.
11. Disease refractory to aromatase inhibitors (AI)
12. Haematologic and biochemical indices within acceptable limits
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 oophorectomy, bilateral
tubular ligation or is post-menopausal (total cessation of menses for ≥ 1 year
Exclusion criteria:
1. Presence of life-threatening metastatic visceral disease, defined as extensive hepatic
involvement or any degree of brain or leptomeningeal involvement (past or present), or
symptomatic pulmonary lymphangitic spread. Patients with discrete pulmonary
parenchymal metastases are eligible, provided their respiratory function is not
compromised as a result of disease.
2. More than one line of prior chemotherapy for metastatic breast cancer
3. Prior chemotherapy, biological therapy, androgens, thalidomide, immunotherapy, other
anticancer agents or any investigational agents within 14 days of starting study
treatment (not including 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 4 weeks of starting study treatment, or strontium-90 (or other
radiopharmaceuticals) within the past 3 months or major surgery within 4 weeks 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 no
greater than CTCAE grade 1 at the time of starting study treatment
4. Prior treatment with fulvestrant or everolimus
5. Prior treatment with PI3K inhibitors, Akt inhibitors or other mTOR inhibitors.
6. Patients receiving concomitant immunosuppressive agents or chronic systemic
corticosteroids (≥10 mg prednisolone or an equivalent dose of other anti-inflammatory
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. intra-articular) are allowed. Patients
on stable low dose of corticosteroids for at least two weeks before randomisation are
allowed
7. Current refractory nausea and vomiting, chronic gastrointestinal disease or inability
to swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of the study medication
8. Clinically significant pulmonary dysfunction
9. Significant cardiovascular disease
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 40 years of age)
12. Clinically significant abnormalities of glucose metabolism
13. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 within 2 weeks
before the first dose of study treatment
14. Exposure to potent or moderate inhibitors or inducers of CYP2C8 within 1 week before
the first dose of study treatment.
15. Application of haemopoietic growth factors (e.g. G-CSF, GM-CSF) within 2 weeks before
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 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. History of hypersensitivity to active or inactive excipients of AZD2014 or everolimus
or drugs with a similar chemical structure or class to AZD2014 or everolimus
18. History of hypersensitivity to active or inactive excipients of fulvestrant and/or
castor oil.
19. Patients presenting with anaemia symptoms (haemoglobin ≤ 90 g/L).
20. Currently receiving (and are 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 (including no breast feeding from two weeks before the first
dose of study medication, till 8 weeks after the last dose of study medication).
