Estrogen receptor-positive advanced or metastatic breast cancer
Conditions
Interventions
Product Name: AZD2014
Product Code: AZD2014
Pharmaceutical Form: Tablet
Trade Name: Afinitor
Product Name: Everolimus
Pharmaceutical Form: Tablet
INN or Proposed INN: Everolimus
CAS Number: 159351-69
Sponsors
Queen Mary, University of London
Eligibility
Sex/Gender
All
Inclusion criteria
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: 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 IHC or 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 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
Exclusion criteria
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. 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 start of 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 (=10mg 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; patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months: a.Myocardial infarction, acute coronary syndromes (including unstable angina), or coronary angioplasty/stenting/bypass grafting. b.Symptomatic congestive heart failure (CHF) New York Heart Association (NYHA) Classes II-IV or LVEF 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 40 years 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 (64 mmol/mol) (conver
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The main aims of this study are to: • Determine whether dual inhibition of mTORC 1 and mTORC2 with AZD2014 will increase the anti-tumour activity of endocrine treatment with fulvestrant in ER-positive advanced or metastatic breast cancer. • Determine whether inhibition of both mTORC 1 and mTORC2 using AZD2014 will have superior anti-tumour activity compared to inhibition of mTORC1 alone with everolimus, when combined with fulvestrant. • Explore whether additional efficacy is likely to be present in a subgroup with PI3K-pathway activation for whom it is hypothesised that there will be greater sensitivity to mTOR inhibitors • Characterize the patient population who might benefit from fulvestrant plus AZD2014 to identify potential predictors of sensitivity The primary objectives of this study are to: • Estimate the clinical benefit of fulvestrant + AZD2014 relative to fulvestrant + everolimus or fulvestrant alone, as measured by investigator-assessed progression-free survival (PF;Secondary Objective: The secondary objectives of this study are to: • Estimate the clinical benefit of fulvestrant + AZD2014 relative to fulvestrant + everolimus or fulvestrant alone, as measured by PFS as assessed by an independent review facility [IRF] • Assess the clinical activity, as measured by response rate (RECIST 1.1), clinical benefit rate, duration of clinical benefit and duration of response, of fulvestrant + AZD2014 relative to fulvestrant + everolimus or fulvestrant alone • Establish the safety and tolerability of fulvestrant + AZD2014 relative to fulvestrant + everolimus or fulvestrant alone • Estimate the overall survival benefit of fulvestrant + AZD2014 relative to fulvestrant + everolimus or fulvestrant alone • Investigate the effects of fulvestrant +/- AZD2014 or everolimus on bone-turnover biomarkers • Compare the differences in patient reported outcomes as measured by the Functional Assessment of Cancer Therapy-General (FACT-G) scale together with th | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 C-terminal cross-linking telopeptide of Type I collagen (ßCTx) and N-terminal 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 (FACT-G) scale together with the Breast-Anti-A and Endocrine Symptom (FACT-Band Anti-A-ES) 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 al | — |
Countries
United Kingdom
Outcome results
None listed