Estrogen receptor positive advanced breast cancer MedDRA version: 18.0 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 18.0 Level: LLT Classification code 10070575 Term: Estrogen receptor positive breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 18.0 Level: PT Classification code 100
Conditions
Interventions
Product Name: AZD5363
Product Code: AZD5363
Pharmaceutical Form: Capsule
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use
Product Name: AZD5363
Product Cod
Sponsors
Velindre NHS Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Provision of informed consent prior to any study specific procedures. 2. Adult female patients, aged = 18 years. 3. Postmenopausal patients. 4. Histological confirmation of ER+ve breast cancer on primary tumour at diagnosis or on biopsy of a metastasis. 5. Histological confirmation of HER2 negative breast cancer on primary tumour at diagnosis or on biopsy of a metastasis. 6. Clinical or histological confirmation of metastatic or locally advanced disease not amenable to curative surgical resection 7. ECOG performance status 0 to 2 with no deterioration over the previous 2 weeks 8. Minimum life expectancy of 12 weeks. 9. Measurable or non-measurable disease 10.Progressive disease whilst receiving a third generation aromatase inhibitor for locally advanced or metastatic BC or relapsed with metastatic disease whilst receiving a third generation AI in the adjuvant setting. The AI does not need to be the last treatment immediately prior to recruitment. 11.No more than 3 prior lines of endocrine therapy for ABC. If an attempt to downstage a locally advanced tumour with endocrine therapy was made in the absence of MBC, and the tumour operated upon, then this does not count as a line of therapy for ABC. In contrast, if the tumour remained inoperable then this treatment should be included as a line of therapy for ABC. 12.No more than 1 line of cytotoxic chemotherapy for ABC (Adjuvant and neo-adjuvant chemotherapy are not classed as lines of chemotherapy for ABC). A chemotherapy regimen used to treat ABC but that was discontinued due to toxicity, during, or within 6 weeks of the first dose, with a maximum of one cycle delivered and no evidence of disease progression clinically or radiologically at the time subsequent therapy was initiated, is not considered a line of therapy). 13.Suitable for further endocrine therapy according to the treating clinician. 14.Radiological or objective clinical evidence of recurrence or progression on or after the last systemic therapy prior to enrolment. 15.Provision of archival tumour sample for PIK3CA mutation and PTEN by IHC testing. If insufficient tumour available contact WCTU for further information. 16.Provision of baseline plasma sample for PIK3CA mutation testing on cfDNA. 17.Patient has adequate bone marrow and organ function 18.Patients with type II diabetes mellitus that is well controlled by dietary measures alone and have an HgA1c =65 years) yes F.1.3.1 Number of subjects for this age range 70
Exclusion criteria
Exclusion criteria: 1. Previous treatment with fulvestrant or inhibitors of the PI3K/mTOR/Akt pathway to treat breast cancer 2. Clinically significant abnormalities of glucose metabolism as defined by any of the following: a. Diagnosis of diabetes mellitus type I; b. 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) c. Fasting Plasma Glucose = 7.0mmol/L (126 mg/dL) at screening. Fasting is defined as no caloric intake for at least 8 hours. 3. Rapidly progressive visceral disease not suitable for further endocrine therapy 4. Last dose chemotherapy, immunotherapy targeted therapy, biologic therapy or tumour embolisation must be more than 21 days (more than 6 weeks for nitrosurea or mitomycin C) prior to the first dose of study treatment (fulvestrant). 5. Last dose of palliative radiotherapy must be more than 7 days prior to the first dose of study treatment (fulvestrant) 6. Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment (fulvestrant). 7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment. 8. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required. 9. Any of the following cardiac criteria: a. Mean resting corrected QT interval (QTc) >470 msec obtained from 3 consecutive ECGs. b. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block. c. 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. d. 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. e.Uncontrolled hypotension f.Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram or MUGA scan. 10.With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment. 11.Elevated Alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastasis or if liver function is otherwise considered adequate in the investigator’s judgement. 12.Proteinuria 13.Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5363 14.History of hypersensitivity to active or inactive excipients of AZD5363 or fulvestrant 15.Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. 16.Past medical history of interstitial lung disease, drug-induced interstitial lung
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1 safety run in: To assess the safety and appropriate dose level of the trial drug AZD5363 in combination with fulvestrant. Randomised Phase 2: • To assess the efficacy of AZD5363 in combination with fulvestrant compared with fulvestrant plus placebo in women with ER positive cancers resistant to aromatase inhibitor therapy. • To examine the relative effectiveness of fulvestrant treatment plus AZD5363 compared to fulvestrant plus placebo in patients with and without activation of the tumour PI3K/Akt/PTEN pathway.;Secondary Objective: Phase 1 safety run in: To make a preliminary assessment of the anti-tumour activity of AZD5363 in combination with fulvestrant Randomised Phase 2: • To assess the safety and tolerability of AZD5363 in combination with fulvestrant compared with fulvestrant plus placebo • To examine the effectiveness of fulvestrant plus AZD5363 vs fulvestrant plus placebo in sub-populations of patients with and without activation of the tumour PI3K/Akt/PTEN pathway Both phases: • To assess how AZD5363 treatment may affect the blood concentration of fulvestrant • To store genetic samples for future translational research, aimed at the identification of markers which may predict the response to treatment;Primary end point(s): To establish the anti-tumour activity of the combination of AZD5363 with fulvestrant as measured by progression-free survival (PFS) compared with fulvestrant and placebo. This is the time from randomisation to any disease progression and/or any death, defined according to strict RECIST v1.1 criteria. Lesions will be compared to baseline measurements to assess progression.;Timepoint(s) of evaluation of this end point: From date of randomisation until the date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to 6 months after the last patient is randomised. | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Up to 12 months after the last patient is randomised except for: - Fulvestrant pharmacokinetics will be evaluated at cycle 1 day 15, cycle 2 day 1 and cycle 3 day 1; - Samples collected for future translational research (exploratory biomarkers)at baseline, week 8 and upon disease progression. ;Secondary end point(s): - Safety, tolerability and feasibility of use (the number of patients with adverse events and the number of patients requiring dose modifications) - Objective response rate and clinical benefit as assessed by RECIST 1.1 criteria - Overall survival, time from randomisation to death with those still alive censored at date last seen - The influence of mutational status of PIK3CA and the presence of complete loss of PTEN on outcome in the two treatment groups - Fulvestrant pharmacokinetics - Samples collected for future translational research (exploratory biomarkers) | — |
Countries
United Kingdom
Contacts
Public ContactTracie Madden
Wales Cancer Trials Unit
Outcome results
None listed