AKT Inhibitor in Oestrogen Positive Breast Cancer

NCT ID: NCT02077569

Last Updated: 2017-05-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-01-31
• Study Completion Date: 2017-02-21

Brief Summary

To compare the effect of four and a half days treatment of a range of doses of AZD5363 on selected markers of the AKT pathway and anti-proliferation compared with placebo in oestrogen receptor positive breast cancers.

To assess the tolerability of four and a half days treatment of AZD5363.

Detailed Description

The principal research questions to be addressed are whether (or not) AZD5363 is "hitting its therapeutic target" sufficiently and to the extent that is required to produce efficacy in pre-clinical experiments.

The primary endpoint markers have been selected to determine this.

Reductions in markers of the AKT pathway and increases in markers of anti-proliferation will characterise the degree of biological activity arising from the inhibition of AKT across a range of doses of AZD5363.

Conditions

Invasive Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: TRIPLE

Study Groups

AZD5363 480mg

STAGE 1 ONLY AZD5363 480mg Twice daily dosing for 4 and 1/2 days (9 doses) Oral Capsule

Group Type: EXPERIMENTAL

AZD5363

Intervention Type: DRUG

Stage 1: AZD5363 480mg or placebo twice daily oral dosing for 4 and 1/2 days (9 doses) Stage 2: AZD5363 360mg or 240mg daily oral dosing for 4 and 1/2 days (9 doses)

Placebo

STAGE 1 ONLY Twice daily dosing for 4 and 1/2 days (9 doses) Oral Capsule

Group Type: PLACEBO_COMPARATOR

AZD5363

Intervention Type: DRUG

Stage 1: AZD5363 480mg or placebo twice daily oral dosing for 4 and 1/2 days (9 doses) Stage 2: AZD5363 360mg or 240mg daily oral dosing for 4 and 1/2 days (9 doses)

AZD360mg

STAGE 2 AZD5363 360mg Twice daily dosing for 4 and 1/2 days (9 doses) Oral Capsule

Group Type: EXPERIMENTAL

AZD5363

Intervention Type: DRUG

Stage 1: AZD5363 480mg or placebo twice daily oral dosing for 4 and 1/2 days (9 doses) Stage 2: AZD5363 360mg or 240mg daily oral dosing for 4 and 1/2 days (9 doses)

AZD5363 240mg

STAGE 2 AZD5363 240mg Twice daily dosing for 4 and 1/2 days (9 doses) Oral Capsule

Group Type: EXPERIMENTAL

AZD5363

Intervention Type: DRUG

Stage 1: AZD5363 480mg or placebo twice daily oral dosing for 4 and 1/2 days (9 doses) Stage 2: AZD5363 360mg or 240mg daily oral dosing for 4 and 1/2 days (9 doses)

Interventions

AZD5363

Stage 1: AZD5363 480mg or placebo twice daily oral dosing for 4 and 1/2 days (9 doses) Stage 2: AZD5363 360mg or 240mg daily oral dosing for 4 and 1/2 days (9 doses)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Written informed consent

2. WHO performance status 0-1.

3. Able to swallow & retain oral medication.

4. Patients who fall in to either category (a) or (b):

1. Post-menopausal patients

2. Pre-menopausal patients who also meet at least one of the criteria (i), (ii) or (iii) below:

i) hysterectomy or bilateral fallopian tube ligation at least 6 weeks ago plus a negative pregnancy test.

ii) true abstinence iii) willing to have pregnancy testing and use 2 forms of contraception

5. Female patients, aged 18 years and over, with histological confirmation of ER positive invasive breast carcinoma.

6. Stage 1/2/3 or Stage 4 with primary tumour in the breast amenable to biopsies. New primary breast tumours (ipsi- or contra-lateral) despite prior endocrine treatment for an earlier primary breast tumour with at least 12 months interval between cessation of endocrine therapy and Visit 1 are eligible.

7. Scheduled to have chemotherapy based on tumour characteristics and local treatment protocols.

8. Tumours large enough to provide sufficient tissue to be taken by core-cut or tru-cut biopsy to provide tissue sections for the marker assays.

2. Known ER negative tumour.

3. Female patients with histological confirmation of ER+ve invasive breast carcinoma not scheduled to have chemotherapy

4. Exposure to potent inhibitors or inducers of CYP3A4 or CYP2D6 or substrates of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St Johns Wort).

5. Clinically significant abnormalities of glucose metabolism

6. Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment.

7. Spinal cord compression or brain metastases.

8. Evidence of severe or uncontrolled systemic disease.

9. Any of the following cardiac criteria:

• Mean resting corrected QT interval (QTc)>450 msec obtained from 3 consecutive ECGs; - Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events.
• 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.
• Uncontrolled hypotension.

10. Absolute neutrophil count <1.5 x 10,000,000,000/L

11. Platelet count <100 x 10,000,000,000/L.

12. Haemoglobin <90 g/L

13. ALT >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases.

14. Elevated ALP is not exclusionary if due to the presence of bone metastasis and liver function is otherwise considered adequate

15. Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of liver metastases.

16. Creatinine >1.5 times ULN concurrent with creatinine clearance <50 ml/min; confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN

17. Proteinuria >3+ on dipstick analysis.

18. 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.

19. History of hypersensitivity to active or inactive excipients of AZD5363 or drugs with a similar chemical structure or class to AZD5363.

20. Current disease or condition known to interfere with absorption, distribution, metabolism or excretion of drugs.

21. Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.

22. Evidence of dementia, altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent

23. Previous allogeneic bone marrow transplant.

24. Known immunodeficiency syndrome.

25. Pregnant or lactating patients

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Cancer Research UK

OTHER

Sponsor Role: collaborator

National Cancer Research Network

NETWORK

Sponsor Role: collaborator

University of Nottingham

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John FR Robertson, MD

Role: STUDY_CHAIR

University of Nottingham

Locations

Royal Derby Hospital

Derby, Derbyshire, United Kingdom

Plymouth Hospitals NHS Trust

Derriford, Plymouth, Devon, United Kingdom

Royal Bournemouth Hospital

Bournemouth, Dorset, United Kingdom

Poole Hospital NHS Foundation Trust

Poole, Dorset, United Kingdom

Leicester Royal Infirmary

Leicester, Leicestershire, United Kingdom

Western General Hospital

Edinburgh, Lothian, United Kingdom

Royal Liverpool University Hospital

Liverpool, Merseyside, United Kingdom

Kingsmill Hospital

Sutton in Ashfield, Nottinghamshire, United Kingdom

Sheffield Cancer Research Centre

Sheffield, South Yorkshire, United Kingdom

University Hospital Birmingahm

Birmingham, West Midlands, United Kingdom

Leeds St James Institue of Oncology

Leeds, West Yorkshire, United Kingdom

Countries

United Kingdom

Other Identifiers

12076

Identifier Type: -

Identifier Source: org_study_id