| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| early stage breast cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057654 |
| E.1.2 | Term | Breast cancer female |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
PRIMARY OBJECTIVE
To compare the effect of three different dose levels of AZD5363 versus a placebo (dummy drug)on the reduction in the growth of cancer cells and the direct effect on selected biological markers of the AKT pathway of four and a half days treatment in oestrogen receptor positive breast cancers by measuring the biological changes in the tumour using the biomarkers outlined below:
• pPRAS40
• pGSK3b
• Ki67
Stage 1 will compare 480mg BD versus placebo.
Stage 2 will compare 360mg BD versus 240mg BD.
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| E.2.2 | Secondary objectives of the trial |
SECONDARY OBJECTIVES
1) To compare the effect on the reduction in the growth of cancer cells and the direct effect on selected biological markers of the AKT pathway of four and a half days treatment of three different dose levels of AZD5363 versus placebo in oestrogen receptor positive breast cancers by measuring the biological changes in the tumour and circulation via measurement of:
• Tumour pAKT
• Platelet-rich plasma
o Total and pPRAS40
o Total and pGSK3b
o Total and pAKT
• Tumour tissue
o Cleaved caspase 3
o pS6
o FOXO3a
2) To measure tolerability and toxicity due to short term exposure to AZD5363.
EXPLORATORY ANALYSES:
It is envisaged that a number of tissue and blood based marker assays will be performed to assess if they provide any additional information on the activity of AZD5363 e.g.
• Tissue markers e.g. PI3K, MAPK, HER2, PTEN, IGFR1, AR and total AKT
• Blood markers – e.g. Autoantibodies to cancer associated antigens (especially those associated with |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Provision of written informed consent
WHO performance status 0-1
Able to swallow and retain oral medication
Pre-menopausal (if surgically sterile or use acceptable contraception) or post-menopausal.
Aged 18 years or over with histological confirmation of ER positive invasive breast carcinoma
Stage 1/2/3 or Stage 4 with primary tumour in the breast amenable to biopsies
scheduled to have chemotherapy (with or without surgery). 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.
Tumours large enough to provide sufficient tissue to be taken by core-cut or tru-cut biopsy.
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| E.4 | Principal exclusion criteria |
1 Any prior treatment for breast cancer except new primary breast tumours despite prior endocrine treatment for an earlier primary breast tumour with at least 12 months interval between cessation of endocrine therapy and Visit 1.
2 Known ER negative tumour.
3 Female patients with histological confirmation of ER positive invasive breast carcinoma not scheduled to have chemotherapy (with or without surgery) based on tumour characteristics and local treatment protocols
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 John’s Wort).
5 Clinically significant abnormalities of glucose metabolism as defined by any of the following:
Diagnosis of diabetes mellitus type I or II (irrespective of management).
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)
Fasting Plasma Glucose ≥ 7.0mmol/L (126 mg/dL) at screening. Fasting is defined as no caloric intake for at least 8 hours.
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 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:
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 eg, complete left bundle branch block, third degree heart block.
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, a history of congenital long QT syndrome, family history of long QT syndrome or a history of unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval. Further Information regarding this is given in Appendix 8.
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.
Uncontrolled hypotension – SBP <90 mmHg and/or DBP <50 mmHg.
10 Absolute neutrophil count <1.5 x 109/L.
11 Platelet count <100 x 109/L.
12 Haemoglobin <9 g/dL (<5.59 mmol/L). [Note: any blood transfusion must be >14 days prior to the determination of a haemoglobin ≥9 g/dL (≥5.59 mmol/L)].
13 Alanine aminotransferase (ALT) >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases.
14 Elevated Alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastasis and liver function is otherwise considered adequate in the investigator’s judgement.
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 (measured or calculated by Cockcroft and Gault equation); 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoints
Changes in:
• pPRAS40,
• pGSK3b,
• Ki67
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| There will be a seamless transition from stage 1 to stage 2 with no break in patient recruitment. During stage 1 the biological markers will start to be measured. These biomarkers will be completed as swiftly as possible after stage 1 has finished. Following an analysis of these biomarker data obtained through stage 1 stage 2 will be stopped if there is a lack of significant knockdown by AZD5363 in terms of all the biomarkers included in the primary endpoints. Decisions will be made to proceed to recruit further patients to take part in stage 2 or not. |
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| E.5.2 | Secondary end point(s) |
1) Changes in alternative biological markers which relate to the AKT pathway.
• Tumour pAKT
• Tumour: cleaved caspase 3; pS6 (IHC); FOXO3a
• Blood (platelet-rich plasma): Total and pPRAS40; Total and pGSK3b; Total and pAKT
2) the tolerability of AZD5363 as measured by incidence and severity of adverse events
Exploratory Endpoints:
To assess blood and tissue based markers related to other cellular pathways – for example:
• Blood: Autoantibodies to cancer-associated antigens in the AKT pathway
• Tumour: PI3K, MAPK, HER2, PTEN, IGFR1, AR and total AKT
Safety endpoints
The duration of treatment (4 and a half days) will be short in comparison to prior and ongoing studies of the compound and the known side effect profile makes it unlikely that a study of this duration will be stopped for toxicity reasons. Nevertheless side effects will be collected according to the NCI-CTC criteria and there will be an analysis of toxicity at the end of Stage 1 and again at the end of Stage 2.
Stopping rules and discontinuation
Efficacy:
As this is a study of the short-term (four and a half days) exposure of the compound aiming to measure the biological (not clinical) effects, there will be no stopping rules based on clinical efficacy or futility analyses.
Biological endpoints:
During stage 1 analysis all the biological markers which are listed as primary endpoints will commence during the recruitment period. These biomarker measurements will be completed as swiftly as possible after stage 1 has finished. Analyses of these biomarker data obtained through Stage 1 will be performed as swiftly as possible.
Stage 2 will continue if the DSMC decide that significant knockdown by AZD5363 (as pre-defined) in terms of any the biomarkers included as primary endpoints has been achieved.
Knockdown only in biomarkers in the Secondary endpoints will not be accepted as sufficient for the continuation of stage 2 unless there are substantive new data and even then only on the recommendation of the DSMC along with the joint agreement of the Investigators, the Steering Committee and AstraZeneca which is supplying the drug/placebo.
If the DSMC concludes that no effect of the drug can be identified in Stage 1, the on-going enrolment to Stage 2 will be discontinued.
Safety endpoints
Serum haematology and biochemistry will be measured periodically during the course of the study and patients will be monitored for adverse events during that time and for at least 30 days after the end of treatment.
Clinical adverse events will be collected and assessed as part of this study
Timepoints:
pre-treatment and after 4.5 days of treatment
Safety endpoints
Serum haematology and biochemistry will be measured periodically during the course of the study and patients will be monitored for adverse events during that time and for at least 30 days after the end of treatment.
Clinical adverse events will be collected and assessed as part of this study
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints:
pre-treatment and after 4.5 days of treatment
Safety endpoints
Serum haematology and biochemistry will be measured periodically during the course of the study and patients will be monitored for adverse events during that time and for at least 30 days after the end of treatment.
Clinical adverse events will be collected and assessed as part of this study
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| Last Visit Last Subject will define the end of the trial. Follow uyp for 30 days for pharmacovigilance |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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