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PAKT: AZD5363 in Combination With Paclitaxel in Triple-Negative Advanced or Metastatic Breast Cancer (PAKT)

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified April 2015 by Queen Mary University of London.
Recruitment status was:  Recruiting
Sponsor:
Collaborators:
AstraZeneca
Cancer Research UK
Information provided by (Responsible Party):
Queen Mary University of London
ClinicalTrials.gov Identifier:
NCT02423603
First received: July 11, 2014
Last updated: April 17, 2015
Last verified: April 2015
  Purpose

Normally, cells in human body divide in an orderly way. However in cancer cells, some important proteins, which help control cell growth, start to behave abnormally resulting in faster growth and multiplication. In this study, we are looking at a protein called AKT that helps the cancer cells to develop. Blocking the action of AKT with a drug like AZD5363 may slow down or stop the cancer growing. The development of AZD5363 is intended to provide a new treatment option for patients with cancer. The standard chemotherapy agent, Paclitaxel, is given to destroy cancer cells. AZD5363 may also make the cancer more sensitive to Paclitaxel and so make this agent more effective.

A gene called PIK3CA has an important relationship with AKT. In tumours where this gene has been altered, or said to have 'mutated', the response to AZD5363 may be better. PIK3CA mutations are found commonly in breast cancers, and we will test for the presence of these mutations in both blood and tumour tissue samples that we ask you to provide. This study will also look at the relationship between tumours with PIK3CA mutations and the effect of the treatment.


Condition Intervention Phase
Metastatic Breast Cancer Drug: Paclitaxel Drug: AZD5363 Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II, Double-blind, Randomised, Placebo-controlled Study of the AKT Inhibitor AZD5363 in Combination With Paclitaxel in Triple-Negative Advanced or Metastatic Breast Cancer (PAKT).

Resource links provided by NLM:


Further study details as provided by Queen Mary University of London:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: Date of randomisation to date of first tumour progression or death (this can range on average between 3 weeks and 32 weeks). ]
    Progression-free survival, defined as the time from the date of randomisation to the date of first documented tumour progression (using RECIST 1.1) or death from any cause, whichever occurs first.


Estimated Enrollment: 140
Study Start Date: May 2014
Estimated Study Completion Date: January 2017
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Paclitaxel + AZD5363

Patients receive Paclitaxel on Day 1, Day 8 and Day 15 plus AZD5363/Placebo on Days 2-5, Days 9-12, and Days 16-19.

Upon Paclitaxel withdrawal,

Patient receive AZD5363/Placebo on Days 2-5, Days 9-12, Days 16-19 and Days 23-27.

Drug: Paclitaxel
Patient receive Once a week for three weeks - with one week off treatment
Other Name: Taxol
Drug: AZD5363
Patients receive AZD5363/Placebo in an intermittent treatment schedule. Please see study arms for full information.
Placebo Comparator: Paclitaxel + Placebo

Patients receive Paclitaxel on Day 1, Day 8 and Day 15. plus AZD5363/Placebo on Days 2-5, Days 9-12, and Days 16-19.

Upon Paclitaxel withdrawal,

Patient receive AZD5363/Placebo on Days 2-5, Days 9-12, Days 16-19 and Days 23-27.

Drug: Paclitaxel
Patient receive Once a week for three weeks - with one week off treatment
Other Name: Taxol
Drug: Placebo
Patients receive AZD5363/Placebo in an intermittent treatment schedule. Please see study arms for full information.

Detailed Description:

The term triple-negative breast cancer (TNBC) is generally used to define tumours that do not express oestrogen receptors (ER), progesterone receptors (PR) and HER2 receptors. This subtype comprises 10-15% of all breast cancers.

TNBC has an aggressive clinical course, shares features with basal-like tumours, and has a poorer outcome compared with other subtypes. Clinically, TNBC's are a challenge to treat because there is no role for endocrine or HER2-directed therapy. Chemotherapy is effective, but neo-adjuvant studies have shown that despite initial chemo-sensitivity, TNBC's still had a worse outcome, particularly in women in whom a pathologically confirmed complete response was not achieved. Consequently, there is a clear need to develop specific treatment strategies for the subgroup of TNBC's both in the early and advanced disease setting.

AZD5363 is a potent, selective inhibitor of the kinase activity of the serine/threonine AKT/PKB (protein kinase B) that is being developed as a potential treatment for solid and haematological malignancies. AKT is part of the AGC family of kinases. Mammalian cells express three closely related AKT isoforms: AKT1 (PKBa), AKT2 (PKBß) and AKT3 (PKBgamma), all encoded by different genes.

This is a placebo-controlled, multi-centre, 2-arm randomised phase II trial of Paclitaxel + AZD5363 versus Paclitaxel + placebo in patients with triple-negative (ER-negative, PR-negative/unknown, HER2-negative) advanced or metastatic breast cancer.

Patients will be randomised into either of the Arms Paclitaxel + Placebo OR Paclitaxel + AZD5363.

Randomisation will be stratified by the following criteria:

  • Number of metastatic sites (<3, =3)
  • (Neo)Adjuvant chemotherapy (end of (neo)adjuvant chemotherapy =12 months ago, end of (neo)adjuvant chemotherapy >12 months or no prior (neo)adjuvant chemotherapy).
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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. Patient must have

    • 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 CT, or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, OR
    • lytic or mixed 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. Triple-negative disease, defined as tumour cells being

    • Negative for ER with <1% of tumour cells positive for ER on IHC or IHC score of ≥2
    • Negative for PR with <1% of tumour cells positive for PR on IHC or IHC score of ≥2 or PR unknown
    • Negative for HER2 with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH
  8. Formalin fixed paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing
  9. Patients must be able to swallow and retain oral medication
  10. Haematologic and biochemical indices within protocol specified ranges
  11. ECOG performance status 0-2
  12. Non-childbearing potential. If patient is of childbearing potential, she must have a negative serum pregnancy test and agree to use adequate contraception
  13. Willing and able to provide written informed consent

Exclusion Criteria:

  1. Patients with confirm brain metastases or a history of primary central nervous system tumours or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases.
  2. Prior chemotherapy for metastatic breast cancer
  3. Radiotherapy with a wide field of radiation within 4 weeks before the first dose of study medication
  4. Prior treatment with PI3K inhibitors, AKT inhibitors or mTOR inhibitors
  5. Prior treatment with paclitaxel or docetaxel in the (neo)adjuvant setting within 12 months from inclusion into this study
  6. Pre-existing sensory or motor polyneuropathy ≥ Grade 2 according to CTCAE
  7. Malabsorption syndrome or other condition that would interfere with enteral absorption
  8. Clinically significant pulmonary dysfunction
  9. Prolongation defined as a QTc interval >470msecs or other significant abnormalities in rhythm, conduction or morphology of resting ECG including 2nd degree (Type II) or 3rd degree AV block or bradycardia (ventricular rate <50 beats/min)
  10. Any factors that increase risk of QTc prolongation or risk of arrythmic events
  11. 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, or cardiac ejection fraction outside institutional range of normal or <50%
  12. Clinically significant abnormalities of glucose metabolism
  13. Patients with proteinuria or creatine >1.5xULN concurrent with creatinine clearance <50mL/min
  14. Exposure to potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment
  15. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study entry
  16. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
  17. Detained persons or prisoners
  18. Pregnant or nursing women
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02423603

Contacts
Contact: Hayley Cartwright 02078828487 bci-pakt@qmul.ac.uk
Contact: Kelly Mousa bci-pakt@qmul.ac.uk

Locations
United Kingdom
Betsi Cadwaladr University Health Board Not yet recruiting
Bangor, United Kingdom, LL57 2PW
Contact: Catherine Bale       catherine.bale@wales.nhs.uk   
Principal Investigator: Catherine Bale         
Principal Investigator: Niladri Ghosal         
Principal Investigator: Jill Bishop         
Belfast Health and Social Care Trust Not yet recruiting
Belfast, United Kingdom, BT9 7AB
Contact: Jane Hurwitz       jane.hurwitz@belfasttrust.hscni.net   
Principal Investigator: Jane Hurwitz         
Cambridge University Hospitals NHS Foundation Trust Not yet recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: Richard Baird       rdb39@medschl.cam.ac.uk   
Principal Investigator: Richard Baird         
East Kent Hospitals University NHS Foundation Trust Not yet recruiting
Canterbury, United Kingdom, CT1 3NG
Contact: Carys Thomas, `       carys.thomas@nhs.net   
Principal Investigator: Carys Thomas         
Velindre Cancer Centre Recruiting
Cardiff, United Kingdom, CF14 2TL
Contact: Jacinta Abraham       jacinta.abraham@wales.nhs.uk   
Principal Investigator: Jacinta Abraham         
University Hospitals Coventry and Warwickshire NHs Trust Recruiting
Coventry, United Kingdom, CV2 2DX
Contact: Christopher Poole       cjpoole@mac.com   
Principal Investigator: Christopher Poole         
NHS Lothian Not yet recruiting
Edinburgh, United Kingdom, EH4 2XR
Contact: Angela Bowman       angela.bowman@luht.scot.nhs.uk   
Principal Investigator: angela Bowman         
Beatson West of Scotland Cancer Centre Not yet recruiting
Glasgow, United Kingdom, G12 0YN
Contact: Iain Macpherson         
Principal Investigator: Iain Macpherson         
Royal Surrey County Hospital NHS Foudation Trust Not yet recruiting
Guildford, United Kingdom, GU2 7XX
Contact: Robert Laing       robertlaing@nhs.net   
Principal Investigator: Robert Laing         
Leeds Teaching Hospitals NHs Trust Recruiting
Leeds, United Kingdom, LS9 7TF
Contact: Timothy Perren       tim.perren@leedsth.nhs.uk   
Principal Investigator: Timothy Perren         
University Hospitals of Leicester NHs Trust Recruiting
Leicester, United Kingdom, LE5 4QF
Contact: Samreen Ahmed       Samreen.Ahmed@uhl-tr.nhs.uk   
Principal Investigator: Samreen Ahmed         
South London Healthcare NHS Trust Not yet recruiting
London, United Kingdom, DA14 6LT
Contact: Hartmut Kristeleit       h.kristeleit@nhs.net   
Principal Investigator: Hartmut Kristeleit         
Barts Health NHS Trust Not yet recruiting
London, United Kingdom, EC1M 6BQ
Contact: Rebecca Roylance       rebecca.roylance@bartshealth.nhs.uk   
Principal Investigator: Rebecca Roylance         
University College London Hospitals Not yet recruiting
London, United Kingdom, NW1 2PG
Contact: Robert Stein       r.stein@ucl.ac.uk   
Principal Investigator: Robert Stein         
Royal Free Hampstead NHS Trust Not yet recruiting
London, United Kingdom, NW3 2QG
Contact: Alison Jones       alisonjones6@nhs.net   
Principal Investigator: Alison Jones         
Barking, Havering and Redbridge University Hospitals NHS Trust Recruiting
London, United Kingdom, RM7 0AG
Contact: Eliot Sims       sims.eliot@bhrhospitals.nhs.uk   
Principal Investigator: Eliot Sims         
Guys and St Thomas' NHS Foundation Trust Recruiting
London, United Kingdom, SE1 9RT
Contact: Andrew Tutt       andrew.tutt@kcl.ac.uk   
Principal Investigator: Andrew Tutt         
Royal Marsden NHS Foundation Trust-Fulham Recruiting
London, United Kingdom, SW3 6JJ
Contact: Nicholas Turner       nicholas.turner@rmh.nhs.uk   
Principal Investigator: Nicholas Turner         
Imperial College Healthcare NHS Trust Recruiting
London, United Kingdom, W2 1NY
Contact: Justin Stebbing       j.stebbing@imperial.ac.uk   
Principal Investigator: Justin Stebbin         
East Cheshire NHs Trust Recruiting
Macclesfield, United Kingdom, SK10 3BL
Contact: Lisa Barraclough       lisa.barraclough@christie.nhs.uk   
Principal Investigator: Lisa Barraclough         
Maidstone and Tunbridge Wells NHS Trust Not yet recruiting
Maidstone, United Kingdom, ME16 9
Contact: Catherine Harper-Wynne       charperwynne@nhs.net   
Principal Investigator: Catherine Harper-Wynne         
Principal Investigator: Charlotte Abson         
The Christie NHS Foundation Trust Not yet recruiting
Manchester, United Kingdom, M20 4BX
Contact: Anne Armstrong       anne.armstrong@christie.nhs.uk   
Principal Investigator: Anne Armstrong         
Newcastle Upon Tyne Hospitlas NHs Foundation Trust Not yet recruiting
Newcastle, United Kingdom, NE7 7DN
Contact: Anthony Branson       tony.branson@nhs.net   
Principal Investigator: Anthony Branson         
Nottingham University Hospitals NHs Trust Recruiting
Nottingham, United Kingdom, NG7 2UH
Contact: Stephen Chan       steve.chan@nuh.nhs.uk   
Principal Investigator: Stephen Chan         
southampton University Hospitals NHS Trust Recruiting
Southampton, United Kingdom, SO16 6YD
Contact: Ellen Copson       e.copson@soton.ac.uk   
Principal Investigator: Ellen Copson         
Southend University Hospital NHS Foundation Trust Not yet recruiting
Southend, United Kingdom, SS0 0RY
Contact: Hafiz Algurafi       hafiz.algurafi@southend.nhs.uk   
Principal Investigator: Hafiz Algurafi         
University Hospital of North Staffordshire NHS Trust Not yet recruiting
Stoke-on-Trent, United Kingdom, ST4 7LN
Contact: Murray Brunt       murray.brunt@uhns.nhs.uk   
Principal Investigator: Murray Brunt         
Royal Marsden - Sutton Recruiting
Sutton, United Kingdom
Contact: Nicholas Turner       nicholas.turner@icr.ac.uk   
Abertawe Bro Margannwg University Health Board Not yet recruiting
Swansea, United Kingdom, SA2 8QA
Contact: Gianfilippo Bertelli       gianfilippo.bertelli@wales.nhs.uk   
Principal Investigator: Gianfilippo Bertelli         
Royal Cornwall Hospitals NHS Trust Recruiting
Truro, United Kingdom, TR1 3LJ
Contact: Duncan Wheatley       duncan.wheatley@rcht.cornwall.nhs.uk   
Principal Investigator: Duncan Wheatley         
Yeovil District Hospital NHS Foundation Trust Recruiting
Yeovil, United Kingdom, BA21 4AT
Contact: Urmila Barthakur       urmila.barthakur@ydh.nhs.uk   
Principal Investigator: Urmila Barthakur         
Sponsors and Collaborators
Queen Mary University of London
AstraZeneca
Cancer Research UK
Investigators
Study Chair: Peter Schmid Queen Mary University London
Principal Investigator: Nicholas Turner Royal Marsden Hospital NHS- Institute of Cancer Research
  More Information

Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT02423603     History of Changes
Other Study ID Numbers: 009246QM
2013-001521-43 ( EudraCT Number )
Study First Received: July 11, 2014
Last Updated: April 17, 2015

Keywords provided by Queen Mary University of London:
Triple Negative Breast Cancer
Metastatic
AKT Inhibitor
Advanced
AZD5363
Paclitaxel
PAKT

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 23, 2017