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

Metastatic Breast Cancer Clinical Trial

— PAKT  

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).

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02423603
• Other study ID #: 009246QM
• Secondary ID: 2013-001521-43
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: May 14, 2014
• Est. completion date: July 31, 2024

Study information

• Verified date: June 2024
• Source: Queen Mary University of London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

PAKT was an investigator-led, placebo-controlled, randomized phase II trial performed in 42 academic medical centers in the United Kindom, South Korea, France, Hungary, Romania, and Georgia. Patients were randomly assigned (1:1) to receive paclitaxel plus capivasertib or paclitaxel plus placebo. Stratification was by number of metastatic sites (< 3 v ≥ 3) and interval from the end of prior adjuvant or neoadjuvant chemotherapy (≤ 12 v > 12 months v no prior chemotherapy).

Paclitaxel was administered as a once-per-week intravenous infusion of 90 mg/m2 over approximately 1 hour on days 1, 8, and 15 of each 28-day treatment cycle. Capivasertib 400 mg or placebo was administered orally twice per day on an intermittent weekly dosing schedule, with treatment on days 2 to 5 of weeks 1, 2, and 3 within each 28-day cycle. All treatments were continued until disease progression, development of unacceptable toxicity, or withdrawal of consent. If paclitaxel treatment was discontinued before disease progression, patients could continue to receive capivasertib or placebo alone. In case of adverse events (AEs), capivasertib or placebo could be reduced to 320 mg twice per day and subsequently to 240 mg twice per day. Capivasertib or placebo could be interrupted for up to 4 weeks for toxicity.

Tumor assessments included computed tomography scanning or magnetic resonance imaging of the chest, abdomen, and pelvis at baseline, every 8 weeks during treatment, and at progression. Patients who discontinued treatment for any reason other than progression were required to follow the same schedule of assessments until progression, initiation of another treatment, death, or withdrawal of consent.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 140
• Est. completion date: July 31, 2024
• Est. primary completion date: June 30, 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

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

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

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

Locations

Country	Name	City	State
France	ICO René Gauducheau	Nantes
France	Centre André-lacassagne	Nice
France	Centre Hospitalier Prive Saint-Gregoire	Saint-Grégoire
Georgia	Institute of Clinical Oncology	Tbilisi
Hungary	Országos Onkológiai Intézet	Budapest
Hungary	University of Pécs - Clinical Center Institute of Oncotherapy	Pécs
Hungary	Zala County Hospital Szent Rafael	Zalaegerszeg
Korea, Republic of	Chungbuk National University Hospital	Cheongju
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Samsung Medical Centre	Seoul
Korea, Republic of	Yonsei University Health System	Seoul
Romania	Prof. Dr. I. Chiricuta Oncology Institute	Cluj-Napoca
Romania	Sf. Nectarie SRL Oncologie Medical Center	Craiova
Romania	Center of Oncology Euroclinic	Ia?i
United Kingdom	Betsi Cadwaladr University Health Board	Bangor
United Kingdom	Belfast Health and Social Care Trust	Belfast
United Kingdom	Glan Clwyd Hospital BCU Health Board NHS Wales	Bodelwyddan
United Kingdom	Brighton and Sussex University Hospitals NHS Trust	Brighton
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	East Kent Hospitals University NHS Foundation Trust	Canterbury
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	University Hospitals Coventry and Warwickshire NHs Trust	Coventry
United Kingdom	NHS Lothian	Edinburgh
United Kingdom	Medway NHS Foundation Trust	Gillingham
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Leeds Teaching Hospitals NHs Trust	Leeds
United Kingdom	Barking, Havering and Redbridge University Hospitals NHS Trust	London
United Kingdom	Barts Health NHS Trust	London
United Kingdom	Guys and St Thomas' NHS Foundation Trust	London
United Kingdom	Imperial College Healthcare NHS Trust	London
United Kingdom	Lewisham and Greenwich NHS Trust	London
United Kingdom	Royal Marsden NHS Foundation Trust-Fulham	London
United Kingdom	University College London Hospitals	London
United Kingdom	Maidstone and Tunbridge Wells NHS Trust	Maidstone
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Southampton University Hospitals NHS Trust	Southampton
United Kingdom	Southend University Hospital NHS Foundation Trust	Southend
United Kingdom	University Hospital of North Staffordshire NHS Trust	Stoke-on-Trent
United Kingdom	Royal Marsden - Sutton	Sutton
United Kingdom	Abertawe Bro Margannwg University Health Board	Swansea
United Kingdom	Royal Cornwall Hospitals NHS Trust	Truro
United Kingdom	Ysbyty Wrexham Maelor Hospital	Wrexham
United Kingdom	Yeovil District Hospital NHS Foundation Trust	Yeovil

Sponsors (3)

Lead Sponsor	Collaborator
Queen Mary University of London	AstraZeneca, Cancer Research UK

Countries where clinical trial is conducted

France,  Georgia,  Hungary,  Korea, Republic of,  Romania,  United Kingdom, 

References & Publications (1)

Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLau — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival	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.	Date of randomisation to date of first tumour progression or death (this can range on average between 3 weeks and 32 weeks).