Clinical trial NCT02423603: PAKT: AZD5363 in Combination With Paclitaxel in Triple-Negative Advanced or Metastatic Breast Cancer
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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Keywords: Triple Negative Breast Cancer
Metastatic
AKT Inhibitor
Advanced
AZD5363
Paclitaxel
PAKT
Capivasertib
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
Collaborators: name: AstraZeneca
name: Cancer Research UK
First posted: 2015-04-22
Enrollment: 71
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility 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
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

Primary outcomes:
measure: Progression-free survival
timeFrame: Date of randomisation to date of first tumour progression or death (this can range on average between 3 weeks and 32 weeks).
Secondary outcomes:
Other outcomes:
Locations:
city: Nantes
country: France
facility: ICO René Gauducheau
city: Nice
country: France
facility: Centre André-lacassagne
city: Saint-Grégoire
country: France
facility: Centre Hospitalier Prive Saint-Gregoire
city: Tbilisi
country: Georgia
facility: Institute of Clinical Oncology
city: Budapest
country: Hungary
facility: Országos Onkológiai Intézet
city: Pécs
country: Hungary
facility: University of Pécs - Clinical Center Institute of Oncotherapy
city: Zalaegerszeg
country: Hungary
facility: Zala County Hospital Szent Rafael
city: Cheongju
country: Korea, Republic of
facility: Chungbuk National University Hospital
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Centre
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System
city: Cluj-Napoca
country: Romania
facility: Prof. Dr. I. Chiricuta Oncology Institute
city: Craiova
country: Romania
facility: Sf. Nectarie SRL Oncologie Medical Center
city: Iași
country: Romania
facility: Center of Oncology Euroclinic
city: Bangor
country: United Kingdom
facility: Betsi Cadwaladr University Health Board
city: Belfast
country: United Kingdom
facility: Belfast Health and Social Care Trust
city: Bodelwyddan
country: United Kingdom
facility: Glan Clwyd Hospital BCU Health Board NHS Wales
city: Brighton
country: United Kingdom
facility: Brighton and Sussex University Hospitals NHS Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Canterbury
country: United Kingdom
facility: East Kent Hospitals University NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: Coventry
country: United Kingdom
facility: University Hospitals Coventry and Warwickshire NHs Trust
city: Edinburgh
country: United Kingdom
facility: NHS Lothian
city: Gillingham
country: United Kingdom
facility: Medway NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHs Trust
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: University College London Hospitals
city: London
country: United Kingdom
facility: Barking, Havering and Redbridge University Hospitals NHS Trust
city: London
country: United Kingdom
facility: Guys and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: Lewisham and Greenwich NHS Trust
city: London
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust-Fulham
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: Maidstone
country: United Kingdom
facility: Maidstone and Tunbridge Wells NHS Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Southampton
country: United Kingdom
facility: Southampton University Hospitals NHS Trust
city: Southend
country: United Kingdom
facility: Southend University Hospital NHS Foundation Trust
city: Stoke-on-Trent
country: United Kingdom
facility: University Hospital of North Staffordshire NHS Trust
city: Sutton
country: United Kingdom
facility: Royal Marsden - Sutton
city: Swansea
country: United Kingdom
facility: Abertawe Bro Margannwg University Health Board
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospitals NHS Trust
city: Wrexham
country: United Kingdom
facility: Ysbyty Wrexham Maelor Hospital
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital NHS Foundation Trust
Study officials:
affiliation: Queen Mary University London
name: Peter Schmid
role: STUDY_CHAIR
affiliation: Royal Marsden Hospital NHS- Institute of Cancer Research
name: Nicholas Turner
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial. J Clin Oncol. 2020 Feb 10;38(5):423-433. doi: 10.1200/JCO.19.00368. Epub 2019 Dec 16.