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

Sponsor

Queen Mary University of London (Other)

Overall Status

Unknown status

CT.gov ID

NCT02423603

Collaborator

AstraZeneca (Industry), Cancer Research UK (Other)

140

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Paclitaxel Drug: AZD5363 Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

140 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (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).

Actual Study Start Date :

May 1, 2014

Anticipated Primary Completion Date :

Jun 1, 2020

Anticipated Study Completion Date :

Jun 1, 2020

Arms and Interventions

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

Arm

Intervention/Treatment

Active Comparator: Paclitaxel + AZD5363

Drug: Paclitaxel

Patient receive Once a week for three weeks - with one week off treatment

Other Names:

Taxol

Drug: AZD5363

Patients receive AZD5363/Placebo in an intermittent treatment schedule. Please see study arms for full information.

Other Names:

Capivasertib

Placebo Comparator: Paclitaxel + Placebo

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. 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.

Drug: Paclitaxel

Patient receive Once a week for three weeks - with one week off treatment

Other Names:

Taxol

Drug: Placebo

Patients receive AZD5363/Placebo in an intermittent treatment schedule. Please see study arms for full information.

Outcome Measures

Primary Outcome Measures

Progression-free survival [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent prior to admission to this study
Women, age > 18 years
Histologically confirmed breast cancer
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)
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.

Radiological or clinical evidence of recurrence or progression
Triple-negative disease
Formalin fixed paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing
Patients must be able to swallow and retain oral medication
Haematologic and biochemical indices within protocol specified ranges
ECOG performance status 0-2
Non-childbearing potential. If patient is of childbearing potential, she must have a negative serum pregnancy test and agree to use adequate contraception
Willing and able to provide written informed consent

Exclusion Criteria:

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.
Prior chemotherapy for metastatic breast cancer
Radiotherapy with a wide field of radiation within 4 weeks before the first dose of study medication
Prior treatment with PI3K inhibitors, AKT inhibitors or mTOR inhibitors
Prior treatment with paclitaxel or docetaxel in the (neo)adjuvant setting within 12 months from inclusion into this study
Pre-existing sensory or motor polyneuropathy ≥ Grade 2 according to CTCAE
Malabsorption syndrome or other condition that would interfere with enteral absorption
Clinically significant pulmonary dysfunction
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)
Any factors that increase risk of QTc prolongation or risk of arrythmic events
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%
Clinically significant abnormalities of glucose metabolism
Patients with proteinuria or creatine >1.5xULN concurrent with creatinine clearance <50mL/min
Exposure to potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment
Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study entry
Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
Detained persons or prisoners
Pregnant or nursing women

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	ICO René Gauducheau	Nantes	France
2	Centre André-lacassagne	Nice	France
3	Centre Hospitalier Prive Saint-Gregoire	Saint-Grégoire	France
4	Institute of Clinical Oncology	Tbilisi	Georgia
5	Országos Onkológiai Intézet	Budapest	Hungary
6	University of Pécs - Clinical Center Institute of Oncotherapy	Pécs	Hungary
7	Zala County Hospital Szent Rafael	Zalaegerszeg	Hungary
8	Chungbuk National University Hospital	Cheongju	Korea, Republic of
9	National Cancer Center	Goyang-si	Korea, Republic of
10	Asan Medical Center	Seoul	Korea, Republic of
11	Korea University Guro Hospital	Seoul	Korea, Republic of
12	Samsung Medical Centre	Seoul	Korea, Republic of
13	Yonsei University Health System	Seoul	Korea, Republic of
14	Prof. Dr. I. Chiricuta Oncology Institute	Cluj-Napoca	Romania
15	Sf. Nectarie SRL Oncologie Medical Center	Craiova	Romania
16	Center of Oncology Euroclinic	Iași	Romania
17	Betsi Cadwaladr University Health Board	Bangor	United Kingdom	LL57 2PW
18	Belfast Health and Social Care Trust	Belfast	United Kingdom	BT9 7AB
19	Glan Clwyd Hospital BCU Health Board NHS Wales	Bodelwyddan	United Kingdom	LL18 5UJ
20	Brighton and Sussex University Hospitals NHS Trust	Brighton	United Kingdom	BN2 5BE
21	Cambridge University Hospitals NHS Foundation Trust	Cambridge	United Kingdom	CB2 0QQ
22	East Kent Hospitals University NHS Foundation Trust	Canterbury	United Kingdom	CT1 3NG
23	Velindre Cancer Centre	Cardiff	United Kingdom	CF14 2TL
24	University Hospitals Coventry and Warwickshire NHs Trust	Coventry	United Kingdom	CV2 2DX
25	NHS Lothian	Edinburgh	United Kingdom	EH4 2XR
26	Medway NHS Foundation Trust	Gillingham	United Kingdom	ME7 5NY
27	Beatson West of Scotland Cancer Centre	Glasgow	United Kingdom	G12 0YN
28	Leeds Teaching Hospitals NHs Trust	Leeds	United Kingdom	LS9 7TF
29	Barts Health NHS Trust	London	United Kingdom	EC1M 6BQ
30	University College London Hospitals	London	United Kingdom	NW1 2PG
31	Barking, Havering and Redbridge University Hospitals NHS Trust	London	United Kingdom	RM7 0AG
32	Guys and St Thomas' NHS Foundation Trust	London	United Kingdom	SE1 9RT
33	Lewisham and Greenwich NHS Trust	London	United Kingdom	SE18 4QH
34	Royal Marsden NHS Foundation Trust-Fulham	London	United Kingdom	SW3 6JJ
35	Imperial College Healthcare NHS Trust	London	United Kingdom	W2 1NY
36	Maidstone and Tunbridge Wells NHS Trust	Maidstone	United Kingdom	ME16 9QQ
37	The Christie NHS Foundation Trust	Manchester	United Kingdom	M20 4BX
38	Nottingham University Hospitals NHS Trust	Nottingham	United Kingdom	NG5 1PB
39	Southampton University Hospitals NHS Trust	Southampton	United Kingdom	SO16 6YD
40	Southend University Hospital NHS Foundation Trust	Southend	United Kingdom	SS0 0RY
41	University Hospital of North Staffordshire NHS Trust	Stoke-on-Trent	United Kingdom	ST4 6QG
42	Royal Marsden - Sutton	Sutton	United Kingdom	SM2 5PT
43	Abertawe Bro Margannwg University Health Board	Swansea	United Kingdom	SA2 8QA
44	Royal Cornwall Hospitals NHS Trust	Truro	United Kingdom	TR1 3LJ
45	Ysbyty Wrexham Maelor Hospital	Wrexham	United Kingdom	LL18 5UJ
46	Yeovil District Hospital NHS Foundation Trust	Yeovil	United Kingdom	BA21 4AT

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