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.

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