Description:
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.
Title
- Brief Title: 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).
Clinical Trial IDs
- ORG STUDY ID:
009246QM
- SECONDARY ID:
2013-001521-43
- NCT ID:
NCT02423603
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| Paclitaxel | Taxol | Paclitaxel + AZD5363 |
| AZD5363 | Capivasertib | Paclitaxel + AZD5363 |
| Placebo | | Paclitaxel + Placebo |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Paclitaxel + AZD5363 | Active Comparator | 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. | |
| Paclitaxel + Placebo | Placebo Comparator | 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. | |
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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | 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). |
| Safety Issue: | |
| Description: | 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. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Queen Mary University of London |
Trial Keywords
- Triple Negative Breast Cancer
- Metastatic
- AKT Inhibitor
- Advanced
- AZD5363
- Paclitaxel
- PAKT
- Capivasertib
Last Updated
February 25, 2020
