Phase III Study of Capivasertib + Paclitaxel versus Placebo + Paclitaxel as First line Treatment for Patients with Locally Advanced or Metastatic Triple-negative Breast Cancer (TNBC)

A Phase III Double-blind Randomised Study Assessing the Efficacy and Safety of Capivasertib + Paclitaxel Versus Placebo + Paclitaxel as First-line Treatment for Patients with Histologically Confirmed, Locally Advanced (Inoperable) or Metastatic Triple negative Breast Cancer (TNBC)

Inclusion Criteria:

1. Histologically confirmed TNBC from most recently collected tumour tissue sample
2. Metastatic or locally recurrent disease; locally recurrent disease most not be amenable to resection with curative intent (patient who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible)
3. ECOG/WHO PS: 0-1
4. Measurable disease according to RECIST 1.1 and/or lytics or mixedbone lesions that can be assessed by CT or MRI in the absence of measurable disease
5. FFPE tumour sample from primary/recurrent cancer

Exclusion Criteria:

1. Prior Chemotherapy in the neoadjuvant or adjuvant setting within 6 months from the end of chemotherapy to the date of randomization; taxane chemotherapy in the neoadjuvant or adjuvant setting within 12 months from the end of chemotherapy to the start of randomization

2. Prior systematic therapy for inoperable locally advanced or metastatic disease

3. Prior treatment with any of the treatments listed below. Patients are not eligible to enter the study if they have received any of the medications specified below or are unable to meet the cautions and restrictions:

   • AKT, PI3K, and/or mTOR inhibitors
   • Capivasertib in the present study (ie, any dosing with capivasertib due to previous participation in this study)
   • Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks of the first dose of study treatment. A longer washout may be required for drugs with a long halflife (eg, biologics) as agreed by the sponsor
   • Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John's wort), or drugs that are sensitive to CYP3A4 inhibition within 1 week prior to the first dose of study treatment.

4. Radiotherapy with a wide field of radiation within 4 weeks before the first dose of study treatment (capivasertib/placebo)

5. Pre-existing sensory or motor polyneuropathy ≥grade 2 according to NCI CTCAE v5

6. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment

7. Any of the following cardiac criteria at screening:

   • Mean resting corrected QT interval (QTc) >470 msec obtained from 3 consecutive ECGs
   • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block)
   • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for Torsades de Pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
   • 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 New York Heart Association (NYHA) grade ≥2
   • Uncontrolled hypotension - SBP <90 mmHg and/or DBP <50 mmHg
   • Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram (or multiplegated acquisition [MUGA] scan if an echocardiogram cannot be performed or is inconclusive).

8. Clinically significant abnormalities of glucose metabolism as defined by any of the following at screening:

   • Patients with diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment
   • HbA1c ≥8.0% (63.9 mmol/mol)

9. Inadequate bone marrow reserve or organ function at screening

10. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.