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

Prior treatment

• 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
• 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

Other illness

• 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.
• Malabsorption syndrome or other condition that would interfere with enteral absorption
• Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.

Lab values

• 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

Other

• Pre-existing sensory or motor polyneuropathy ≥ Grade 2 according to CTCAE
• Clinically significant pulmonary dysfunction
• Detained persons or prisoners
• Pregnant or nursing women

• 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