Patient case: 45-year-old female with colon cancer; genetic feature: PIK3CA (E545K)

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

Summary: Normally, cells in human body divide in an orderly way. However in cancer cells, some important proteins, which help control cell growth, start to behave abnormally resulting in faster growth and multiplication. In this study, we are looking at a protein called AKT that helps the cancer cells to develop. Blocking the action of AKT with a drug like AZD5363 may slow down or stop the cancer growing. The development of AZD5363 is intended to provide a new treatment option for patients with cancer. The standard chemotherapy agent, Paclitaxel, is given to destroy cancer cells. AZD5363 may also make the cancer more sensitive to Paclitaxel and so make this agent more effective.
  A gene called PIK3CA has an important relationship with AKT. In tumours where this gene has been altered, or said to have 'mutated', the response to AZD5363 may be better. PIK3CA mutations are found commonly in breast cancers, and we will test for the presence of these mutations in both blood and tumour tissue samples that we ask you to provide. This study will also look at the relationship between tumours with PIK3CA mutations and the effect of the treatment.

Detailed description: The term triple-negative breast cancer (TNBC) is generally used to define tumours that do not express oestrogen receptors (ER), progesterone receptors (PR) and HER2 receptors. This subtype comprises 10-15% of all breast cancers.
  TNBC has an aggressive clinical course, shares features with basal-like tumours, and has a poorer outcome compared with other subtypes. Clinically, TNBC's are a challenge to treat because there is no role for endocrine or HER2-directed therapy. Chemotherapy is effective, but neo-adjuvant studies have shown that despite initial chemo-sensitivity, TNBC's still had a worse outcome, particularly in women in whom a pathologically confirmed complete response was not achieved. Consequently, there is a clear need to develop specific treatment strategies for the subgroup of TNBC's both in the early and advanced disease setting.
  AZD5363 is a potent, selective inhibitor of the kinase activity of the serine/threonine AKT/PKB (protein kinase B) that is being developed as a potential treatment for solid and haematological malignancies. AKT is part of the AGC family of kinases. Mammalian cells express three closely related AKT isoforms: AKT1 (PKBa), AKT2 (PKBß) and AKT3 (PKBgamma), all encoded by different genes.
  This is a placebo-controlled, multi-centre, 2-arm randomised phase II trial of Paclitaxel + AZD5363 versus Paclitaxel + placebo in patients with triple-negative (ER-negative, PR-negative/unknown, HER2-negative) advanced or metastatic breast cancer.
  Patients will be randomised into either of the Arms Paclitaxel + Placebo OR Paclitaxel + AZD5363.
  Randomisation will be stratified by the following criteria:
  -  Number of metastatic sites (<3, =3)
  -  (Neo)Adjuvant chemotherapy (end of (neo)adjuvant chemotherapy =12 months ago, end of (neo)adjuvant chemotherapy >12 months or no prior (neo)adjuvant chemotherapy).

Eligibility: 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, defined as tumour cells being
  -  Negative for ER with <1% of tumour cells positive for ER on IHC or IHC score of ≥2
  -  Negative for PR with <1% of tumour cells positive for PR on IHC or IHC score of ≥2 or PR unknown
  -  Negative for HER2 with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH
  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

Relevance to patient case: not relevant