Phase 1 (n=9-12)

      As fulvestrant and AZD5363 have not previously been administered to this population, we have
      incorporated an initial phase I dose escalation:

        -  3 patients will receive fulvestrant 500mg on day 1 and 400mg AZD5363 oral capsules or
           tablets bd 4 days on and 3 days off. They will be assessed for dose limiting toxicity
           (DLT) on day 1, 15 and 28 of cycle 1. The safety review committee (SRC) will meet to
           review DLT reports when the third patient finishes cycle 1.

        -  If 400mg is tolerable (0/3-6 or 1-6 has a DLT) then the dose of AZD5363 will be
           escalated to 480mg.

        -  If 480mg is tolerable in a cohort of 6 patients then 480mg will be the Maximum tolerated
           dose (MTD).

        -  If 480mg is not tolerable (2/6 patients have a DLT), then the 400mg dose will be the
           MTD.

        -  If 400mg is not tolerable (2 or more patients have a DLT) then the dose will be reduced
           to 320mg for the next cohort of 6 patients.

        -  if 320mg is tolerable in a cohort of 6 patients, then 320mg will be the MTD.

        -  if 320mg is not tolerable, then the trial will not proceed. If patients are withdrawn
           for reasons other than toxicity during Stage 1 before DLT assessments then they will be
           replaced.

      Phase 2 (n=136)

      Recruitment in to Phase 2 will commence after all 6 patients in Stage 1 have completed at
      least 1 cycle of therapy and the SRC have given the go-ahead. Patients will be randomised to
      one of two arms:

      Arm A (control arm): Fulvestrant + placebo The control arm will consist continuous 28 day
      cycles of fulvestrant 500mg on day 1, plus placebo capsule or tablet bd 4 days on and 3 days
      off.

      Arm B (experimental arm): Fulvestrant + AZD5363 The experimental arm will consist continuous
      28 day cycles of fulvestrant 500mg on day 1, plus AZD5363 capsule or tablet bd 4 days on and
      3 days off.

      A further safety assessment will be made after 20 patients have been randomised to receive
      AZD5363 or placebo and have at least 1 cycle of protocol treatment in stage 2.

      Phase 2 will have 3 stages, this is because we want to investigate whether tumours with
      certain characteristics are more likely to respond to the AZD5363. As mentioned above, we
      will test the tumour tissue for the presence of a PIK3CA mutation (a gene encoding catalytic
      subunit of class 1 PI3K) and for low levels of phosphatase and tensin homolog (PTEN).
      Laboratory research has shown that tumours with these characteristics may respond better to
      the AZD5363. Tumours which do not have these characteristics are called wild-type, and we
      want to make sure we don't recruit too many of these patients if they might not benefit from
      the treatment.

      We will start off by recruiting all eligible patients. However, when we know that we have 40
      patients with wild-type tumours, and they have been on trial treatment for eight weeks, we
      will stop recruiting patients with wild-type tumours. This means that we will do a blood test
      to confirm the tumour has the PIK3CA mutation before a patient can be entered onto the study.

      We will perform a review of the tumour measurements in this wild-type group to determine
      whether the tumours of the patients receiving AZD5363 have shrunk more than patients
      receiving placebo. If there is no evidence that the tumour has shrunk in the AZD5363 group
      compared to placebo, we will not recruit any more patients with wild-type tumours. If there
      is evidence that that the tumours have shrunk in the AZD5363 group, we will start recruiting
      patients with wild-type tumours again.