A Phase I/II Study of AZD5363 Combined With Paclitaxel in Patients With Advanced or Metastatic Breast Cancer. Comprising a Safety Run-In and a Placebo-controlled Randomised Expansion in ER+ve Patients Stratified by PIK3CA Mutation Status.
This is a Phase I/II multicentre, study investigating the safety, tolerability and efficacy
of a twice-daily oral formulation of AZD5363 when combined with a weekly intravenous
paclitaxel infusion in patients with advanced or metastatic breast cancer. Study treatment
is given in 28-day cycles, comprising three weeks on-therapy followed by one week
The study will be conducted in two parts:
Part A. Approximately 40 patients will be recruited to this Phase I multiple ascending-dose
safety run-in evaluation of each of two intermittent dosing schedules (2 days per week or 4
days per week) of AZD5363 given in combination with weekly paclitaxel. The study population
is female patients, 18 years or older, with advanced or metastatic breast cancer.
The purpose of Part A is to assess the comparative safety, tolerability, pharmacokinetics
and preliminary efficacy of both schedules to determine one dose and schedule of AZD5363 to
take forward to study Part B in combination with weekly paclitaxel.
Part A assessments will be made in dose-escalating cohorts of 3 to 6 patients to determine a
recommended dose in each of the schedules. A total of 6 patients must be evaluated at a
selected dose level for it to be confirmed as the recommended dose. All dose evaluations
and recommendations will be conducted by a Safety Review Committee.
Part A Patients will undergo assessments up to to withdrawal from the study or to
discontinuation of study therapy.
Part B. A minimum of 100 patients will be recruited to this Phase II double-blind,
placebo-controlled, stratified and randomised evaluation of two treatment regimens: AZD5363
(at a dose selected and schedule from Part A) in combination with weekly paclitaxel vs.
weekly paclitaxel plus placebo. The study population is female patients with Estrogen
Receptor Positive advanced or metastatic breast cancer; of which approximately 50 will have
the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) mutation.
Part B patients will be stratified by PIK3CA tumour mutation status as: tumour mutation
positive or tumour mutation not-detected. Under each stratum patients will be randomised to
receive either paclitaxel + AZD5363 or paclitaxel + placebo.
The purpose of Part B is to assess relative efficacy of both active and placebo regimens by
comparison of: progression-free survival, overall survival, tumour response, safety and
tolerability in the overall ER+ve advanced or metastatic breast cancer population, and in a
subgroup of these patients with the PIK3CA tumour mutation. Patient safety and therapy
tolerability will be monitored by an independent Safety Review Committee throuighout the
course of Part B.
Part B patients will be followed for assessment of overall survival, or to withdrawal from
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Part A: Safety and tolerability of AZD5363 when combined with paclitaxel, in terms of numbers of patients with adverse events and serious adverse events.
Adverse events and toxicities recorded from patient screening to first of: date of withdrawal from study, date of death or date of patient completion of study. Average participation approximately 18 weeks.
Paul Stockman, MBCHB, PHD
United Kingdom: Medicines and Healthcare Products Regulatory Agency