Investigating Safety, Tolerability and Efficacy of AZD5363 When Combined With Paclitaxel in Breast Cancer Patients
Condition: Advanced or Metastatic Breast Cancer; ER+ve Advanced or Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The purpose of this study is to investigate the safety and efficacy of different doses and
      schedules of AZD5363, when in combination with paclitaxel, in treatment of patients with
      advanced or metastatic breast cancer. Also to investigate a selected dose and schedule of
      AZD5363 in combination with paclitaxel vs. paclitaxel in combination with placebo in
      treatment of patients with estrogen receptor-positive advanced or metastatic breast cancer,
      including a subgroup who have the phosphoinositide-3-kinase, catalytic, alpha polypeptide
      (PIK3CA) tumour mutation.
    

Detailed description: 
      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 off-therapy.

      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
      the study.
    

Intervention name(s): AZD5363 when combined with weekly paclitaxel.; AZD5363 when combined with weekly paclitaxel.; AZD5363when combined with weekly paclitaxel.; A placebo in combination with weekly paclitaxel.
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): AZD5363: oral capsule, twice daily in a weekly 2 days on-treatment, 5 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.; AZD5363: oral capsule, twice daily in a weekly 4 days on-treatment, 3 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.; Either a 2/5 or 3/4 intermittent dosing schedule of AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.; Either a 2/5 or 3/4 intermittent dosing schedule of placebo matched to AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. placebo and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.
Intervention MeSH terms: Paclitaxel; Albumin-Bound Paclitaxel
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: advanced breast cancer,; metastatic breast cancer,; ER+ve breast cancer,; Estrogen receptor positive breast cancer,; PIK3CA mutated advanced or metastatic breast cancer; AKT inhibitor