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Investigating Safety, Tolerability and Efficacy of AZD5363 When Combined With Paclitaxel in Breast Cancer Patients

NCT01625286

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Investigating Safety, Tolerability and Efficacy of AZD5363 When Combined With Paclitaxel in Breast Cancer Patients
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: D3610C00002
  • SECONDARY ID: 2011-006312-31
  • NCT ID: NCT01625286

Conditions

  • Advanced or Metastatic Breast Cancer
  • ER+ve Advanced or Metastatic Breast Cancer

Interventions

DrugSynonymsArms
AZD5363 when combined with weekly paclitaxel.Part A: Intermittent schedule (2/5)
AZD5363 when combined with weekly paclitaxel.Part A: Intermittent schedule (4/3)
AZD5363when combined with weekly paclitaxel.Part B: AZD5363 combined with paclitaxel
A placebo in combination with weekly paclitaxel.Part B: paclitaxel combined with placebo

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Part A: Intermittent schedule (2/5)ExperimentalSee intervention description below.
  • AZD5363 when combined with weekly paclitaxel.
Part A: Intermittent schedule (4/3)ExperimentalSee intervention description below.
  • AZD5363 when combined with weekly paclitaxel.
Part B: AZD5363 combined with paclitaxelActive ComparatorSee intervention description below.
  • AZD5363when combined with weekly paclitaxel.
Part B: paclitaxel combined with placeboPlacebo ComparatorSee intervention description below.
  • A placebo in combination with weekly paclitaxel.

Eligibility Criteria

        Inclusion Criteria:

          -  Provision of informed consent.

          -  Female patient.

          -  Aged at least 18 years.

          -  Histological or cytological confirmation of breast cancer with evidence of advanced or
             metastatic disease (must be ER+ve, HER2-ve, in Part B).

          -  World Health Organisation (WHO) performance status 0-1 with no deterioration over the
             previous 2 weeks and minimum life expectancy of 12 weeks.

        Exclusion Criteria:

          -  Clinically significant abnormalities of glucose metabolism.

          -  Spinal cord compression or brain metastases unless asymptomatic, treated and stable
             (not requiring steroids).

          -  Evidence of severe or uncontrolled systemic diseases, including active bleeding
             diatheses or active infections including hepatitis B, C and HIV.

          -  Any prior exposure to agents which inhibit AKT as the primary pharmacological
             activity.

          -  Part A: more than two prior courses of chemotherapy (including taxanes) for advanced
             or metastatic breast cancer.

        Part B: any prior chemotherapy for advanced or metastatic breast cancer.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A: Safety and tolerability of AZD5363 when combined with paclitaxel, in terms of numbers of patients with adverse events and serious adverse events.
Time Frame: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.
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Part A: Preliminary anti-tumour activity of AZD5363 when combined with paclitaxel, by assessment of overall response rate (ORR) and percentage of patients without progressive disease at 12 weeks.
Time Frame:Tumour assessment by RECIST at patient screening and at 12 weeks after date of start of study therapy.
Safety Issue:
Description:
Measure:Part B: Relative efficacy of AZD5363, compared to placebo, when combined with paclitaxel, by assessment of ORR at 12 weeks, best objective response (BOR) and durable response rate (DDR).
Time Frame:Tumour assessment by RECIST at patient screening and at 12 weeks after date of start of study therapy (ORR) and first of: date of first documented progression, date of study withdrawal or date of death. Average participation approximately 18 weeks.
Safety Issue:
Description:
Measure:Part B: Relative anti-tumour activity of AZD5363, compared to placebo, when combined with paclitaxel, by comparison of change in tumouir size at 12 weeks.
Time Frame:Tumour assessment by RECIST at screening and at 12 weeks after date of start of study therapy.
Safety Issue:
Description:
Measure:Part B: Safety and tolerability of AZD5363 when combined with paclitaxel,in terms of numbers of patients with adverse events and serious adverse events.
Time Frame:Adverse events and toxicities recorded from patient screening to first of: date of study withdrawal, date of death or 28 days after date of discontinuation of all study therapies. Average participation approximately 24 weeks.
Safety Issue:
Description:
Measure:Part B: Effect on patient's quality of life (QoL) due to receipt of AZD5363 when combined with paclitaxel, by assessing changes from baseline score in a patient-completed QoL questionnaire (EORTC QLQ-30 / BR-23).
Time Frame:QoL questionnaires completed at screening and at 12 weekly intervals from screening until first of: date of study withdrawal, date of death or date of discontinuation of all study therapies. Average participation approximately 24 weeks.
Safety Issue:
Description:
Measure:Parts A and B: Assessment of the plasma concentration profile of AZD5363 when combined with paclitaxel.
Time Frame:AZD5363 plasma concentration samples will be collected during the first treatment cycle on: Part A days 2, 3, 5, 9, 16 and 23, and Part B days 2, 9 and 16, from date of start of study therapy.
Safety Issue:
Description:
Measure:Parts A and B: Assessment of the plasma concentration (PK) profile of paclitaxel alone and when combined with AZD5363.
Time Frame:Paclitaxel plasma concentration samples will be collected during the first treatment cycle on: Part A days 1, 2, 9, and 16, and Part B days 1 and 2, from date of start of study therapy.
Safety Issue:
Description:
Measure:Parts A and B: Assessment of the pharmacokinetic/pharmacodynamic relationship between plasma concentration of AZD5363 and plasma concentrations of pharmacodynamic biomarkers and correlation with anti-tumour activity.
Time Frame:PD samples will be collected on:Part A days 1,2,3,5,9,16,23; Part B days 1,2,16 from therapy start & day 1 of each cycle. PK sampling & anti-tumour activity assessment timepoints are as decribed previously. Average participation approximately 18 weeks.
Safety Issue:
Description:
Measure:Part B: Overall survival of patients treated with AZD5363, compared to placebo, when in combination with paclitaxel by assessment of time to death.
Time Frame:First of: date of study withdrawal or date of death. Average participation approximately 52 weeks.
Safety Issue:
Description:
Measure:Part A&B:To assess the toxicity burden associated with diarrhoea in relation to the number and duration of episodes and variations in intensity within episodes of the event's occurrence.
Time Frame:Time Frame: Adverse events and toxicities recorded from patient screening to first of: date of study withdrawal, date of death or 28 days after date of discontinuation of all study therapies. Average participation approximately 24 weeks
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:AstraZeneca

Trial 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

Last Updated

December 14, 2017