Clinical Trial: NCT01625286 - My Cancer Genome

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

URL:

https://clinicaltrials.gov/show/NCT01625286

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

Drug	Synonyms	Arms
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

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

Name	Type	Description	Interventions
Part A: Intermittent schedule (2/5)	Experimental	See intervention description below.	AZD5363 when combined with weekly paclitaxel.
Part A: Intermittent schedule (4/3)	Experimental	See intervention description below.	AZD5363 when combined with weekly paclitaxel.
Part B: AZD5363 combined with paclitaxel	Active Comparator	See intervention description below.	AZD5363when combined with weekly paclitaxel.
Part B: paclitaxel combined with placebo	Placebo Comparator	See 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:	Dose-limiting Toxicity (DLT) Events - Part A
Time Frame:	During Part A DLT evaluation period (Cycle 1, up to 28 days)
Safety Issue:
Description:	An Adverse Event (AE) or laboratory abnormality considered to be related to study drug, that starts at any time during the DLT evaluation period (Cycle 1) and is dose limiting

Secondary Outcome Measures

Measure:	Change in Tumour Size at 12 Weeks
Time Frame:	RECIST tumour assessments every 12 weeks
Safety Issue:
Description:	Percentage change from baseline to week 12 in sum of longest diameters of target lesions as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1). Based on patients with measurable disease who had sufficient data available to either calculate or impute a change at 12 weeks

Measure:	Objective Response Rate (ORR) at Week 12
Time Frame:	RECIST tumour assessments every 12 weeks
Safety Issue:
Description:	Percentage of patients who have at least one visit response of Complete Response or Partial Response prior to any evidence of progression at week 12 as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm; Objective Response Rate (ORR) = CR + PR

Measure:	Best Objective Response (BOR)
Time Frame:	From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
Safety Issue:
Description:	Number of patients, taking their BOR, which is their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.

Measure:	Overall Objective Response Rate
Time Frame:	From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
Safety Issue:
Description:	Percentage of patients, taking their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm. Overall Response Rate (ORR) = CR + PR

Measure:	Number of Subjects Without Progression Disease at Week 12 - Part A
Time Frame:	up to 12 weeks
Safety Issue:
Description:	Percentage of patients with a 12 week visit response of CR, PR or SD (as defined by RECIST 1.1) with no evidence of previous progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.

Measure:	Duration of Response (DOR) - Part B
Time Frame:	From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
Safety Issue:
Description:	Date of first documentation of response (Complete Response/Partial Response) until the date of disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.. If a subject does not progress following a response, then their DOR will use the PFS censoring time.

Measure:	Durable Response Rate (DRR) - Part B
Time Frame:	From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
Safety Issue:
Description:	Percentage of patients who have a Complete Response (CR) or Partial Response (PR) lasting continuously for at least 24 weeks as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: PR, >=30% decrease in the sum of the longest diameter of target lesions; CR, disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.

Measure:	Overall Survival - Part B
Time Frame:	From date of randomisation, assessed every 12 weeks, up until the time of final statistical analysis. (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
Safety Issue:
Description:	The interval between the date of randomisation and the date of patient death due to any cause. All Part B patients were analysed, number of deaths is presented.

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

June 11, 2021

Clinical Trials /

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