Fulvestrant +/- Akt Inhibition in Advanced Aromatase Inhibitor Resistant Breast Cancer (FAKTION)

August 5, 2022 updated by: Dr Margherita Carucci, Velindre NHS Trust

A Phase 1b/2 Randomised Placebo Controlled Trial of Fulvestrant +/- AZD5363 in Postmenopausal Women With Advanced Breast Cancer Previously Treated With a Third Generation Aromatase Inhibitor

This is a two stage study, with an initial dose escalation phase I study and subsequent double blind randomised phase II controlled trial. Eligible patients are post-menopausal women with metastatic ER+ breast cancer not suitable for surgical resection. Patients should be suitable for endocrine treatment, but have received no more than 3 previous lines of endocrine treatment and up to 1 line of chemotherapy for metastatic disease. They will also have had progressive disease during treatment with an aromatase inhibitor. Following the dose-escalation in stage 1, patients will be randomised to receive fulvestrant plus either placebo or 480mg (or maximum tolerated dose) of AZD5363 oral capsules or tablets taken once daily.

Patients will receive fulvestrant in combination with either placebo or AZD5363 until disease progression. Patients may continue to receive fulvestrant and AZD5363/placebo treatment even after the last trial visit.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

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 If patients are withdrawn for reasons other than toxicity during Stage 1 before DLT assessments then they will be replaced.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.

Study Type

Interventional

Enrollment (Actual)

149

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Bangor, United Kingdom
        • Ysbyty Gwynedd
      • Bebington, United Kingdom
        • Clatterbridge Cancer Centre
      • Blackburn, United Kingdom
        • Royal Blackburn Hospital
      • Blackpool, United Kingdom
        • Blackpool Victoria Hospital
      • Cardiff, United Kingdom
        • Velindre NHS Trust
      • Durham, United Kingdom
        • University Hospital of North Durham
      • Edinburgh, United Kingdom
        • Great Western General Hospital
      • Huddersfield, United Kingdom
        • Calderdale and Huddersfield NHS Foundation Trust
      • Ipswich, United Kingdom
        • The Ipswich Hospital NHS Trust
      • Lancaster, United Kingdom
        • University Hospitals Morecambe Bay
      • Leeds, United Kingdom
        • St James's University Hospital
      • London, United Kingdom
        • Royal Free Hospital
      • London, United Kingdom
        • Mount Vernon Cancer Centre
      • Plymouth, United Kingdom
        • Derriford Hospital
      • Preston, United Kingdom
        • Royal Preston Hospital
      • Rhyl, United Kingdom
        • Glan Clwyd Hospital
      • Romford, United Kingdom
        • Queen's Hospital
      • Southampton, United Kingdom
        • Southampton General Hospital
      • Stoke-on-Trent, United Kingdom
        • Royal Stoke University Hospital
      • Wigan, United Kingdom
        • Royal Albert and Edward Infirmary -Wrightington
    • Greater Manchester
      • Manchester, Greater Manchester, United Kingdom
        • Christie Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Post-menopausal Women
  • Life expectancy 3 months
  • Histological confirmation of ER+ breast cancer
  • Clinical or histological confirmation of metastatic or locally advanced disease not amenable to surgical resection
  • Measurable or non-measurable disease
  • Adequate bone marrow, renal and hepatic function
  • Eastern Cooperative Oncology Group (ECOG) performance status < or equal to 2
  • Progressive disease whilst receiving an aromatase inhibitor (AI) for metastatic breast cancer (MBC)
  • Relapsed with metastatic disease whilst receiving an AI in adjuvant setting
  • Up to 3 prior lines of endocrine therapy for Advanced Breast Cancer
  • Up to 1 line of chemotherapy for Advanced Breast Cancer
  • Patient willing to donate archival tumour sample
  • Patient willing to donate baseline blood sample
  • Suitable for further endocrine therapy

Exclusion Criteria:

  • Previous treatment with fulvestrant or PI3K/mTOR(mammalian target of rapamycin )/Akt inhibitor therapy
  • Treatment with chemotherapy, immunotherapy or targeted, biologic or tumour embolisation within 21 days of study drug administration
  • Palliative radiotherapy within 7 days of study drug
  • Clinically significant abnormalities in glucose metabolism
  • Rapidly progressive visceral disease not suitable for further endocrine therapy
  • Known brain or leptomeningeal metastases
  • Any co-existing medical condition precluding trial entry including significant cardiac disease (to be defined in the protocol)
  • Concomitant medication unsuitable for combination with trial medication

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: AZD5363 plus fulvestrant
Fulvestrant 500mg and AZD5363 4 days on 3 days off at dose determined in safety run in (maximum 480mg and minimum 320mg bd)
Drug: AZD5363
Up to 480mg oral tablets twice a day, taken four days on, 3 days off treatment.
Drug: Fulvestrant
2 x 250mg injections, received on Days 1 and 15 of cycle 1, and on day 1 of each subsequent 28 day cycle.
Active Comparator: Placebo plus fulvestrant
Fulvestrant 500mg D1, D15 (cycle 1) and D1 of a 28 cycle thereafter. AZD5363 placebo 4 days on 3 days off
Drug: Fulvestrant
2 x 250mg injections, received on Days 1 and 15 of cycle 1, and on day 1 of each subsequent 28 day cycle.
Drug: Placebo
Placebo tablets taken twice a day, 4 days on treatment, 3 days off treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase 1b primary outcome measure: Maximum Tolerated Dose of AZD5363 in combination with fulvestrant
Time Frame: 6 months
To establish the MTD of AZD5363 in combination with fulvestrant and to establish a recommended phase 2 dose
6 months
Phase 2 primary outcome: Progression free survival (PFS)
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months after the last patient is randomised
To establish the anti-tumour activity of the combination of AZD5363 with fulvestrant as measured by progression-free survival (PFS). This is the time from enrolment to any disease progression and/or any death, defined according to strict Response Evaluation Criteria in Solid Tumors(RECIST) v1.1 criteria. Lesions will be compared to baseline measurements to assess progression.
From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months after the last patient is randomised

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with adverse events
Time Frame: Up to 12 months after the last patient is randomised
To determine the number of patients reporting adverse events and to summarise the different types of adverse events experienced in each trial arm.
Up to 12 months after the last patient is randomised
Objective response rate
Time Frame: Up to 12 months after the last patient is randomised
The objective response rate will be used to determine the proportion of patients who responded to treatment.
Up to 12 months after the last patient is randomised
Overall survival
Time Frame: Up to 12 months after the last patient is randomised
The time from randomisation to death, with those still alive censored at date last seen
Up to 12 months after the last patient is randomised
The influence of mutational status of PIK3CA and the presence of complete loss of PTEN on outcome in the two treatment groups
Time Frame: Up to 12 months after the last patient is randomised
The mutational status of PIK3CA and the presence of complete loss of PTEN will be assessed at baseline.
Up to 12 months after the last patient is randomised
Fulvestrant pharmacokinetics
Time Frame: Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 3 Day 1
The minimum concentration (Cmin) of fulvestrant will be measured to determine whether AZD5363 affects the metabolism of fulvestrant.
Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 3 Day 1
Number of patients requiring dose modifications
Time Frame: Up to 12 months after the last patient is randomised
The number of participants requiring dose modifications of AZD5363 and fulvestrant will be summarised for each trial arm. This will be broken down into the number of patients who withdraw from treatment and the number who were dose reduced while on treatment.
Up to 12 months after the last patient is randomised

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Velindre NHS Trust

Collaborators

AstraZeneca
Cardiff and Vale University Health Board
Covance
Cenduit LLC

Investigators

  • Study Chair: Sacha Howell, FRCP PhD, The University of Manchester and The Christie NHS Foundation Trust
  • Study Chair: Robert Jones, MRCP PhD, Cardiff University and Velindre Cancer Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2014

Primary Completion (Actual)

March 1, 2019

Study Completion (Anticipated)

December 1, 2023

Study Registration Dates

First Submitted

October 21, 2013

First Submitted That Met QC Criteria

November 19, 2013

First Posted (Estimate)

November 25, 2013

Study Record Updates

Last Update Posted (Actual)

August 10, 2022

Last Update Submitted That Met QC Criteria

August 5, 2022

Last Verified

August 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FAKTION

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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