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

NCT01992952 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: FAKTION
• Study Type: interventional
• Target: 149
• Locations: 1 country
• Sites: 21

Brief Summary

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.

Conditions

Estrogen Receptor Positive Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Phase 1b primary outcome measure: Maximum Tolerated Dose of AZD5363 in combination with fulvestrant

  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)

  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 Outcomes (6)

• Number of patients with adverse events

  Up to 12 months after the last patient is randomised

• Objective response rate

  Up to 12 months after the last patient is randomised

• Overall survival

  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

  Up to 12 months after the last patient is randomised

• Fulvestrant pharmacokinetics

  Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 3 Day 1

Study Arms (2)

AZD5363 plus fulvestrant

EXPERIMENTAL

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; Drug: Fulvestrant

Placebo plus fulvestrant

ACTIVE COMPARATOR

Fulvestrant 500mg D1, D15 (cycle 1) and D1 of a 28 cycle thereafter. AZD5363 placebo 4 days on 3 days off

Drug: Placebo; Drug: Fulvestrant

Interventions

AZD5363 DRUG

Up to 480mg oral tablets twice a day, taken four days on, 3 days off treatment.

AZD5363 plus fulvestrant

Placebo DRUG

Placebo tablets taken twice a day, 4 days on treatment, 3 days off treatment

Placebo plus fulvestrant

Fulvestrant DRUG

2 x 250mg injections, received on Days 1 and 15 of cycle 1, and on day 1 of each subsequent 28 day cycle.

AZD5363 plus fulvestrant; Placebo plus fulvestrant

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Velindre NHS Trust: lead
• AstraZeneca: collaborator
• Cenduit LLC: collaborator
• Covance: collaborator
• Cardiff and Vale University Health Board: collaborator

Study Sites (21)

Velindre NHS Trust

Cardiff, Cardiff, United Kingdom

Location

Christie Hospital

Manchester, Greater Manchester, United Kingdom

Location

Ysbyty Gwynedd

Bangor, United Kingdom

Location

Clatterbridge Cancer Centre

Bebington, United Kingdom

Location

Royal Blackburn Hospital

Blackburn, United Kingdom

Location

Blackpool Victoria Hospital

Blackpool, United Kingdom

Location

University Hospital of North Durham

Durham, United Kingdom

Location

Great Western General Hospital

Edinburgh, United Kingdom

Location

Calderdale and Huddersfield NHS Foundation Trust

Huddersfield, United Kingdom

Location

The Ipswich Hospital NHS Trust

Ipswich, United Kingdom

Location

University Hospitals Morecambe Bay

Lancaster, United Kingdom

Location

St James's University Hospital

Leeds, United Kingdom

Location

Mount Vernon Cancer Centre

London, United Kingdom

Location

Royal Free Hospital

London, United Kingdom

Location

Derriford Hospital

Plymouth, United Kingdom

Location

Royal Preston Hospital

Preston, United Kingdom

Location

Glan Clwyd Hospital

Rhyl, United Kingdom

Location

Queen's Hospital

Romford, United Kingdom

Location

Southampton General Hospital

Southampton, United Kingdom

Location

Royal Stoke University Hospital

Stoke-on-Trent, United Kingdom

Location

Royal Albert and Edward Infirmary -Wrightington

Wigan, United Kingdom

Location

Related Publications (2)

• Howell SJ, Casbard A, Carucci M, Ingarfield K, Butler R, Morgan S, Meissner M, Bale C, Bezecny P, Moon S, Twelves C, Venkitaraman R, Waters S, de Bruin EC, Schiavon G, Foxley A, Jones RH. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial. Lancet Oncol. 2022 Jul;23(7):851-864. doi: 10.1016/S1470-2045(22)00284-4. Epub 2022 Jun 4.

  PMID: 35671774 DERIVED

• Jones RH, Casbard A, Carucci M, Cox C, Butler R, Alchami F, Madden TA, Bale C, Bezecny P, Joffe J, Moon S, Twelves C, Venkitaraman R, Waters S, Foxley A, Howell SJ. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):345-357. doi: 10.1016/S1470-2045(19)30817-4. Epub 2020 Feb 5.

  PMID: 32035020 DERIVED

Related Links

• Primary analysis results
• Updated and expanded biomarker results

MeSH Terms

Interventions

capivasertib; Fulvestrant

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• 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

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Trial Manager

Study Record Dates

• First Submitted: October 21, 2013
• First Posted: November 25, 2013
• Study Start: May 7, 2014
• Primary Completion: March 1, 2019
• Study Completion: December 31, 2025
• Last Updated: November 26, 2025

Record last verified: 2025-11

Locations

GB (21)