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

• ClinicalTrials.gov Identifier: NCT01992952
• Recruitment Status: Active, not recruiting
• First Posted: November 25, 2013
• Last Update Posted: August 10, 2022
• Sponsor: Velindre NHS Trust
• Collaborators: AstraZeneca; Cenduit LLC; Covance; Cardiff and Vale University Health Board
• Information provided by (Responsible Party): Dr Margherita Carucci, Velindre NHS Trust

Tracking Information

• First Submitted Date: October 21, 2013
• First Posted Date: November 25, 2013
• Last Update Posted Date: August 10, 2022
• Actual Study Start Date: May 2014
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 19, 2013)

• 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
• 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 19, 2013)

• 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.
• 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.
• 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
• 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.
• 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.
• 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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Fulvestrant +/- Akt Inhibition in Advanced Aromatase Inhibitor Resistant Breast Cancer
• Official Title: 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

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.

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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Estrogen Receptor Positive Breast Cancer

Intervention

• Drug: AZD5363
  Up to 480mg oral tablets twice a day, taken four days on, 3 days off treatment.
• Drug: Placebo
  Placebo tablets taken twice a day, 4 days on treatment, 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.

Study Arms

• 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)
  Interventions:

  • Drug: AZD5363
  • Drug: Fulvestrant
• 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
  Interventions:

  • Drug: Placebo
  • Drug: Fulvestrant

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 13, 2018): 149
• Original Estimated Enrollment (submitted: November 19, 2013): 150
• Estimated Study Completion Date: December 2023
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT01992952
• Other Study ID Numbers: FAKTION
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Dr Margherita Carucci, Velindre NHS Trust
• Original Responsible Party: Wales Cancer Trials Unit
• Current Study Sponsor: Velindre NHS Trust
• Original Study Sponsor: Wales Cancer Trials Unit

Collaborators

• AstraZeneca
• Cenduit LLC
• Covance
• Cardiff and Vale University Health Board

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

• PRS Account: Velindre NHS Trust
• Verification Date: August 2022