Clinical trial NCT01992952: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Estrogen Receptor Positive Breast Cancer
Lead sponsor: Velindre NHS Trust
Sponsor class: OTHER_GOV
Collaborators: name: AstraZeneca
name: Cenduit LLC
name: Covance
name: Cardiff and Vale University Health Board
First posted: 2013-11-25
Enrollment: 149
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Phase 1b primary outcome measure: Maximum Tolerated Dose of AZD5363 in combination with fulvestrant
timeFrame: 6 months
measure: Phase 2 primary outcome: Progression free survival (PFS)
timeFrame: 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:
measure: Number of patients with adverse events
timeFrame: Up to 12 months after the last patient is randomised
measure: Objective response rate
timeFrame: Up to 12 months after the last patient is randomised
measure: Overall survival
timeFrame: Up to 12 months after the last patient is randomised
measure: The influence of mutational status of PIK3CA and the presence of complete loss of PTEN on outcome in the two treatment groups
timeFrame: Up to 12 months after the last patient is randomised
measure: Fulvestrant pharmacokinetics
timeFrame: Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 3 Day 1
measure: Number of patients requiring dose modifications
timeFrame: Up to 12 months after the last patient is randomised
Other outcomes:
Locations:
city: Manchester
country: United Kingdom
facility: Christie Hospital
state: Greater Manchester
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
city: Bebington
country: United Kingdom
facility: Clatterbridge Cancer Centre
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Cardiff
country: United Kingdom
facility: Velindre NHS Trust
city: Durham
country: United Kingdom
facility: University Hospital of North Durham
city: Edinburgh
country: United Kingdom
facility: Great Western General Hospital
city: Huddersfield
country: United Kingdom
facility: Calderdale and Huddersfield NHS Foundation Trust
city: Ipswich
country: United Kingdom
facility: The Ipswich Hospital NHS Trust
city: Lancaster
country: United Kingdom
facility: University Hospitals Morecambe Bay
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: London
country: United Kingdom
facility: Mount Vernon Cancer Centre
city: London
country: United Kingdom
facility: Royal Free Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
city: Rhyl
country: United Kingdom
facility: Glan Clwyd Hospital
city: Romford
country: United Kingdom
facility: Queen's Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Wigan
country: United Kingdom
facility: Royal Albert and Edward Infirmary -Wrightington
Study officials:
affiliation: The University of Manchester and The Christie NHS Foundation Trust
name: Sacha Howell, FRCP PhD
role: STUDY_CHAIR
affiliation: Cardiff University and Velindre Cancer Centre
name: Robert Jones, MRCP PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.