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

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.

Sex

Female

Minimum age

18 Years

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

• DERIVEDHowell 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
• DERIVEDJones 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