Clinical Trials /

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

NCT01992952

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Fulvestrant</span> +/- Akt Inhibition in Advanced <span class="go-doc-concept go-doc-intervention">Aromatase Inhibitor</span> Resistant <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • 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
  • Clinical Trial IDs

    NCT ID: NCT01992952

    ORG ID: FAKTION

    Trial Conditions

    Estrogen Receptor Positive Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    AZD5363 AZD5363 plus fulvestrant
    Placebo Placebo plus fulvestrant
    Fulvestrant AZD5363 plus fulvestrant, Placebo plus fulvestrant

    Trial Purpose

    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.

    Trial Arms

    Name Type Description Interventions
    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) AZD5363, 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 Placebo, Fulvestrant

    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 endocrine therapy for MBC

    - Up to 1 line of chemotherapy in the metastatic setting

    - Patient willing to donate archival tumour sample

    - Patient willing to donate baseline blood sample

    - Adequate bone marrow and organ function

    - Suitable for further endocrine therapy

    Exclusion Criteria:

    - Previous treatment with fulvestrant or PI3K/mTOR(mammalian target of rapamycin )/Akt
    inhibitor therapy

    - 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

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

    Phase 2 primary outcome: Progression free survival (PFS)

    Secondary Outcome Measures

    Number of patients with adverse events

    Objective response rate

    Overall survival

    The influence of mutational status of PIK3CA and the presence of complete loss of PTEN on outcome in the two treatment groups

    Fulvestrant pharmacokinetics

    Number of patients requiring dose modifications

    Trial Keywords