Clinical Trials /

Fulvestrant +/- Vandetanib in Advanced Aromatase Inhibitor Resistant Breast Cancer

NCT02530411

Description:

A randomised double blind placebo controlled phase II study of fulvestrant with or without the addition of vandetanib as treatment for patients with metastatic breast cancer resistant to aromatase inhibitor therapy.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Fulvestrant</span> +/- Vandetanib 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 +/- Vandetanib in Advanced Aromatase Inhibitor Resistant Breast Cancer
  • Official Title: A Randomised Double Blind Placebo Controlled Phase II Study of Fulvestrant With or Without the Addition of Vandetanib as Treatment for Patients With Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy
  • Clinical Trial IDs

    NCT ID: NCT02530411

    ORG ID: 2014/VCC/0013

    NCI ID: 2014-001208-23

    Trial Conditions

    Neoplasms

    Trial Interventions

    Drug Synonyms Arms
    Fulvestrant FASLODEX (also previously known as ZD9238) Experimental, Control
    Vandetanib CAPRELSA (also previously known as ZACTIMA, ZD6474) Experimental

    Trial Purpose

    A randomised double blind placebo controlled phase II study of fulvestrant with or without
    the addition of vandetanib as treatment for patients with metastatic breast cancer resistant
    to aromatase inhibitor therapy.

    Detailed Description

    For patients with advanced breast cancer that has spread around the body, hormone therapy is
    often the best treatment. As well as being very effective, this means that patients do not
    experience the toxicity and inconvenience of chemotherapy. However, eventually the cancer is
    likely to become resistant to hormone therapy and in this situation, although other hormone
    drugs can be used, they sometimes do not work very well. So it is important to find ways of
    getting the cancer to respond to hormone treatment again.

    There are many different ways in which breast cancer cells become resistant to hormone
    treatments, including a 'signalling' pathway in the cells called RET [Receptor tyrosine
    kinase RET] REarranged during Transfection. Research has shown increased activity of RET
    signalling pathways in hormone resistant cancer cells.

    Vandetanib is an oral drug that inhibits RET signalling in cells and has been shown in
    laboratory studies to prevent the growth of breast cancer cells which have become resistant
    to hormone therapy. Hormone therapy drugs include tamoxifen, and the aromatase inhibitors
    (anastrozole, letrozole and exemestane). The investigators therefore believe that giving
    vandetanib together with hormone therapy may help prevent resistance to treatment in
    patients with breast cancer. In this trial the investigators will combine this drug with
    fulvestrant, another hormone therapy drug which is sometimes used alone in patients who have
    developed resistance to aromatase inhibitors, or tamoxifen. So patients entering the trial
    will have one drug, fulvestrant, which is known to work and may also be given the
    experimental drug, vandetanib.

    To properly determine if vandetanib works as the investigators believe, this study will
    compare the activity of vandetanib combined with fulvestrant with fulvestrant combined with
    an inactive, 'placebo' tablet in a group of patients for whom treatment with single agent
    fulvestrant is thought appropriate. The investigators plan to recruit a total of 160
    patients. Half of them will be given fulvestrant and vandetanib and half will be given
    fulvestrant and placebo, and the treatment a particular patient will get will be chosen by
    random chance. Neither the patient nor the patients doctor will know whether the patient is
    getting vandetanib or the inactive placebo. The most important measure of effect will be the
    time until the cancer grows again, but the study will also look closely at the side effects
    of the drugs. The investigators will also look at whether the way in which an individual
    responds relates to the results from laboratory studies on the RET pathways carried out on
    previously stored tumour samples. This will mean that patients will not need to have
    additional biopsy samples taken.

    Trial Arms

    Name Type Description Interventions
    Experimental Experimental Fulvestrant 500mg Intra Muscular (IM) Day 1 (D1), D15, then D1 of every 28 day cycle Vandetanib 300 mg Per os (po) daily Clinician review D1, D15, weeks 4, 8, 12, 16, 20, 24 then 12 weekly. Computerised Axial Tomography (CT) at week 8, 16, 24 then 12 weekly. Fulvestrant, Vandetanib
    Control Placebo Comparator Fulvestrant 500mg IM D1, D15, then D1 of every 28 day cycle Placebo po daily Clinician review D1, D15, weeks 4, 8, 12, 16, 20, 24 then 12 weekly. CT at week 8, 16, 24 then 12 weekly. Fulvestrant

    Eligibility Criteria

    Inclusion criteria:

    1. Female 18 years

    2. Post-menopausal

    3. Minimum life expectancy 12 weeks

    4. Histological confirmation of ER+ve breast cancer on primary tumour at diagnosis/on
    biopsy of metastasis

    5. Histological confirmation of HER2 negative breast cancer on primary tumour at
    diagnosis/on biopsy of a metastasis

    6. Clinical or histological confirmation of metastatic or locally advanced disease not
    amenable to curative surgical resection

    7. ECOG 0-2 with no deterioration over previous 2 weeks

    8. Measurable or non-measurable disease

    9. Adequate bone marrow and organ function

    10. Progressive disease whilst receiving third generation aromatase inhibitor for locally
    advanced or metastatic BC or relapsed with metastatic disease whilst receiving third
    generation AI in adjuvant setting

    11. Radiological or objective clinical evidence of recurrence or progression on or after
    last systemic therapy prior to enrolment

    12. 3 prior lines of endocrine therapy for ABC

    13. 1 line of cytotoxic chemotherapy for ABC

    14. Suitable for further endocrine therapy

    15. Availability of archival tumour sample or fresh biopsy

    16. Informed consent

    17. Normal cardiac function

    Exclusion criteria:

    1. Previous treatment with fulvestrant or inhibitors of RET pathway

    2. Last dose chemotherapy, immunotherapy targeted therapy, biological therapy or tumour
    embolisation <21 days (<6 weeks for nitrosurea or mitomycin C) prior to study
    treatment

    3. Last dose of palliative radiotherapy <7 days prior to study treatment

    4. Rapidly progressive visceral disease not suitable for further endocrine therapy

    5. Spinal cord compression or brain/meningeal metastases unless asymptomatic, treated
    and stable and not requiring steroids for 4 weeks study treatment

    6. Any of the following cardiac criteria: Significant cardiac event, superior vena cava
    syndrome, NYHA classification of heart disease 2 within 12 weeks before
    randomisation, or presence of cardiac disease that increases risk of ventricular
    arrhythmia; History of arrhythmia which is symptomatic or requires treatment,
    symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic
    sustained ventricular tachycardia; Congenital long QT syndrome; History of QT
    prolongation associated with other medications that required discontinuation of that
    medication; QTcB >480msec on screening ECG

    7. Electrolyte values: Potassium <4.0 mmol/L despite supplementation, or above CTCAE
    Grade 1 upper limit, at randomisation; Magnesium below the normal range despite
    supplementation, or above CTCAE Grade 1 upper limit, at randomisation; Calcium
    (ionised or serum) below the normal range despite supplementation, or above Grade 1
    upper limit, at randomisation

    8. Creatinine clearance <30 ml/min. Patients with creatinine clearance <50 mL/min will
    start at a permanently reduced vandetanib dose of 200 mg.

    9. Major surgery (excluding placement of vascular access) within 4 weeks before study
    treatment

    10. Evidence of severe or uncontrolled systemic diseases, including uncontrolled
    hypertension, active bleeding diatheses, or active infection including hepatitis B,
    hepatitis C and HIV

    11. With the exception of alopecia, any unresolved toxicities from previous therapy
    greater than CTCAE grade 1 before study treatment

    12. Elevated ALP in absence of bone metastasis

    13. History of hypersensitivity to active or inactive excipients of vandetanib or
    fulvestrant

    14. Evidence of dementia, altered mental status or any psychiatric condition that would
    prohibit understanding or rendering of informed consent

    15. Participation in another study with investigational product during last 30 days

    16. Inability or unwillingness to comply with study procedures, including inability to
    take regular oral medication

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Progression-Free Survival (PFS)

    Secondary Outcome Measures

    Objective Response Rate

    Overall Survival

    Exploratory analysis: The influence of RET signalling pathway components expression on vandetanib activity.

    Safety and tolerability of the fulvestrant/vandetanib trial drug regime measured by the number of participants with reported serious adverse events (composite outcome measure).

    Feasibility of use of the combined vandetanib/fulvestrant trial drug regime measured by the number of participants requiring dose delays, reductions and/or study withdrawal to manage reported serious adverse events.

    Clinical Benefit Rate (measuring the proportion of patients with no disease progression after six months of treatment)

    Trial Keywords

    Hormone resistance

    vandetanib

    fulvestrant