Clinical Trials /

Study to Compare the Effects of AZD9496 vs Fulvestrant in Breast Cancer.

NCT03236974

Description:

This is an open label randomised multicentre pre-surgical pharmacodynamics study to compare and assess the biological effects of AZD9496 and fulvestrant in postmenopausal women with estrogen receptor (ER) positive (ER+), human epidermal growth factor receptor 2 (HER-2) negative (HER2-) primary breast cancer. Patients will receive AZD9496 or fulvestrant and will have an on-treatment image -guided core biopsy after 5-14 days of commencing treatment.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study to Compare the Effects of AZD9496 vs Fulvestrant in Breast Cancer.
  • Official Title: An Open Label, Randomised, Pre-surgical, Pharmacodynamics Study to Compare the Biological Effects of AZD9496 Versus Fulvestrant in Postmenopausal Women With ER Positive HER-2 Negative Primary Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: D6090C00002
  • NCT ID: NCT03236974

Conditions

  • Postmenopausal Women With ER+ HER2- Primary Breast Cancer

Interventions

DrugSynonymsArms
Standard Arm - FulvestrantFulvestrantStandard arm
AZD9496Study drugAZD9496

Purpose

This is an open label randomised multicentre pre-surgical pharmacodynamics study to compare and assess the biological effects of AZD9496 and fulvestrant in postmenopausal women with estrogen receptor (ER) positive (ER+), human epidermal growth factor receptor 2 (HER-2) negative (HER2-) primary breast cancer. Patients will receive AZD9496 or fulvestrant and will have an on-treatment image -guided core biopsy after 5-14 days of commencing treatment.

Detailed Description

      This is an open label, randomized, multi-centre study in postmenopausal women with primary
      ER+ HER2- breast cancer. Patients will be randomised to an oral dose of 250 mg bd AZD9496 or
      500mg fulvestrant i.m. administered on one occasion. Patients diagnosed with primary breast
      cancer who are scheduled for surgery with curative intent will be consented to the study
      including consent to use the formalin fixed paraffin embedded (FFPE) diagnostic tumor biopsy
      sample and fresh frozen tumor biopsy sample (if available) for research purposes. Patients
      may also consent to provide an optional pretreatment fresh frozen tumor biopsy sample if this
      was not obtained at the time of initial diagnostic biopsy. If the diagnostic biopsy was taken
      ≥ 6 weeks prior to starting treatment or was not of sufficient quality, new tumor core
      biopsies (FFPE and fresh frozen) must be taken. Following the screening visit, eligible
      patients will be randomised to receive one of the following study treatments:

        -  AZD9496 administered at 250 mg bd orally for 5-14 days commencing on Day 1, and
           continuing up to the day of biopsy OR

        -  fulvestrant 500 mg administered as two consecutive 5 ml intramuscular injections on Day
           1, one in each buttock.

      After the morning dose of AZD9496 on the day of biopsy dosing will be stopped. If following
      initiation of AZD9496 treatment, dosing will be stopped if biopsy is postponed beyond Day 14.
      Patients will be considered not evaluable for the study if biopsy is postponed beyond day 14
      of AZD9496/fulvestrant treatment initiation. Core tumor biopsies will be taken at either the
      time of definitive surgery or at a separate visit prior to surgery in the period between (and
      including) day 5 and day 14. Subjects who are scheduled to start a subsequent neoadjuvant
      therapy must have their core tumor biopsies performed before commencing neoadjuvant
      treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Standard armActive ComparatorFulvestrant, 500 mg
  • Standard Arm - Fulvestrant
AZD9496Experimental250 mg bd taken orally for 5-14 days
  • AZD9496

Eligibility Criteria

        Inclusion criteria:

          1. Signed and dated informed consent form (ICF)

          2. Women >=18 years

          3. Patients with newly diagnosed resectable primary breast cancer scheduled to undergo
             treatment with curative intent by surgery

          4. Histologically confirmed invasive breast cancer involving a palpable tumor of any
             size, or a tumor with an ultrasound assessed diameter of ≥ 1.0 cm

          5. Any clinical nodal status

          6. ER+breast cancer

          7. HER2- breast cancer defined as a negative in situ hybridization test or an
             immno-histochemistry (IHC) status of 0 or 1+

          8. Eastern Co-operative Oncology group (ECOG) performance status 0-1

          9. Post-menopausal status defined as meeting at least one of the following criteria: Have
             undergone a bilateral oophorectomy; Age ≥60 years; Age ≥50 years and with cessation of
             regular menses ≥12 months and with an intact uterus in the absence of oral
             contraception or hormone-replacement therapy (HRT) prior to the diagnosis of breast
             cancer; Age <60 years and with cessation of regular menses ≥12 months and follicle
             stimulating hormone (FSH) and oestradiol levels in the postmenopausal range

        Exclusion criteria:

          1. Pre-treatment biopsy sample not likely to provide adequate tissue sections for the
             biomarker assays

          2. Previous systemic or local treatment for the new primary breast cancer currently under
             investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments)

          3. Inflammatory breast cancer

          4. Evidence of metastases

          5. Patients currently receiving medications or herbal supplements known to be strong
             inhibitors/inducers of CYP3A4/5 or strong inhibitors of CYP2C8 or that are sensitive
             substrates of CYP2C8 inhibition

          6. Concurrent treatment with other experimental drugs within 4 weeks prior to receiving
             study treatment

          7. Use of hormone-replacement therapy from <4 weeks of the diagnostic/baseline core
             biopsy to the start of trial treatment

          8. Patients with second primary cancer. Any endocrine therapies or other anti-cancer
             therapies must have been ceased at least 12 months prior to enrollment.

          9. Any of the following cardiac criteria:

               -  Mean resting QT interval corrected for heart rate (QTc) > 470 msec obtained from
                  3 ECGs using Fridericia's formula

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events

         10. Experience of any of the following in the preceding 6 months: coronary artery bypass
             graft (CABG), angioplasty, vascular stent, myocardial infarction (MI), angina
             pectoris, congestive heart failure New York Heart Association (NYHA) Grade ≥2,
             cerebrovascular accident (CVA), transient ischaemic attack (TIA), deep venous or
             arterial thrombosis, pulmonary embolism, bleeding diathesis (i.e., disseminated
             intravascular coagulation, clotting factor deficiency) or requirement of anticoagulant
             therapy

         11. As judged by the Investigator, any evidence of severe or uncontrolled systemic
             diseases,

         12. Uncontrolled symptomatic thyroid dysfunction (hyperthyroidism or hypothyroidism).

         13. Unexplained symptomatic endometrial disorders.

         14. Refractory nausea and vomiting, uncontrolled chronic GI diseases, inability to swallow
             the formulated product or previous significant bowel resection that would preclude
             adequate absorption of AZD9496.

         15. Inadequate bone marrow reserve or organ function as demonstrated by any of the
             following laboratory values: absolute neutrophil count < 1.5 x 109/L, Platelet count <
             100 x 109/L, Haemoglobin < 90 g/L, alanine aminotransferase (ALT) > 2.5x upper limit
             of normal (ULN), aspartate aminotransferase (AST) > 2.5 x ULN, Total bilirubin > 1.5 x
             ULN or > 3 x in case of Gilbert's Syndrome, glomerular filtration rate < 50 mL/min

         16. Direct involvement in the planning and conduct of the study

         17. History of hypersensitivity to AZD9496

         18. History of hypersensitivity to fulvestrant and/or castor oil

         19. Judgment by the investigator that the patient should not participate in the study if
             unlikely to comply with study procedures, restrictions and requirements In addition,
             the following is considered a criterion for exclusion from the exploratory genetic
             research: Previous allogeneic bone marrow transplant; Non-leukocyte depleted whole
             blood transfusion within 120 days of the date of the genetic sample collection
      
Maximum Eligible Age:120 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pharmacodynamics changes to estrogen receptor (ER) expression following treatment with AZD9496 or fulvestrant
Time Frame:Tumour biopsy taken at baseline within 6 weeks of planned start of study treatment; on-treatment tumour biopsy taken following 5-14 day on study treatment
Safety Issue:
Description:Evaluation of AZD9496 and fulvestrant activity in the tumour by assessment of pharmacodynamics biomarker changes i.e. ER expression

Secondary Outcome Measures

Measure:Pharmacodynamics changes to progesterone receptor (PgR) expression following treatment with AZD9496 or fulvestrant
Time Frame:Tumour biopsy taken at baseline within 6 weeks of planned start of study treatment; on-treatment tumour biopsy taken following 5-14 day on study treatment
Safety Issue:
Description:Evaluation of AZD9496 and fulvestrant activity in the tumour by assessment of pharmacodynamics biomarker changes i.e. PgR expression
Measure:Pharmacodynamics changes to Ki67 protein biomarker expression following treatment with AZD9496 or fulvestrant
Time Frame:Tumour biopsy taken at baseline within 6 weeks of planned start of study treatment; on-treatment tumour biopsy taken following 5-14 day on study treatment
Safety Issue:
Description:Evaluation of AZD9496 and fulvestrant activity in the tumour by assessment of pharmacodynamics biomarker changes i.e. Ki67 protein biomarker expression
Measure:Safety and tolerability of AZD9496
Time Frame:From first dose until 28 days after last dose of AZD9496
Safety Issue:
Description:Safety and tolerability will be assessed in terms of adverse events (AEs), laboratory data, vital signs and ECG changes.
Measure:Safety and tolerability of fulvestrant
Time Frame:From first dose until 28 days after fulvestrant
Safety Issue:
Description:Safety and tolerability will be assessed in terms of adverse events (AEs), laboratory data and vital signs
Measure:Plasma concentration of AZD9496 - stand alone biopsy visit option
Time Frame:Blood samples collected close as possible to time of biopsy, 1-2 hours after biopsy and optional 3-4 hours after biopsy
Safety Issue:
Description:Determination of AZD9496 concentrations in plasma
Measure:Plasma concentration of fulvestrant
Time Frame:A blood sample will be collected anytime before biopsy.
Safety Issue:
Description:Determination of fulvestrant concentration in plasma
Measure:Plasma concentration of AZD9496 - on the table biopsy option
Time Frame:Blood samples collected close as possible to time of biopsy, at least 2 hours after biopsy and 8-12 hours after last dose or at discharge which is defined as up to 12 hours after last dose
Safety Issue:
Description:Determination of AZD9496 concentration in plasma

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Last Updated

October 11, 2017