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

NCT03236974 | Completed Phase 1 DMC

• 1 other identifier: D6090C00002
• Study Type: interventional
• Target: 49
• Locations: 2 countries
• Sites: 12

Brief Summary

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.

Conditions

Postmenopausal Women With ER+ HER2- Primary Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Pharmacodynamics changes to estrogen receptor (ER) expression following treatment with AZD9496 or fulvestrant

  Evaluation of AZD9496 and fulvestrant activity in the tumour by assessment of pharmacodynamics biomarker changes i.e. ER expression

  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

Secondary Outcomes (7)

• Pharmacodynamics changes to progesterone receptor (PgR) expression following treatment with AZD9496 or fulvestrant

  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

• Pharmacodynamics changes to Ki67 protein biomarker expression following treatment with AZD9496 or fulvestrant

  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 and tolerability of AZD9496

  From first dose until 28 days after last dose of AZD9496

• Safety and tolerability of fulvestrant

  From first dose until 28 days after fulvestrant

• Plasma concentration of AZD9496 - stand alone biopsy visit option

  Blood samples collected close as possible to time of biopsy, 1-2 hours after biopsy and optional 3-4 hours after biopsy

Study Arms (2)

Standard arm

ACTIVE COMPARATOR

Fulvestrant, 500 mg

Drug: Standard Arm - Fulvestrant

AZD9496

EXPERIMENTAL

250 mg bd taken orally for 5-14 days

Drug: AZD9496

Interventions

Standard Arm - Fulvestrant DRUG

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

Also known as: Fulvestrant

Standard arm

AZD9496 DRUG

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

Also known as: Study drug

AZD9496

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed and dated informed consent form (ICF)
• Women \>=18 years
• Patients with newly diagnosed resectable primary breast cancer scheduled to undergo treatment with curative intent by surgery
• Histologically confirmed invasive breast cancer involving a palpable tumor of any size, or a tumor with an ultrasound assessed diameter of ≥ 1.0 cm
• Any clinical nodal status
• ER+breast cancer
• HER2- breast cancer defined as a negative in situ hybridization test or an immno-histochemistry (IHC) status of 0 or 1+
• Eastern Co-operative Oncology group (ECOG) performance status 0-1
• 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

You may not qualify if:

• Pre-treatment biopsy sample not likely to provide adequate tissue sections for the biomarker assays
• Previous systemic or local treatment for the new primary breast cancer currently under investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments)
• Inflammatory breast cancer
• Evidence of metastases
• 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
• Concurrent treatment with other experimental drugs within 4 weeks prior to receiving study treatment
• Use of hormone-replacement therapy from \<4 weeks of the diagnostic/baseline core biopsy to the start of trial treatment
• Patients with second primary cancer. Any endocrine therapies or other anti-cancer therapies must have been ceased at least 12 months prior to enrollment.
• 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
• 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
• As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases,
• Uncontrolled symptomatic thyroid dysfunction (hyperthyroidism or hypothyroidism).

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (12)

Research Site

Erlangen, 91054, Germany

Location

Research Site

Minden, 32429, Germany

Location

Research Site

München, 81377, Germany

Location

Research Site

Schwerin, 19049, Germany

Location

Research Site

Derby, DE22 3DT, United Kingdom

Location

Research Site

Edinburgh, EH4 2XU, United Kingdom

Location

Research Site

London, EC1M 6BQ, United Kingdom

Location

Research Site

London, SE1 9RT, United Kingdom

Location

Research Site

London, W12 0NN, United Kingdom

Location

Research Site

Manchester, M23 9LT, United Kingdom

Location

Research Site

Poole, BH15 2JB, United Kingdom

Location

Research Site

Sutton in Ashfield, NG17 4JL, United Kingdom

Location

Related Publications (1)

• Robertson JFR, Evans A, Henschen S, Kirwan CC, Jahan A, Kenny LM, Dixon JM, Schmid P, Kothari A, Mohamed O, Fasching PA, Cheung KL, Wuerstlein R, Carroll D, Klinowska T, Lindemann JPO, MacDonald A, Mather R, Maudsley R, Moschetta M, Nikolaou M, Roudier MP, Sarvotham T, Schiavon G, Zhou D, Zhou L, Harbeck N. A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer. Clin Cancer Res. 2020 Aug 15;26(16):4242-4249. doi: 10.1158/1078-0432.CCR-19-3387. Epub 2020 Mar 31.

  PMID: 32234755 DERIVED

Related Links

• Results of this clinical trial are available on www.astrazenecaclinicaltrials.com

MeSH Terms

Interventions

Fulvestrant; AZD9496; Drug Evaluation

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Drug Development; Investigative Techniques; Evaluation Studies as Topic

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Not applicable, thisis an open-label study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 18, 2017
• First Posted: August 2, 2017
• Study Start: October 5, 2017
• Primary Completion: February 12, 2019
• Study Completion: February 12, 2019
• Last Updated: February 6, 2020

Record last verified: 2020-02

Locations

GB (8); DE (4)