A Study to Investigate Efficacy and Safety With Oral AZD9833 Compared With Intramuscular Fulvestrant in Post-menopausal Women at Least 18 Years of Age With Advanced ER-positive HER2 Negative Breast Cancer

SERENA-2: A Randomised, Open-Label, Parallel-Group, Multicentre Phase 2 Study Comparing the Efficacy and Safety of Oral AZD9833 Versus Fulvestrant in Women With Advanced ER-Positive HER2-Negative Breast Cancer

This study is randomized, open-label, parallel-group, multicentre Phase 2 study aimed to compare the efficacy and safety of oral AZD9833 versus intramuscular (IM) fulvestrant in women with advanced breast cancer.

Post-menopausal women with histologically or cytologically confirmed metastatic or loco-regionally recurrent ER-positive HER2-negative breast cancer before randomization and fulfilling all of the inclusion criteria and none of the exclusion criteria will be included.

After the screening visit and confirmation of eligibility, patients will be randomly assigned in a 1:1:1:1 ratio to receive 1 of the following 4 treatments, consisting of 4-week treatment cycles until disease progression (assessed by the Investigator as defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1):

• AZD9833 (Dose A)
• AZD9833 (Dose B)
• AZD9833 (Dose C)
• Fulvestrant (500 mg) During the treatment period, patients will have scheduled visits until treatment discontinuation. After the end of treatment, patients will attend 2 safety follow-up visits (at the time of treatment discontinuation and 28 days later) and will continue to be followed for survival.

As of December 2020, the Sponsor stopped enrolment to Dose C.

Inclusion Criteria:

• Post-menopausal female patients aged at least 18 years.

• Metastatic or loco-regionally recurrent ER-positive HER2-negative adenocarcinoma of the breast.

• Radiological or other objective evidence of progression on or after the last systemic therapy prior to starting study treatment.

• Patients must have at least 1 lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter or in absence of measurable disease as defined above, at least 1 lytic or mixed (lytic+sclerotic) bone lesion.

• Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance status 0 to 1.

• Prior endocrine therapy as follows:

  1. Recurrence or progression on at least one line of endocrine therapy
  2. No more than 1 line of endocrine therapy for advanced disease
  3. No more than 1 line of chemotherapy for advanced disease
  4. Prior treatment with CDK4/6 inhibitors is permitted
  5. No prior treatment with fulvestrant, oral selective oestrogen receptor degrader (SERD), or related therapies

• Inclusion criterion for the paired tumour biopsy research subgroup:

Washout from prior tamoxifen: 4 months to elapse from last tamoxifen dose to pre-dose on-study biopsy.

Exclusion Criteria:

Intervention with any of the following:

• Any cytotoxic chemotherapy, investigational agents or other anti-cancer drugs for the treatment of breast cancer from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment.
• Use of systemic oestrogen-containing hormone replacement therapy within 6 months prior to the first dose of study treatment.
• Medications or herbal supplements known to be strong inhibitors/inducers of cytochrome P450 3A4/5 and sensitive CYP2B6 substrates, and drugs which are substrates of CYP2C9 and/or CYP2C19 which have a narrow therapeutic index or inability to stop use within the washout period prior to receiving the first dose of study treatment.
• Drugs that are known to prolong QT and have a known risk of torsades de pointes.
• The following cardiovascular criteria: QTcF >470 ms, resting heart rate <45 bpm, clinically significant abnormalities of resting electrocardiogram, uncontrolled hypertension, symptomatic hypotension, factors that increase the risk for QTc prolongation, left ventricular ejection fraction <50%.
• Radiotherapy with a limited field of radiation for palliation within 1 week of dosing, or to > 30% of bone marrow or a wide field within 4 weeks of dosing.
• Major surgical procedure or significant traumatic injury.
• Presence of life-threatening metastatic visceral disease or uncontrolled central nervous system metastatic disease.
• Inadequate bone marrow reserve or organ function.
• Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9833.
• History of hypersensitivity to active or inactive excipients of AZD9833 or fulvestrant.
• Previous randomisation in the present study.
• Women of childbearing potential.