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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced ER-Positive HER2-Negative Breast Cancer

Intervention / Treatment
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* Drug: AZD9833
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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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: Recurrence or progression on at least one line of endocrine therapy No more than 1 line of endocrine therapy for advanced disease No more than 1 line of chemotherapy for advanced disease Prior treatment with CDK4/6 inhibitors is permitted 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD9833 Dose A<br>The patients will receive AZD9833 (Dose A). | Drug: AZD9833<br>* Dosage formulation: AZD9833 tablets will be administered orally.<br>|
| Experimental: AZD9833 Dose B<br>The patients will receive AZD9833 (Dose B). | Drug: AZD9833<br>* Dosage formulation: AZD9833 tablets will be administered orally.<br>|
| Experimental: AZD9833 Dose C<br>The patients will receive AZD9833 (Dose C). | Drug: AZD9833<br>* Dosage formulation: AZD9833 tablets will be administered orally.<br>|
| Active Comparator: Fulvestrant 500 mg<br>The patients will receive Fulvestrant (500 mg). | Drug: Fulvestrant<br>* Dosage formulation: Fulvestrant will be administered via intramuscular (IM) injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was assessed by the Investigator as defined by response evaluation criteria in solid tumors (RECIST) version 1.1. PFS was defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or received another anti-cancer therapy prior to progression. Disease progression was defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. Data from the 300mg arm should be interpreted with caution as recruitment to the 300mg arm was stopped early at 20 patients randomised and therefore the 300mg data is highly variable. | From date of randomisation to date of objective disease progression (or last evaluable assessment in the absence of progression) or death (up to data cut-off of 29 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was assessed by the Investigator as defined by RECIST version 1.1. The ORR was defined as investigator assessed Complete Response or Partial Response prior to progression in patients with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Adjusted response rate was presented in this analysis. Data from the 300mg arm should be interpreted with caution as recruitment to the 300mg arm was stopped early at 20 patients randomised and therefore the 300mg data is highly variable. | From screening until disease progression (up to data cut-off of 29 months) | 
| Duration of Response (DoR) | DoR was assessed by the Investigator as defined by RECIST version 1.1. The DoR was defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. | From screening until disease progression or last evaluable assessment in the absence of progression (up to data cut-off of 29 months) | 
| Percentage Change in Tumour Size at 16 Weeks | The percentage change in tumour size at 16 weeks was obtained for each patient, based on RECIST measurements taken at baseline and at 16 weeks. Tumour size is the sum of the longest diameters of the target lesions (TLs). Percentage change in the sum of longest TLs diameters at 16 weeks was measured. | At Week 16 | 
| Overall Survival (OS) | The OS was defined as the time from randomisation to death due to any cause. | From the date of randomisation until death (up to data cut-off of 29 months) | 
| Clinical Benefit Rate at 24 Weeks (CBR24) | Clinical benefit rate was defined as patients with best objective response of complete response or partial response in the first 25 weeks or who have stable disease for at least 23 weeks after randomization. Adjusted response rate was presented in this analysis. Data from the 300mg arm should be interpreted with caution as recruitment to the 300mg arm was stopped early at 20 patients randomised and therefore the 300mg data is highly variable. | At Week 24 | 
| Plasma Concentrations of AZD9833 | The plasma concentrations of AZD9833 at steady state were evaluated. | Cycle 1 Day 15 (pre-dose), Cycle 1 Day 15 (2h), Cycle 1 Day 15 (4h) and Cycle 2 Day 1 (pre-dose), (each cycle is 28 days in length) | 
| Percent Change From Baseline in ER and PgR Expression and Ki67 Labelling Index | The pharmacodynamics of AZD9833 and fulvestrant in a subgroup of patients. | From baseline to Cycle 2 Day 1 (each cycle is 28 days in length) | 
| Changes From Baseline in Health Related Quality of Life (HRQoL) | To evaluate the effect of AZD9833 and fulvestrant on the patients' health-related quality of life, as assessed by patient completed HRQoL questionnaires. | From Day 1 until end of treatment and safety follow up (up to data cut-off of 29 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open-Label, Parallel-Group, Fulvestrant, ER-Positive HER2-Negative Breast Cancer, Metastatic, AZD9833, Oral SERD, Camizestrant