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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced ER-Positive HER2-Negative Breast Cancer
• Intervention / Treatment: Drug: AZD9833; Drug: Fulvestrant

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brasschaat, Belgium, 2930
    • Research Site
  • Charleroi, Belgium, 6000
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
  • Haine-Saint-Paul, Belgium, 7100
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Libramont-Chevigny, Belgium, 6800
    • Research Site
  • Namur, Belgium, 5000
    • Research Site
• Canada
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Research Site
    • Montreal, Quebec, Canada, H3T 1E2
      • Research Site
    • Montreal, Quebec, Canada, H1T 2M4
      • Research Site
• France
  • Paris, France, 75005
    • Research Site
  • Vandoeuvre les Nancy, France, 54519
    • Research Site
• Georgia
  • Batumi, Georgia, 6000
    • Research Site
  • Tbilisi, Georgia, 0186
    • Research Site
  • Tbilisi, Georgia, '0112
    • Research Site
  • Tbilisi, Georgia, '0159
    • Research Site
  • Tbilisi, Georgia, '0186
    • Research Site
  • Tbilisi, Georgia, 0159
    • Research Site
• Germany
  • Berlin, Germany, 10707
    • Research Site
  • Düsseldorf, Germany, 40225
    • Research Site
  • Essen, Germany, 45136
    • Research Site
• Hungary
  • Budapest, Hungary, 1122
    • Research Site
  • Debrecen, Hungary, 4032
    • Research Site
  • Kaposvár, Hungary, 7400
    • Research Site
  • Kecskemét, Hungary, 6000
    • Research Site
  • Nyíregyháza, Hungary, 4400
    • Research Site
  • Pécs, Hungary, 7624
    • Research Site
  • Szeged, Hungary, 6725
    • Research Site
• Israel
  • Jerusalem, Israel, 91031
    • Research Site
  • Jerusalem, Israel, 9112001
    • Research Site
  • Nahariya, Israel, 22100
    • Research Site
  • Petah Tikva, Israel, 4941492
    • Research Site
• Italy
  • Bologna, Italy, 40138
    • Research Site
  • Catanzaro, Italy, 88100
    • Research Site
  • Meldola, Italy, 47014
    • Research Site
  • Messina, Italy, 98158
    • Research Site
  • Milan, Italy, 20141
    • Research Site
  • Milano, Italy, 20121
    • Research Site
  • Monza, Italy, 20900
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Roma, Italy, 00128
    • Research Site
  • Umbria, Italy, 5100
    • Research Site
• Korea, Republic of
  • Goyang-si, Korea, Republic of, 10408
    • Research Site
  • Incheon, Korea, Republic of, 405-760
    • Research Site
• Poland
  • Bydgoszcz, Poland, 85-796
    • Research Site
  • Piła, Poland, 64-920
    • Research Site
  • Rzeszów, Poland, 35-021
    • Research Site
  • Skorzewo, Poland, 60-185
    • Research Site
  • Warszawa, Poland, 02-781
    • Research Site
  • Łódź, Poland, 93-513
    • Research Site
• Portugal
  • Almada, Portugal, 2805-267
    • Research Site
  • Lisboa, Portugal, 1649-035
    • Research Site
  • Lisboa, Portugal, 1449-005
    • Research Site
  • Lisboa, Portugal, 1400-038
    • Research Site
  • Lisboa, Portugal, 1998-018
    • Research Site
  • Loures, Portugal, 2674-514
    • Research Site
  • Porto, Portugal, 4099-001
    • Research Site
• Russian Federation
  • Kazan, Russian Federation, 420029
    • Research Site
  • Krasnodar, Russian Federation, 350040
    • Research Site
  • Kursk, Russian Federation, 305035
    • Research Site
  • Moscow, Russian Federation, 115478
    • Research Site
  • Moscow, Russian Federation, 123056
    • Research Site
  • Pyatigorsk, Russian Federation, 357502
    • Research Site
  • Ryazan, Russian Federation, 390011
    • Research Site
  • Saint Petersburg, Russian Federation, 197082
    • Research Site
  • Saint-Petersburg, Russian Federation, 197758
    • Research Site
  • Volgograd, Russian Federation, 400138
    • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • Barcelona, Spain, 08190
    • Research Site
  • Madrid, Spain, 28050
    • Research Site
  • Madrid, Spain, 28033
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
  • Zaragoza, Spain, 50009
    • Research Site
• Ukraine
  • Cherkasy, Ukraine, 18009
    • Research Site
  • Chernivtsі, Ukraine, 58013
    • Research Site
  • Dnipro, Ukraine, 49102
    • Research Site
  • Kyiv, Ukraine, 03039
    • Research Site
  • M. Kyiv, Ukraine, 02094
    • Research Site
  • S. Khodosivka, Ukraine, 08173
    • Research Site
  • Uzhhorod, Ukraine, 88000
    • Research Site
• United Kingdom
  • Derby, United Kingdom, DE22 3NE
    • Research Site
  • Leicester, United Kingdom, LE1 5WW
    • Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Research Site
  • California
    • Long Beach, California, United States, 90806
      • Research Site
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Research Site
    • Saint Petersburg, Florida, United States, 33705
      • Research Site
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Research Site
  • Ohio
    • Canton, Ohio, United States, 44710
      • Research Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Research Site
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Wisconsin
    • Eagle River, Wisconsin, United States, 54521
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 128 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Adverse Events	The safety and tolerability of AZD9833 when compared to fulvestrant in women with advanced ER-positive HER2-negative breast cancer was evaluated.	From the date of first dose up to the safety follow-up period (28 days after last dose of AZD9833 and 56 days after last dose of fulvestrant) (up to data cut-off of 29 months)

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2020
• Primary Completion (Actual): August 30, 2022
• Study Completion (Estimated): March 29, 2024

Study Registration Dates

• First Submitted: December 27, 2019
• First Submitted That Met QC Criteria: December 27, 2019
• First Posted (Actual): January 2, 2020

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Metastatic; Fulvestrant; Open-Label; AZD9833; Camizestrant; Oral SERD; Parallel-Group; ER-Positive HER2-Negative Breast Cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant
• Other Study ID Numbers: D8530C00002; 2019-003706-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No