Phase III Study to Assess AZD9833+ CDK4/6 Inhibitor in HR+/HER2-MBC With Detectable ESR1m Before Progression (SERENA-6)

ER-Positive HER2-Negative Breast Cancer Clinical Trial

— SERENA-6  

Official title:

A Phase III, Double-blind, Randomised Study to Assess Switching to AZD9833 (a Next Generation, Oral SERD) + CDK4/6 Inhibitor vs Continuing Aromatase Inhibitor (Letrozole or Anastrozole)+ CDK4/6 Inhibitor in HR+/HER2-MBC Patients With Detectable ESR1Mutation Without Disease Progression During 1L Treatment With Aromatase Inhibitor+ CDK4/6 Inhibitor- A ctDNA Guided Early Switch Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04964934
• Other study ID #: D8534C00001
• Secondary ID: 2023-503990-39-0
• Status: Recruiting
• Phase: Phase 3
• Start date: June 30, 2021
• Est. completion date: November 26, 2027

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study is intended to show superiority of AZD9833 in combination with CDK4/6 inhibitor (palbociclib, abemaciclib or ribociclib) versus aromatase inhibitors (anastrozole or letrozole) in combination with CDK4/6 inhibitor in patients with hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) metastatic breast cancer with detectable ESR1 mutation.

Description:

Breast cancer is the most common type of cancer among women. In people with breast cancer, the body is not able to control the growth of some cells. These extra cells can form tumors in the breast. When tumor cells move to different parts of the body this is called advanced cancer. Researchers are looking for better ways to treat advanced breast cancer. This trial will look at six drugs: palbociclib, abemaciclib, ribociclib, letrozole, anastrozole, and AZD9833. AZD9833 is the trial drug, and is the only drug not yet approved for use. Palbociclib, abemaciclib and ribociclib work in the same way and are a type of cancer drug called a CDK4/6 inhibitor. Letrozole and anastrozole work in the same way and are both a type of cancer drug called an aromatase inhibitor (AI). CDK4/6 inhibitors and AIs work together to block the tumor's ability to grow. These drugs have been approved for combined use in people with advanced breast cancer that is HR-positive and HER2-negative. But if people get mutations in the ESR1 gene, it can make the AI and CDK4/6 inhibitor treatment work less well. The trial drug, AZD9833, is designed to work with a CDK4/6 inhibitor in the same way that an AI does. Researchers think that AZD9833 might work better with a CDK4/6 inhibitor than an AI does in people who get mutations in their ESR1 gene. Participants in this trial will have already been receiving one of the following combinations of a CDK4/6 inhibitor and an AI: - palbociclib + anastrozole - palbociclib + letrozole - abemaciclib + anastrozole - abemaciclib + letrozole - ribociclib + anastrozole - ribociclib + letrozole During the trial, participants will remain on the same CDK4/6 inhibitor that they were taking before the trial. In this trial, the researchers want to find out how well switching a participant with an ESR1 gene mutation from an AI (letrozole or anastrozole) to AZD9833 works in the treatment of advanced breast cancer that is HR-positive and HER2-negative. The researchers will look at which trial treatment helps the participants live longer with the cancer before it gets worse. The researchers also want to know more about how safe AZD9833 is. The trial participants will be split into 2 groups: - Participants in Group A will receive AZD9833, a CDK4/6 inhibitor, and a placebo - Participants in Group B will receive an AI, a CDK4/6 inhibitor, and a placebo A placebo looks like a treatment but does not have any medicine in it. A computer program will be used to randomly choose the treatments each participant gets. This helps make sure the groups are chosen fairly. Researchers do this so that comparing the results of each treatment will be as accurate as possible. The participants will take their trial treatments over 28-day cycles, with a placebo and either AZD9833 or an AI taken once daily by mouth for all 28 days. If the participant is taking abemaciclib, they will take it twice daily by mouth for all 28 days. If the participant is taking palbociclib or ribociclib, they will take it once daily by mouth for 21 days and then stop taking it for the final 7 days of the cycle. The participant will then repeat the 28-day cycle receiving the trial treatment in the same way for as long as they are in the trial. Participants will visit their trial site regularly throughout the trial. At these visits, the trial doctors will check the health of the participants. They will also take blood samples and do scans of the participants' tumors. Participants will take their trial treatment until their cancer gets worse or they decide to leave the trial. *Palbociclib and Abemacliclib cohorts are currently ongoing. Ribociclib cohort will be open pending on availability of the data.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: November 26, 2027
• Est. primary completion date: April 25, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

INCLUSION CRITERIA:

INFORMATION FOR TRIAL PARTICIPANTS - Participants can join the trial if they:

• Have advanced breast cancer that is not able to be treated with surgery or radiation;
• Have an ESR1 mutation in their cancer;
• Have breast cancer that is HR-positive and HER2-negative;
• Are currently being treated with a CDK4/6 inhibitor and an AI and have been taking these drugs for at least 6 months;
• Have not had their cancer get worse after taking an AI and CDK4/6 inhibitor;
• Are able to do their daily activities;
• Are at least 18.

Full list of inclusion criteria:

• Proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent;
• Documentation of histologically confirmed diagnosis of estrogen receptor positive (ER+) /HER2- breast cancer based on local laboratory results;
• Currently on AI (letrozole or anastrozole) + CDK4/6 inhibitor (palbociclib, abemaciclib or ribociclib) ± LHRH as the initial endocrine based treatment for advanced disease;
• Eastern Cooperative Oncology Group performance status of 0 or 1;
• ESR1m detected by central testing of ctDNA;
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
• Adequate organ and marrow function. EXCLUSION CRITERIA:

INFORMATION FOR TRIAL PARTICIPANTS - Participants cannot join the trial if they:

• Had certain types of tumors in the past that may come back;
• Are currently taking any other treatments for their cancer or other conditions including hormone replacements, medications, or supplements that could interfere with the trial treatment;
• Have or have had any major health problem, infection, or recent surgery that could make it difficult or dangerous to participate in this trial.

Full list of exclusion criteria:

• Advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term;
• Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease;
• Any evidence of severe or uncontrolled systemic diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol;
• Patient with known or family history of severe heart disease;
• Previous treatment with AZD9833, investigational SERDs or fulvestrant;
• Currently pregnant (confirmed with positive pregnancy test) or breastfeeding;
• Persistent non-haematological toxicities (CTCAE Grade > 2) caused by CDK4/6 inhibitor and/or AI treatment.

Related Conditions & MeSH terms

• ER-Positive HER2-Negative Breast Cancer

Intervention

Drug:
• AZD9833
Dosage formulation: AZD9833 tablets will be administered orally
• AZD9833 Placebo
Dosage formulation: AZD9833 placebo tablets will be administrated orally.
• Anastrozole
Dosage formulation: anastrozole tablets will be administered orally.
• Anastrozole placebo
Dosage formulation: anastrozole placebo tablets will be administrated orally.
• Letrozole
Dosage formulation: letrozole tablets will be administered orally.
• Letrozole placebo
Dosage formulation: letrozole placebo tablets will be administered orally.
• Palbociclib
Dosage formulation: palbociclib tablets/capsules will be administered orally
• Abemaciclib
Dosage formulation: abemaciclib tablets will be administered orally
• Luteinizing hormone-releasing hormone (LHRH) agonist
Men (when medically applicable) and pre- or peri-menopausal women are required to receive a monthly LHRH agonist.
• Ribociclib
Dosage formulation: ribociclib tablets will be administered orally

Locations

Country	Name	City	State
Australia	Research Site	Birtinya
Australia	Research Site	Darlinghurst
Australia	Research Site	Subiaco
Austria	Research Site	Graz
Austria	Research Site	Innsbruck
Austria	Research Site	Salzburg
Austria	Research Site	Wien
Austria	Research Site	Wien
Belgium	Research Site	Leuven
Belgium	Research Site	Liège
Belgium	Research Site	Namur
Bulgaria	Research Site	Haskovo
Bulgaria	Research Site	Panagyurishte
Bulgaria	Research Site	Pleven
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Levis	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa
Canada	Research Site	Quebec
Canada	Research Site	Vancouver	British Columbia
France	Research Site	Avignon Cedex 09
France	Research Site	Brest
France	Research Site	Clermont-Ferrand
France	Research Site	Dijon
France	Research Site	Limoges
France	Research Site	Lorient cedex
France	Research Site	Lyon Cedex 08
France	Research Site	Marseille
France	Research Site	Metz-Tessy
France	Research Site	Nimes
France	Research Site	Paris Cedex 5
France	Research Site	Rouen
France	Research Site	Saint Herblain Cedex
France	Research Site	Saint-cloud
France	Research Site	Toulouse
France	Research Site	Tours
France	Research Site	Vandoeuvre les Nancy
France	Research Site	Vantoux
France	Research Site	Villejuif Cedex
Germany	Research Site	Ansbach
Germany	Research Site	Aschaffenburg
Germany	Research Site	Augsburg
Germany	Research Site	Bonn
Germany	Research Site	Chemnitz
Germany	Research Site	Dresden
Germany	Research Site	Erlangen
Germany	Research Site	Essen
Germany	Research Site	Freiburg
Germany	Research Site	Immenstadt
Germany	Research Site	Koblenz
Germany	Research Site	Leipzig
Germany	Research Site	Mannheim
Germany	Research Site	München
Germany	Research Site	Paderborn
Germany	Research Site	Ratingen
Germany	Research Site	Ravensburg
Germany	Research Site	Regensburg
Germany	Research Site	Stade
Germany	Research Site	Tübingen
Germany	Research Site	Ulm
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Miskolc
Hungary	Research Site	Szekszárd
Hungary	Research Site	Szolnok
Hungary	Research Site	Zalaegerszeg
Israel	Research Site	Beer Sheva
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Petah Tikva
Israel	Research Site	Ramat Gan
Italy	Research Site	Bergamo
Italy	Research Site	Bologna
Italy	Research Site	Firenze
Italy	Research Site	Meldola
Italy	Research Site	Milan
Italy	Research Site	Milano
Italy	Research Site	Misterbianco
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Roma
Italy	Research Site	Rozzano
Japan	Research Site	Chiba-shi
Japan	Research Site	Chuo-ku
Japan	Research Site	Hidaka-shi
Japan	Research Site	Hirakata-shi
Japan	Research Site	Kitaadachi-gun
Japan	Research Site	Koto-ku
Japan	Research Site	Kumamoto-shi
Japan	Research Site	Matsuyama-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Niigata-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Ota-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Shinagawa-ku
Japan	Research Site	Shinjuku-ku
Japan	Research Site	Takasaki-shi
Japan	Research Site	Takatsuki-shi
Japan	Research Site	Tsukuba
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Cheonan-si
Korea, Republic of	Research Site	Daegu
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Seongnam-si
Korea, Republic of	Research Site	Seongnam-Si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Norway	Research Site	Drammen
Norway	Research Site	Oslo
Poland	Research Site	Bydgoszcz
Poland	Research Site	Gdynia
Poland	Research Site	Konin
Poland	Research Site	Koszalin
Poland	Research Site	Lódz
Poland	Research Site	Lublin
Poland	Research Site	Olsztyn
Poland	Research Site	Poznan
Poland	Research Site	Rzeszów
Poland	Research Site	Tomaszów Mazowiecki
Poland	Research Site	Warszawa
Portugal	Research Site	Guimarães
Portugal	Research Site	Lisboa
Portugal	Research Site	Lisboa
Portugal	Research Site	Lisboa
Portugal	Research Site	Lisboa
Portugal	Research Site	Loures
Portugal	Research Site	Porto
Portugal	Research Site	Porto
Portugal	Research Site	Porto
Portugal	Research Site	Vila Nova de Gaia
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhny Novgorod
Russian Federation	Research Site	Podolsk
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Sankt-Peterburg
Russian Federation	Research Site	St. Petersburg
Slovakia	Research Site	Banská Bystrica
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Kosice
Slovakia	Research Site	Michalovce
Slovakia	Research Site	Partizanske
Spain	Research Site	Badalona
Spain	Research Site	Barcelona
Spain	Research Site	L'Hospitalet de Llobregat
Spain	Research Site	La Coruna
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Málaga
Spain	Research Site	Murcia
Spain	Research Site	Sant Joan Despi
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
Switzerland	Research Site	Bern
Switzerland	Research Site	Chur
Switzerland	Research Site	Winterthur
Taiwan	Research Site	Kaohsiung city
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei 112
Taiwan	Research Site	Taipei City
Taiwan	Research Site	Taoyuan
Turkey	Research Site	Adana
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Istanbul
Turkey	Research Site	Izmir
Turkey	Research Site	Izmir
Turkey	Research Site	Kadikoy/Istanbul
Turkey	Research Site	Karsiyaka
Turkey	Research Site	Kayseri
United Kingdom	Research Site	Blackpool
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Guildford
United Kingdom	Research Site	Liverpool
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Newport
United Kingdom	Research Site	Nottingham
United Kingdom	Research Site	Portsmouth
United Kingdom	Research Site	Reading
United Kingdom	Research Site	Sheffield
United Kingdom	Research Site	Sutton
United Kingdom	Research Site	Taunton
United States	Research Site	Atlanta	Georgia
United States	Research Site	Atlanta	Georgia
United States	Research Site	Atlanta	Georgia
United States	Research Site	Atlanta	Georgia
United States	Research Site	Baltimore	Maryland
United States	Research Site	Bedford	Texas
United States	Research Site	Billings	Montana
United States	Research Site	Blue Ash	Ohio
United States	Research Site	Boston	Massachusetts
United States	Research Site	Bronx	New York
United States	Research Site	Brooklyn	New York
United States	Research Site	Camden	New Jersey
United States	Research Site	Canton	Ohio
United States	Research Site	Chicago	Illinois
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Clifton	New Jersey
United States	Research Site	Columbus	Ohio
United States	Research Site	Dallas	Texas
United States	Research Site	Denver	Colorado
United States	Research Site	Detroit	Michigan
United States	Research Site	East Syracuse	New York
United States	Research Site	Fairhaven	Massachusetts
United States	Research Site	Fort Lauderdale	Florida
United States	Research Site	Fort Myers	Florida
United States	Research Site	Fort Wayne	Indiana
United States	Research Site	Foxboro	Massachusetts
United States	Research Site	Goldsboro	North Carolina
United States	Research Site	Grand Junction	Colorado
United States	Research Site	Grand Rapids	Michigan
United States	Research Site	Greenville	South Carolina
United States	Research Site	Hot Springs National Park	Arkansas
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Irving	Texas
United States	Research Site	Jacksonville	Florida
United States	Research Site	Jacksonville	Florida
United States	Research Site	Kansas City	Missouri
United States	Research Site	Knoxville	Tennessee
United States	Research Site	Little Rock	Arkansas
United States	Research Site	Lone Tree	Colorado
United States	Research Site	Long Beach	California
United States	Research Site	Longview	Texas
United States	Research Site	Lubbock	Texas
United States	Research Site	Memphis	Tennessee
United States	Research Site	Midlothian	Virginia
United States	Research Site	Milford	Massachusetts
United States	Research Site	Nashville	Tennessee
United States	Research Site	New Hyde Park	New York
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	Norfolk	Virginia
United States	Research Site	Oak Lawn	Illinois
United States	Research Site	Omaha	Nebraska
United States	Research Site	Oxford	Mississippi
United States	Research Site	Park Ridge	Illinois
United States	Research Site	Park Ridge	Illinois
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Phoenix	Arizona
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Portland	Oregon
United States	Research Site	Ridgewood	New Jersey
United States	Research Site	Rochester	Minnesota
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Saint Petersburg	Florida
United States	Research Site	Salt Lake City	Utah
United States	Research Site	San Antonio	Texas
United States	Research Site	San Diego	California
United States	Research Site	Santa Rosa	California
United States	Research Site	Shirley	New York
United States	Research Site	South Weymouth	Massachusetts
United States	Research Site	Stanford	California
United States	Research Site	Tacoma	Washington
United States	Research Site	Waukesha	Wisconsin
United States	Research Site	West Columbia	South Carolina
United States	Research Site	West Palm Beach	Florida
United States	Research Site	York	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Bulgaria,  Canada,  France,  Germany,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Norway,  Poland,  Portugal,  Russian Federation,  Slovakia,  Spain,  Switzerland,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS) assessed by the Investigator as defined by response evaluation criteria in solid tumors (RECIST version 1.1)	PFS is defined as the time from randomization to objective disease progression (as assessed by RECIST 1.1) or death.	From randomization until the earlier of the progression event or death (approximately 2 years)
Secondary	Progression-free survival 2 (PFS2)	PFS2 is defined as the time from the randomisation to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy or death.	From randomization to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy or death (approximately 3.5 years)
Secondary	Overall survival (OS)	The OS is defined as the time from randomization to death due to any cause.	From randomization until the date of death due to any cause (approximately 5 years)
Secondary	Chemotherapy free survival	Time to chemotherapy is defined as the time from randomization until the earlier of the start date of chemotherapy or death due to any cause.	From randomization until the earlier of the start date of chemotherapy or death due to any cause (approximately 5 years)
Secondary	Objective response rate (ORR) assessed by the Investigator as defined by RECIST version 1.1	ORR is defined as the proportion of patients who have a complete response (CR) or partial response (PR), as determined by the investigator at local site per RECIST 1.1.	From randomization until a response or in the absence of a response from randomization up until progression, or the last evaluable assessment in the absence of progression (approximately 5 years)
Secondary	Clinical benefit rate at 24 weeks (CBR24)	CBR at 24 weeks is defined as the percentage of participants who have a complete response (CR) or partial response or who have stable disease (SD) per RECIST 1.1 as assessed by the investigator at local site for At least 23 weeks after randomisation for each patient to allow for an early assessment within the assessment window (1 week window for RECIST assessment)	At least 23 weeks after randomisation for each patient (1 week window for RECIST assessment)
Secondary	Change from baseline in EORTC QLQ-C30 scale scores	Change from baseline in scales scores of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Scale scores range from 0-100. For functioning and global health status/ QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden.	From baseline until second progression (approximately 5 years)
Secondary	Change from baseline in EORTC QLQ-BR23 scale scores	Change from baseline in scales scores of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC QLQ-BR23). Scale scores range from 0-100. For functioning scales, higher scores indicate better functioning. For symptom scales, higher scores indicate greater symptom burden.	From baseline until second progression (approximately 5 years)
Secondary	Plasma concentration of AZD9833 at specified timepoints	To assess the steady state PK of AZD9833 in combination with palbociclib or abemaciclib in all participants who receive at least one dose of AZD9833 per the protocol, for whom there are at least one reportable PK concentration.	on Day 15 for each patient