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

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ClinicalTrials.gov Identifier: NCT04964934
Recruitment Status : Recruiting
First Posted : July 16, 2021
Last Update Posted : November 18, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
The study is intended to show superiority of AZD9833 in combination with CDK4/6 inhibitor (palbociclib or abemaciclib) 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

Condition or disease Intervention/treatment Phase
ER-Positive HER2-Negative Breast Cancer Drug: AZD9833 Drug: AZD9833 Placebo Drug: Anastrozole Drug: Anastrozole placebo Drug: Letrozole Drug: Letrozole placebo Drug: Palbociclib Drug: Abemaciclib Drug: Luteinizing hormone-releasing hormone (LHRH) agonist Phase 3

Detailed Description:
A Randomised, Multicentre, Double-Blind, Phase III study will evaluate the safety and efficacy of AZD9833 (next generation oral SERD) in combination with CDK4/6 inhibitor (palbociclib or abemaciclib) versus aromatase inhibitor (anastrozole or letrozole) in combination with CDK4/6 inhibitor for the treatment of patients with HR-positive, HER2- negative metastatic breast cancer with detectable ESR1 Mutation. The goal of the study is to demonstrate superiority of AZD9833 over anastrozole or letrozole in the context of combination with palbociclib or abemaciclib

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 302 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Double-blind, Randomised Study to Assess Switching to AZD9833 (a Next Generation, Oral SERD) + CDK4/6 Inhibitor (Palbociclib or Abemaciclib) 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
Actual Study Start Date : June 30, 2021
Estimated Primary Completion Date : September 28, 2023
Estimated Study Completion Date : June 25, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: AZD9833 + palbociclib or abemaciclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment) or abemaciclib (PO, twice daily, 150,100 or 50 mg) + anastrozole placebo ( PO, once daily) or letrozole placebo ( PO, once daily)
Drug: AZD9833
Dosage formulation: AZD9833 tablets will be administered orally

Drug: Anastrozole placebo
Dosage formulation: anastrozole placebo tablets will be administrated orally.

Drug: Letrozole placebo
Dosage formulation: letrozole placebo tablets will be administered orally.

Drug: Palbociclib
Dosage formulation: palbociclib tablets/capsules will be administered orally

Drug: Abemaciclib
Dosage formulation: abemaciclib tablets will be administered orally

Drug: Luteinizing hormone-releasing hormone (LHRH) agonist
Men (when medically applicable) and pre- or peri-menopausal women are required to receive a monthly LHRH agonist.

Active Comparator: Anastrozole or letrozole + palbociclib or abemaciclib
The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125,100 or 75 mg for 21 consecutive days followed by 7 days off treatment) or abemaciclib (PO, twice daily, 150,100 or 50 mg) + AZD9833 placebo (PO, once daily)
Drug: AZD9833 Placebo
Dosage formulation: AZD9833 placebo tablets will be administrated orally.

Drug: Anastrozole
Dosage formulation: anastrozole tablets will be administered orally.

Drug: Letrozole
Dosage formulation: letrozole tablets will be administered orally.

Drug: Palbociclib
Dosage formulation: palbociclib tablets/capsules will be administered orally

Drug: Abemaciclib
Dosage formulation: abemaciclib tablets will be administered orally

Drug: Luteinizing hormone-releasing hormone (LHRH) agonist
Men (when medically applicable) and pre- or peri-menopausal women are required to receive a monthly LHRH agonist.




Primary Outcome Measures :
  1. Progression-free survival (PFS) assessed by the Investigator as defined by response evaluation criteria in solid tumors (RECIST version 1.1) [ Time Frame: From randomization until the earlier of the progression event or death (approximately 2 years) ]
    PFS is defined as the time from randomization to objective disease progression (as assessed by RECIST 1.1) or death.


Secondary Outcome Measures :
  1. Progression-free survival 2 (PFS2) [ Time Frame: From randomization to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy or death (approximately 3.5 years) ]
    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.

  2. Overall survival (OS) [ Time Frame: From randomization until the date of death due to any cause (approximately 5 years) ]
    The OS is defined as the time from randomization to death due to any cause.

  3. Chemotherapy free survival [ Time Frame: From randomization until the earlier of the start date of chemotherapy or death due to any cause (approximately 5 years) ]
    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.

  4. Objective response rate (ORR) assessed by the Investigator as defined by RECIST version 1.1 [ Time Frame: 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) ]
    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.

  5. Clinical benefit rate at 24 weeks (CBR24) [ Time Frame: At least 23 weeks after randomisation for each patient (1 week window for RECIST assessment) ]
    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)

  6. Change from baseline in EORTC QLQ-C30 scale scores [ Time Frame: From baseline until second progression (approximately 5 years) ]
    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.

  7. Change from baseline in EORTC QLQ-BR23 scale scores [ Time Frame: From baseline until second progression (approximately 5 years) ]
    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.

  8. Plasma concentration of AZD9833 at specified timepoints [ Time Frame: on Day 15 for each patient ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 or abemaciclib) ± LHRH as the initial endocrine based treatment for advanced disease
  • Eastern Cooperative Oncology Group performance status of 0 or 1.
  • ESR1m positive 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:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04964934


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04964934    
Other Study ID Numbers: D8534C00001
First Posted: July 16, 2021    Key Record Dates
Last Update Posted: November 18, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
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 rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified 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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Metastatic
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Physiological Effects of Drugs
Randomised
Multicentre
Double-Blind
Phase III
AZD9833
Next Generation Oral SERD
Anastrozole
Letrozole
Palbociclib
Abemaciclib
Antagonists
Antineoplastic Agents
Estrogen Receptor Antagonists
Hormone Antagonists
camizestrant
ESR1m
Switch Treatment
Endocrine Therapy
Endocrine Resistance
Additional relevant MeSH terms:
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Disease Progression
Disease Attributes
Pathologic Processes
Letrozole
Palbociclib
Anastrozole
Hormones
Prolactin Release-Inhibiting Factors
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Protein Kinase Inhibitors
Antineoplastic Agents, Hormonal