AZD9833 + CDK4/6 Inhibitor for Breast Cancer

(SERENA-6 Trial)

Not currently recruiting at 298 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must be taking: CDK4/6 inhibitors, AIs

Must not be taking: Hormone replacements, SERDs

Disqualifiers: CNS metastases, Severe heart disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Until disease progression or participant withdrawal

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for individuals with advanced breast cancer that cannot be treated with surgery or radiation. Researchers aim to determine if the drug AZD9833, combined with a CDK4/6 inhibitor (a type of cancer medication), outperforms current treatments for those with HR-positive (hormone receptor-positive) and HER2-negative breast cancer, especially if their cancer has an ESR1 mutation. The trial suits those already using a CDK4/6 inhibitor and aromatase inhibitors (such as anastrozole or letrozole) without any worsening of their condition. Participants should be able to perform daily activities despite their cancer. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial requires that you continue taking your current CDK4/6 inhibitor and aromatase inhibitor (AI) medications, as participants must have been on these treatments for at least 6 months to join.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the treatment AZD9833, when combined with a CDK4/6 inhibitor, appears safe. One study found that combining AZD9833 with palbociclib was well-received by patients, who experienced manageable side effects. Another study with AZD9833 and abemaciclib found that patients handled the treatment safely over an average of 7.7 months. Similarly, using AZD9833 with ribociclib showed positive safety results in patients with advanced breast cancer. Overall, these studies suggest that AZD9833 combinations are generally well-tolerated. However, the current trial, being in a later stage, aims to provide more detailed safety information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about AZD9833 combined with CDK4/6 inhibitors like palbociclib, abemaciclib, or ribociclib because it offers a novel approach for treating breast cancer. Unlike traditional hormone therapies like anastrozole or letrozole, AZD9833 is a selective estrogen receptor degrader (SERD), which not only blocks the estrogen receptor but also leads to its degradation. This dual action could potentially overcome resistance seen with other hormone therapies, offering improved effectiveness in hormone receptor-positive breast cancer. Additionally, combining AZD9833 with CDK4/6 inhibitors, which already help control cancer cell growth, might enhance treatment outcomes and extend progression-free survival for patients.

What evidence suggests that this trial's treatments could be effective for metastatic breast cancer?

This trial will compare the effectiveness of AZD9833 combined with CDK4/6 inhibitors such as palbociclib, abemaciclib, or ribociclib against standard treatments for certain breast cancers. Research has shown that AZD9833, when used with these inhibitors, might outperform standard treatments for some breast cancers. Early results suggest that AZD9833 combined with these inhibitors can lead to better outcomes for patients with hormone receptor-positive, HER2-negative metastatic breast cancer, particularly those with the ESR1 mutation. Previous studies found that abemaciclib and ribociclib, in particular, can help patients go longer without their cancer worsening compared to palbociclib. The goal of combining AZD9833 with these potent CDK4/6 inhibitors is to enhance treatment effectiveness for this type of cancer. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults with advanced HR-positive, HER2-negative breast cancer that can't be treated with surgery or radiation. Participants must have been on CDK4/6 inhibitors and aromatase inhibitors for at least 6 months without worsening of their cancer and have a detectable ESR1 mutation. They should be able to perform daily activities and not have severe heart disease, certain CNS metastases, uncontrolled diseases, or previous treatment with AZD9833.

Inclusion Criteria

My cancer did not worsen after treatment with an AI and CDK4/6 inhibitor.

My advanced breast cancer cannot be treated with surgery or radiation.

I am currently being treated with AI and CDK4/6 inhibitors for advanced disease.

Exclusion Criteria

My cancer has spread to vital organs and poses an immediate risk to my life.

I do not have active brain metastases or related conditions.

I have lasting side effects from CDK4/6 inhibitor or AI treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AZD9833 or an AI in combination with a CDK4/6 inhibitor over 28-day cycles

Until disease progression or participant withdrawal

Regular visits for health checks, blood samples, and tumor scans

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 2 years

Long-term follow-up

Participants are monitored for overall survival and progression-free survival

Approximately 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• AZD9833
• Palbociclib

Trial Overview The study tests the effectiveness of AZD9833 combined with a CDK4/6 inhibitor (palbociclib, abemaciclib or ribociclib) against standard treatments using an aromatase inhibitor (anastrozole or letrozole) plus a CDK4/6 inhibitor in patients whose breast cancer has an ESR1 mutation.

How Is the Trial Designed?

Group I: AZD9833 + palbociclib, abemaciclib or ribociclib Experimental Treatment 7 Interventions

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), abemaciclib (PO, twice daily, 150,100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (PO, once daily) or letrozole placebo (PO, once daily)

Group II: Anastrozole or letrozole + palbociclib, abemaciclib or ribociclib Active Control 7 Interventions

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), abemaciclib (PO, twice daily, 150, 100 or 50 mg) or ribociclib (To Be Determined, PO, once daily for 21 consecutive days followed by 7 days off treatment) + AZD9833 placebo (PO, once daily)

Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

Palbociclib has been approved for treating hormone receptor-positive advanced breast cancer due to its ability to improve progression-free survival when used with endocrine agents, highlighting its efficacy in this patient population.

Abemaciclib and ribociclib, two other CDK4/6 inhibitors, are in late-stage clinical development and may offer different benefits, such as single-agent activity and central nervous system penetration, which could influence treatment choices and patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. Barroso-Sousa, R., Shapiro, GI., Tolaney, SM.[2020]

The addition of CDK4 and 6 inhibitors (like abemaciclib, palbociclib, or ribociclib) to endocrine therapy significantly improves progression-free survival and response rates in patients with HR+ and HER2- metastatic breast cancer, establishing these inhibitors as a new standard of care.

Exploratory analyses suggest that abemaciclib may be particularly beneficial for women with poor prognosis indicators, although further confirmation is needed for these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer. Martin, M., Garcia-Saenz, JA., Manso, L., et al.[2021]

Abemaciclib, a CDK4/6 inhibitor, significantly reduced levels of Ki67, a protein that indicates cell proliferation, in women with hormone receptor-positive, HER2-negative breast cancer.

The results from the phase II neoMONARCH trial suggest that using abemaciclib, either alone or with endocrine therapy, may be an effective neoadjuvant treatment for early-stage breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib Shows Promise for Early Breast Cancer. [2019]

Abemaciclib, when added to standard endocrine therapy, significantly reduces the risk of invasive disease and distant recurrence in high-risk early breast cancer patients, showing a 30% reduction in risk and improved invasive disease-free survival at 15.5 months and 27 months.

Over 80% of patients experienced diarrhea as a side effect, highlighting the need for monitoring and management of this adverse effect during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer. Raheem, F., Ofori, H., Simpson, L., et al.[2022]

CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib are effective treatments for hormone receptor-positive advanced breast cancer, with ribociclib and abemaciclib showing improved overall survival in clinical trials.

Abemaciclib is the only CDK4/6 inhibitor that has demonstrated sustained improvement in invasive disease-free survival in early breast cancer, highlighting differences in efficacy among these drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors: existing and emerging differences. Johnston, S., Emde, A., Barrios, C., et al.[2023]

In a phase III trial, abemaciclib combined with endocrine therapy significantly reduced the risk of breast cancer recurrence in patients with hormone receptor positive (HR+), HER2-negative, node-positive early breast cancer, regardless of prior chemotherapy or tumor characteristics.

The combination treatment was generally well-tolerated, with manageable side effects such as diarrhea, infections, and neutropenia, making it a valuable option for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. Fung, S., Blair, HA.[2023]

In a phase I trial involving 26 Chinese patients with advanced cancers, abemaciclib was found to be well tolerated, with most treatment-emergent adverse events being mild (Grade 1 or 2), although 32% experienced neutropenia and 24% experienced thrombocytopenia.

The pharmacokinetic profile showed slow absorption and a half-life of about 24 hours, with a disease control rate of 68%, indicating preliminary antitumor activity, although no complete responses were observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase I Study of Abemaciclib in Chinese Patients with Advanced and/or Metastatic Cancers. Zhang, J., Yang, N., Ji, D., et al.[2021]

Abemaciclib is a potent oral CDK4 and CDK6 inhibitor that effectively treats hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, showing response rates between 19.7% and 59% in major clinical trials.

The drug is well-tolerated, with common side effects including diarrhea and neutropenia, and it offers the advantage of continuous dosing and potential use as a monotherapy, making it a promising option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: The Newest CDK4/6 Inhibitor for the Treatment of Breast Cancer. Palumbo, A., Lau, G., Saraceni, M.[2020]

In a study of 396 female patients with hormone receptor positive, HER2-negative metastatic breast cancer receiving CDK4 and 6 inhibitors, the most common adverse events were neutropenia, diarrhea, and fatigue, with varying frequencies depending on the specific drug used.

The study found that while the overall incidence of adverse events was lower than in clinical trials, the rates of dose reductions and treatment holds due to these events were higher, suggesting that clinicians may be actively managing side effects to help patients continue their therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting. Price, GL., Sudharshan, L., Ryan, P., et al.[2022]

In a retrospective case series of 11 metastatic breast cancer patients who progressed on previous CDK4/6 inhibitors, abemaciclib showed a median progression-free survival of 8 months, indicating its potential efficacy as a subsequent treatment option.

The safety profile of abemaciclib was favorable, with common side effects like diarrhea and asthenia reported, but none were severe (grade ≥ 3), suggesting it is a safe option for patients previously treated with palbociclib or ribociclib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Experience with Abemaciclib in Patients Previously Treated with Another CDK 4/6 Inhibitor in a Tertiary Hospital: A Case Series Study. de Luna Aguilar, AM., Fuentes, JDB., Ortega Anselmi, J., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03616587

NCT03616587 | Study of AZD9833 Alone or in ... This is a multicentre dose escalation and expansion, first-in-human study designed to evaluate the safety and tolerability of AZD9833, alone (Parts A and B) ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11931418/

Real-world effectiveness of CDK4/6i in first-line treatment of ... A systematic review of health-related quality of life outcomes in patients with advanced breast cancer treated with palbociclib. J Comp Eff ...

3. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D8535C00001

Early Breast Cancer (CAMBRIA-2) This is a Phase III open-label study to assess if camizestrant improves outcomes compared to standard adjuvant endocrine therapy for patients with ER+/HER2- ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04711252

NCT04711252 | A Comparative Study of AZD9833 Plus ... The goal of the study is to demonstrate superiority of AZD9833 over anastrozole in the context of combination with palbociclib in first line setting.

5. targetedonc.com targetedonc.com/view/real-world-study-shows-differences-in-efficacy-among-cdk4-6-inhibitors-for-advanced-breast-cancer

Real-World Study Shows Differences in Efficacy Among ... The PALMARES-2 trial reveals that abemaciclib and ribociclib outperform palbociclib in real-world progression-free survival for advanced breast cancer patients.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03616587

NCT03616587 | Study of AZD9833 Alone or in ... This is a multicentre dose escalation and expansion, first-in-human study designed to evaluate the safety and tolerability of AZD9833, alone (Parts A and B) ...

7. aacrjournals.org aacrjournals.org/cancerres/article/83/5_Supplement/P3-07-28/718295/Abstract-P3-07-28-SERENA-1-Updated-analyses-from-a

Abstract P3-07-28: SERENA-1: Updated analyses from a ... Results: As of 1st June 2022, 24 patients had received camizestrant in combination with abemaciclib with a median 7.7 month follow up.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10690091/

The Next-Generation Oral Selective Estrogen Receptor ... Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi.

9. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03616587/

Clinical Trial: NCT03616587 This is a multicentre dose escalation and expansion, first-in-human study designed to evaluate the safety and tolerability of AZD9833, alone (Parts A and B) or ...