Capivasertib + CDK4/6 Inhibitors + Fulvestrant for Breast Cancer

(CAPItello-292 Trial)

Recruiting at 246 trial locations

Overseen By AstraZeneca Breast Cancer Study Locator Service

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must be taking: CDK4/6 inhibitors, Fulvestrant

Must not be taking: AKT inhibitors, PI3K inhibitors

Disqualifiers: Other malignancy, Radiotherapy, Major surgery, 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

895 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining capivasertib, a new drug, with existing treatments like CDK4/6 inhibitors (such as abemaciclib) and fulvestrant for certain types of breast cancer. It specifically targets hormone receptor-positive and HER2-negative breast cancer that is advanced or has spread and cannot be surgically removed. Participants will receive different combinations of these drugs to determine which works best. Ideal candidates for this trial are those who have experienced breast cancer recurrence or progression despite earlier treatments. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to get a clear answer.

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

A previous study showed that combining Capivasertib with Ribociclib and Fulvestrant led to some side effects. The most common were low white blood cell levels and high blood sugar, with severe cases in 15% to 29% of participants. No treatment-related deaths occurred.

Research on the combination of Capivasertib with Abemaciclib and Fulvestrant found that a rash was the most frequent severe side effect, affecting about 15% of patients, while none in the placebo group experienced this.

When Capivasertib was paired with Palbociclib and Fulvestrant, the combination was tolerable even for patients who had undergone extensive previous treatments. This combination was chosen for its overall safety.

This study is in Phase 3, meaning the treatment has already passed initial safety tests and is now being tested on a larger group to confirm its safety and effectiveness. This phase indicates existing evidence of safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for breast cancer because they combine Capivasertib with CDK4/6 inhibitors and Fulvestrant, offering a potentially powerful approach. While standard treatments often involve CDK4/6 inhibitors like Palbociclib, Ribociclib, or Abemaciclib combined with Fulvestrant, the addition of Capivasertib is a game-changer. Capivasertib is an AKT inhibitor, which targets a different pathway involved in cancer cell growth and survival. This unique mechanism could enhance the effectiveness of existing therapies, providing new hope for advanced breast cancer patients.

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

Previous studies showed that adding capivasertib to fulvestrant reduced the risk of disease progression or death by 40% compared to fulvestrant alone. This finding is promising for patients with hormone receptor-positive, HER2-negative advanced breast cancer. In this trial, participants will receive different combinations of these treatments. One arm will test capivasertib plus ribociclib and fulvestrant, while another will test capivasertib plus abemaciclib and fulvestrant. Another arm will involve capivasertib plus fulvestrant and the investigator's choice of CDK4/6 inhibitor (palbociclib or ribociclib). Research has shown that combining capivasertib with CDK4/6 inhibitors, such as ribociclib, abemaciclib, or palbociclib, can further improve outcomes. These combinations have extended the time patients live without their cancer worsening. Overall, evidence suggests that these treatment combinations could effectively manage advanced breast cancer. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic HR+/HER2- breast cancer who have previously tolerated certain drugs (palbociclib, ribociclib, abemaciclib) and are eligible for fulvestrant therapy. They must have had a recurrence or progression of cancer after hormone treatment. Exclusions include brain metastases not stable off steroids, significant prior toxicities from treatments, recent radiotherapy, previous AKT/PI3K/mTOR inhibitors use in the metastatic setting, other primary malignancy within 2 years except if low risk of recurrence.

Inclusion Criteria

Previous treatment with an ET (tamoxifen, AI, or oral SERD) as a single agent or in combination, with radiological evidence of breast cancer recurrence or progression while on, or within 12 months of, completing a (neo)adjuvant ET regimen (only for phase III).

Adult females (pre-/peri-/ and post-menopausal), and adult males.

Histologically confirmed HR+/ HER2- breast cancer determined from the most recent tumour sample (primary or metastatic) per the American Society of Clinical Oncology and College of American Pathologists guideline. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor.

Exclusion Criteria

I have lasting side effects from cancer treatment, but they won't get worse with this study's treatment.

I have not had major surgery or significant injury in the last 4 weeks.

I have not had radiotherapy in the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ib Dose Finding

Initial dose finding to determine the recommended Phase III doses (RP3D) of the triplet combinations

Up to approximately 36 months

Phase III Treatment

Evaluation of efficacy, safety, and added benefit of capivasertib combined with CDK4/6i and fulvestrant

Up to approximately 69 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 69 months

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• Capivasertib
• Fulvestrant
• Ribociclib

Trial Overview The study tests Capivasertib combined with CDK4/6 inhibitors (Palbociclib/Ribociclib/Abemaciclib) and Fulvestrant against just CDK4/6 inhibitors and Fulvestrant in patients with specific breast cancer types. It's an open-label trial where participants know what treatment they're getting; it randomly assigns them to either the test group or control group.

How Is the Trial Designed?

Group I: Capivasertib Plus Ribociclib and Fulvestrant Experimental Treatment 1 Intervention

Capivasertib Plus Ribociclib and Fulvestrant (Ph 1b)

Group II: Capivasertib Plus Palbociclib and Fulvestrant Experimental Treatment 3 Interventions

Capivasertib Plus Palbociclib and Fulvestrant (Ph 1b)

Group III: Capivasertib Plus Fulvestrant and Investigator's choice of CDK4/6i (palbociclib or ribociclib) Experimental Treatment 1 Intervention

Capivasertib Plus Fulvestrant and Investigator's choice of CDK4/6i (palbociclib or ribociclib) (Ph III)

Group IV: Capivasertib Plus Abemaciclib and Fulvestrant Experimental Treatment 1 Intervention

Capivasertib Plus Abemaciclib and Fulvestrant (Ph 1b)

Group V: Fulvestrant and Investigator's choice of CDK4/6i (palbociclib or ribociclib) Active Control 1 Intervention

Fulvestrant and investigator's choice of CDK4/6i (palbociclib or ribociclib) (Ph III)

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

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]

Interim results from the MONARCH3 study show that abemaciclib, a CDK4/6 inhibitor, is an effective first-line treatment for advanced ER-positive, HER2-negative breast cancer.

Patients receiving abemaciclib in combination with letrozole experienced significantly improved progression-free survival compared to those receiving a placebo with endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]

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]

In the MONARCH 2 study involving 669 women with advanced breast cancer, the combination of abemaciclib and fulvestrant significantly improved progression-free survival (PFS) to a median of 16.4 months compared to 9.3 months with fulvestrant alone.

The combination therapy also achieved a higher objective response rate (ORR) of 48.1% versus 21.3% in the control group, while maintaining a tolerable safety profile, with common side effects including diarrhea and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. Sledge, GW., Toi, M., Neven, P., et al.[2022]

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]

Oral CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib significantly improve progression-free survival by 40-45% when combined with endocrine therapy in hormone-responsive HER2-negative advanced breast cancer, particularly in post-menopausal women.

These inhibitors have varying toxicity profiles and monitoring requirements, and ongoing clinical trials are exploring their use in other breast cancer subtypes and in combination with other therapies to overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of CDK4/6 Inhibitors in Breast Cancer. Murphy, CG.[2020]

A total of 1611 individual case safety reports were analyzed, revealing that palbociclib and ribociclib were associated with serious adverse drug reactions (ADRs) like leukopenia and thrombocytopenia, although most patients recovered from these conditions.

In contrast, abemaciclib was linked to mostly non-serious ADRs, indicating a potentially better safety profile, especially when combined with treatments like fulvestrant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematological Events Potentially Associated with CDK4/6 Inhibitors: An Analysis from the European Spontaneous Adverse Event Reporting System. Martins, V., Jesus, M., Pereira, L., et al.[2023]

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]

CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) significantly improve progression-free survival in patients with hormone receptor-positive HER2-negative metastatic breast cancer when used alongside endocrine therapy, with a consistent hazard ratio of around 0.5 across phase III trials.

These treatments are generally well tolerated, with manageable side effects; however, abemaciclib is associated with a higher incidence of diarrhea, while palbociclib and ribociclib are more likely to cause hematological toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibitors Expand the Therapeutic Options in Breast Cancer: Palbociclib, Ribociclib and Abemaciclib. Eggersmann, TK., Degenhardt, T., Gluz, O., et al.[2019]

Abemaciclib is a selective CDK4 & 6 inhibitor that has shown superior potency in inhibiting breast cancer cell proliferation compared to other similar drugs, making it a promising treatment for hormone receptor-positive advanced breast cancer.

In preclinical studies, abemaciclib demonstrated a favorable safety profile, causing less impact on myeloid maturation in bone marrow progenitor cells compared to other CDK4 & 6 inhibitors, which supports its use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuous treatment with abemaciclib leads to sustained and efficient inhibition of breast cancer cell proliferation. Torres-Guzmán, R., Ganado, MP., Mur, C., et al.[2022]

The study reviews the efficacy of three FDA-approved CDK4/6 inhibitors (Palbociclib, Ribociclib, and Abemaciclib) in treating advanced and metastatic hormone receptor-positive breast cancer, highlighting their potential to overcome endocrine resistance.

While these inhibitors show promise in HR+/HER2- breast cancer, the research aims to identify biomarkers that could predict their effectiveness in other breast cancer types, suggesting a need for tailored treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Latest Overview of the Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: The Past, the Present and the Future. Chen, X., Xu, D., Li, X., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04862663

NCT04862663 | Capivasertib + CDK4/6i + Fulvestrant for ... The Phase III part of the study will evaluate the efficacy, safety and the degree of added benefit of the triplet combinations of capivasertib and fulvestrant ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7052734/

Fulvestrant plus capivasertib versus placebo after relapse or ... In the phase 2 BEECH trial, capivasertib did not enhance the efficacy of paclitaxel in oestrogen receptor-positive advanced breast cancer, although endocrine ...

3. onclive.com onclive.com/view/examining-the-evolution-of-treatment-with-cdk4-6-inhibitors-in-metastatic-breast-cancer

Examining the Evolution of Treatment With Targeted ... Anne Favret, MD discusses the evolution of treatment with endocrine-based combination therapies in HR-positive/HER2-negative metastatic breast cancer.

4. targetedonc.com targetedonc.com/view/capivasertib-fulvestrant-extends-pfs-with-limited-toxicity-in-ar-defiant-hr-her2--advanced-breast-cancer

Capivasertib/Fulvestrant Extends PFS With Limited Toxicity ... Treatment with the combination of capivasertib and fulvestrant achieved an improved progression-free survival (PFS) compared with placebo.

5. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2023/capivasertib-in-combination-with-faslodex-fulvestrant-granted-priority-review-in-the-us-for-patients-with-advanced-hr-positive-breast-cancer-06122023.html

Capivasertib in combination with FASLODEX® (fulvestrant) ... Capivasertib in combination with FASLODEX demonstrated a 40% reduction in the risk of disease progression or death versus placebo plus FASLODEX in the overall ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa2214131

Capivasertib in Hormone Receptor–Positive Advanced ... In the overall population, the median progression-free survival was 7.2 months in the capivasertib–fulvestrant group, as compared with 3.6 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12317260/

Capivasertib/Fulvestrant in patients with HR+, HER2-low or ... This data suggests that the Capivasertib/Fulvestrant combination is predominantly beneficial to PI3K/AKT/PTEN altered breast cancer tumours. ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-02086

Abemaciclib Plus Fulvestrant in Advanced Breast Cancer ... Abemaciclib combined with fulvestrant demonstrated efficacy for patients with ABC with progression-free survival (PFS) hazard ratio = 0.73 (95% ...

9. nature.com nature.com/articles/s41467-025-59210-6

Capivasertib plus fulvestrant in patients with HR-positive/ ... The most frequently reported AEs of grade ≥ 3 in the capivasertib–fulvestrant group were rash (15.5% versus 0% in the placebo–fulvestrant group) ...

10. jmcp.org jmcp.org/doi/10.18553/jmcp.2025.31.9.900

Capivasertib cost-effectiveness in treating advanced breast ... This study found that adding capivasertib to fulvestrant is not cost-effective compared with fulvestrant alone for patients with advanced breast ...