Capivasertib + CDK4/6 Inhibitors + Fulvestrant for Breast Cancer

(CAPItello-292 Trial)

Recruiting at 217 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

Trial Summary

What is the purpose of this trial?

A Phase Ib/III Open-label, Randomised Study of Capivasertib plus CDK4/6 Inhibitors and Fulvestrant versus CDK4/6 Inhibitors and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer (CAPItello-292)

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.

What evidence supports the effectiveness of the drug combination Capivasertib + CDK4/6 Inhibitors + Fulvestrant for breast cancer?

Research shows that adding CDK4/6 inhibitors like abemaciclib to endocrine therapy, such as fulvestrant, significantly improves progression-free survival (the time during which the cancer does not get worse) in patients with advanced hormone receptor-positive, HER2-negative breast cancer. This combination has become a standard treatment option, offering better control of the disease compared to endocrine therapy alone. ^{1 2 3 4 5}

Is the combination of Capivasertib, CDK4/6 inhibitors, and Fulvestrant safe for breast cancer treatment?

The combination of Abemaciclib (a CDK4/6 inhibitor) and Fulvestrant has been studied in breast cancer patients and is generally considered safe, with common side effects including diarrhea and infections. Most adverse events were manageable, and serious cases were rare. Safety data for Capivasertib in this combination is not specifically mentioned, but Abemaciclib and Fulvestrant have shown a tolerable safety profile in clinical trials. ^{2 6 7 8 9}

What makes the drug combination of Capivasertib, CDK4/6 inhibitors, and Fulvestrant unique for breast cancer treatment?

This drug combination is unique because it combines CDK4/6 inhibitors like Abemaciclib and Ribociclib, which help stop cancer cell growth, with Fulvestrant, an endocrine therapy, and Capivasertib, which targets a different pathway involved in cancer cell survival. This multi-targeted approach may offer enhanced effectiveness for hormone receptor-positive, HER2-negative breast cancer, especially in cases with a high risk of recurrence. ^{1 3 5 10 11}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer. [2021]

2. United States 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. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

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

4. Australia 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. [2020]

5. New Zealand pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibitors Expand the Therapeutic Options in Breast Cancer: Palbociclib, Ribociclib and Abemaciclib. [2019]

6. France pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Hematological Events Potentially Associated with CDK4/6 Inhibitors: An Analysis from the European Spontaneous Adverse Event Reporting System. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

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

9. Switzerland 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. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Continuous treatment with abemaciclib leads to sustained and efficient inhibition of breast cancer cell proliferation. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer. [2022]