Biomarker-Driven Therapy for Breast Cancer

Recruiting at 1 trial location

Overseen By Katherine Clifton, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Washington University School of Medicine

Must be taking: CDK4/6 inhibitors, Endocrine therapy

Disqualifiers: Prior cytotoxic chemotherapy, Concurrent malignancy, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 24-36 weeks

65 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for hormone receptor-positive, HER2-negative metastatic breast cancer that cannot be surgically removed. Researchers aim to determine if early treatment changes, based on thymidine kinase activity (TKa) blood test results, can extend the period patients remain free of disease progression while on a first-line therapy of a CDK4/6 inhibitor and endocrine therapy. Patients with low TKa after the first treatment cycle will continue their current therapy, while those with high TKa may switch treatments. Patients managing advanced breast cancer and starting this specific therapy might be suitable for the trial. As an unphased trial, this study allows patients to contribute to innovative research that could lead to new treatment strategies.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you will need to start a CDK4/6 inhibitor and endocrine therapy as part of the study.

What prior data suggests that the DiviTum® TKa assay is safe for use in this trial?

Studies have shown that combining CDK4/6 inhibitors with hormone therapy is generally safe for treating certain types of breast cancer. Research indicates that most patients tolerate these treatments well. Common side effects include fatigue and nausea, while serious side effects remain rare. One study confirmed that this combination is effective and safe for patients with hormone receptor-positive, HER2-negative metastatic breast cancer. This means it works for many patients and usually doesn't cause severe problems. In summary, CDK4/6 inhibitors plus hormone therapy have a strong safety record for treating similar conditions. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this approach to breast cancer treatment because it uses a biomarker-driven strategy to tailor therapy. Unlike the standard of care, which generally involves fixed treatment regimens, this method measures Thymidine Kinase activity (TKa) to determine the best course of action. This allows patients with suppressed TKa levels to potentially extend the time between scans, reducing the burden of frequent imaging. Additionally, for patients whose TKa levels are unsuppressed, the protocol supports early switching to alternative therapies, which could lead to more personalized and effective treatment plans. This biomarker-driven approach represents a promising step forward in making breast cancer treatment more precise and adaptable.

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

Research has shown that combining CDK4/6 inhibitors with hormone therapy can effectively treat HR-positive, HER2-negative metastatic breast cancer. One study found that using these drugs as the first treatment helped some patients live for more than four years. Notably, patients taking abemaciclib experienced fewer side effects, such as infections, making the treatment easier to handle. This trial will evaluate the effectiveness of CDK4/6 inhibitors combined with endocrine therapy, with participants monitored using the DiviTum® TKa assay to assess treatment response. This drug combination works by slowing cancer growth by targeting specific proteins that help cancer cells multiply. ^{6 7 8 9 10}

Who Is on the Research Team?

Katherine Clifton, MD

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for post-menopausal women with HR+ HER2- metastatic or unresectable breast cancer. They must be at least 18, have a performance status ≤ 2, and can't have had chemotherapy for metastatic disease. Prior therapy for early-stage breast cancer is okay if it was over a year ago.

Inclusion Criteria

My cancer can be measured by scans, including if it's only in my bones.

I have had treatment for early stage breast cancer, including hormone or chemotherapy.

I completed CDK 4/6 inhibitor therapy over a year ago.

Exclusion Criteria

Concurrent participation in any investigational therapeutic trial for treatment of metastatic breast cancer

I have no other cancers that could affect this trial's treatment.

I have received chemotherapy for cancer that has not spread.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive first-line treatment with a CDK4/6 inhibitor and endocrine therapy. TKa levels are monitored at baseline and C1D15 to determine treatment adjustments.

24-36 weeks

Visits at Baseline, Week 2 (C1D15), C2D1, C4D1, and clinical progression

Follow-up

Participants are monitored for safety and effectiveness after treatment, with progression-free survival and overall survival being assessed.

7 years

Extension

Participants with suppressed TKa levels may delay restaging scans from 24 weeks to 36 weeks and continue monitoring every 3 months.

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• CDK4/6 + Endocrine therapy
• DiviTum® TKa assay

Trial Overview The study tests whether changing treatments based on TKa levels from the DiviTum® assay leads to longer progression-free survival in patients using CDK4/6 inhibitors and endocrine therapy as first-line treatment.

How Is the Trial Designed?

Group I: TKa unsuppressed at Cycle 1 Day 15 Experimental Treatment 2 Interventions

* Study visits will occur at Baseline, Week 2 (C1D15), C2D1, C4D1, and clinical progression. Blood serum samples will be collected and analyzed using DiviTum® TKa at each of these dictated time points. * Patients with lack of TKa suppression at C1D15 (defined as \>145 DuA) will be recommended to switch to an alternative therapy after compliance with the medication is ensured (by pill count) and potential drug-drug interactions are reviewed. These patients will have TKa samples drawn at initiation of second-line therapy and on the first day of subsequent cycles until progression.

Group II: TKa suppressed at Cycle 1 Day 15 Experimental Treatment 2 Interventions

* Study visits will occur at Baseline, Week 2 (C1D15), C2D1, C4D1, and clinical progression. Blood serum samples will be collected and analyzed using DiviTum® TKa at each of these dictated time points. * Patients with suppressed TKa levels at C1D15 will continue on CDK4/6i + endocrine therapy until clinical progression. There will be an option to elongate the time between restaging scans from Q3M to Q6M if TKa remains suppressed in this group. Physicians may repeat TKa in 2 weeks if TKa rise is noted and if TKa again becomes suppressed, may delay imaging. These patients will undergo TKa level monitoring at C2D1, C4D1, every 3 months thereafter, and at the time of clinical progression. The feasibility endpoint relates specifically to the Week 24 imaging time point.

Group III: Physicians Active Control 1 Intervention

-Physicians will be asked to complete surveys as follows: * Physician Survey 1 for patients in the TKa C1D15 Suppressed group who have the option to delay the Week 24 scan at Week 24 * Physician Survey 2 for patients in the TKa C1D15 Unsuppressed group at C1D15 (after TKa results have returned but before switching therapy)

CDK4/6 + Endocrine therapy is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as CDK4/6 inhibitors for:

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

Approved in United States as CDK4/6 inhibitors for:

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

Approved in Canada as CDK4/6 inhibitors for:

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

Approved in Japan as CDK4/6 inhibitors for:

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

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Biovica

Collaborator

Trials

2

Recruited

120+

Published Research Related to This Trial

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]

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]

Ribociclib is a selective CDK4/6 inhibitor that shows strong antitumor activity, particularly in hormone receptor-positive, HER2-negative advanced breast cancer, and is effective when combined with other therapies.

Preclinical studies indicate that ribociclib is more potent in CDK4-dependent cancer cells and that traditional viability assays may underestimate its effects, highlighting the importance of using direct cell number assessments in evaluating drug efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models. Kim, S., Tiedt, R., Loo, A., et al.[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]

Palbociclib, the first oral CDK4/6 inhibitor, significantly improves median progression-free survival in advanced ER-positive/HER2-negative breast cancer, showing 24.8 months with letrozole compared to 14.5 months with placebo, and 9.2 months with fulvestrant compared to 3.8 months with placebo.

The main side effect of palbociclib is neutropenia, which can be managed through dose adjustments, resulting in a favorable safety profile and delayed deterioration of quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib-The First of a New Class of Cell Cycle Inhibitors. Schmidt, M., Sebastian, M.[2018]

Abemaciclib, a CDK 4/6 inhibitor, offers a continuous dosing schedule and a different toxicity profile compared to other inhibitors like palbociclib and ribociclib, showing similar clinical benefits in treating ER+/HER2- advanced metastatic breast cancer.

The ongoing MONARCH-E trial may reveal the potential of abemaciclib in early-stage treatment, particularly for high-risk patients, while emerging biomarker research could help identify which tumors respond best to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib, a potent cyclin-dependent kinase 4 and 6 inhibitor, for treatment of ER-positive metastatic breast cancer. Lee, KA., Shepherd, ST., Johnston, SR.[2020]

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]

Specific CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib have been approved for treating advanced hormone receptor-positive breast cancer, showing a significant benefit in progression-free survival during phase III trials.

While these therapies are generally well-tolerated, the most common side effects include neutropenia, fatigue, nausea, and diarrhea, and currently, only estrogen receptor positivity is known to predict response to these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities. Lynce, F., Shajahan-Haq, AN., Swain, SM.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39754979/

Comparative overall survival of CDK4/6 inhibitors plus an ... Several real-world studies compared CDK4/6i effectiveness, with inconsistent findings. This study compared overall survival (OS) of patients ...

2. esmoopen.com esmoopen.com/article/S2059-7029(25)01439-5/fulltext

Real-world progression-free survival of CDK4/6 inhibitors ... We observed no statistically significant differences in rwPFS in patients with HR-positive/HER2-negative mBC receiving 1L palbociclib, ...

3. nature.com nature.com/articles/s44276-024-00070-w

Real-world effectiveness of CDK 4/6 inhibitors in estrogen ... First-line median OS was 37.8 months (95% CI: 32.5–NA); 49.7 months (95% CI: 44.7–54.1); and 54.4 months (95% CI: 47.9–NA) for abemaciclib, ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)00134-6/fulltext

results from the multicenter PALMARES-2 study The three CDK4/6is have different pharmacology and safety, but no large effectiveness comparisons have been conducted so far.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0960977625006149

Metastatic Breast Cancer: A Propensity-Matched ... Abemaciclib's significantly lower incidence of neutropenia (15.6% vs 32.2%) and severe infections (15.7% vs 25.1%) likely enabled more ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10526227/

An Overview of the Safety Profile and Clinical Impact of CDK4 ... This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0305737223000786

Safety profile of cyclin-dependent kinase (CDK) 4/6 ... We conducted a systematic review and meta-analysis to assess the safety profile of combining CDK4-6i with palliative and ablative RT in both the metastatic and ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2949820124000420

UK multicentre real-world data of the use of cyclin ... These data demonstrate that CDK4/6is are an effective and safe treatment for metastatic HR+/HER2− breast cancer.

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e13013

Efficacy and safety of CDK4/6 inhibitors in HER2-positive ... CDK4/6 inhibitors combined with anti-HER2 therapies showed moderate efficacy in HER2+ breast cancer, offering disease control in most patients, slowing tumor ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11926838/

Clinician's guide: expert insights on the use of CDK4/6 ... This paper explores the integration of adjuvant CDK4/6 inhibitors into clinical practice, focusing on disease-free survival and safety outcomes.