Biomarker-Driven Therapy for Breast Cancer

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

Trial Summary

What is the purpose of this trial?

This is a prospective study to assess the impact of biomarker driven, early therapeutic switching and delayed imaging with the incorporation of DiviTum® serum TK1 activity ("DiviTum® TKa") in patients with HR positive, HER-2 negative metastatic or unresectable breast cancer. Patients will receive first-line treatment with a CDK4/6 inhibitor (CDK4/6i) and endocrine therapy. All patients will have blood drawn for thymidine kinase activity (TKa) testing at baseline and at C1D15. Patients who are found to have a lack of TKa suppression at C1D15 will be recommended to switch to an alternative therapy. Patients with suppressed C1D15 TKa levels will continue on CDK4/6i and endocrine therapy until clinical progression. Patients with TKa which remains suppressed will be recommended to delay restaging scans from 24 weeks to 36 weeks. The investigators hypothesize that a patient's TKa level at C1D15 is prognostic for progression-free survival (PFS) on a CDK4/6 inhibitor and early therapeutic switching in patients with a lack of C1D15 TKa suppression will be associated with prolonged PFS.

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 evidence supports the effectiveness of CDK4/6 inhibitors combined with endocrine therapy for breast cancer?

Research shows that adding CDK4/6 inhibitors like abemaciclib, palbociclib, or ribociclib to endocrine therapy significantly improves progression-free survival and response rates in patients with hormone receptor-positive, HER2-negative advanced breast cancer. These drugs are now a standard treatment option, offering better disease control and maintaining quality of life. ^{1 2 3 4 5}

Is the CDK4/6 + Endocrine therapy safe for humans?

CDK4/6 inhibitors like Palbociclib, Ribociclib, and Abemaciclib are generally considered safe for humans when used for advanced breast cancer, with common side effects including neutropenia (low white blood cell count), fatigue, nausea, and diarrhea. These side effects are usually manageable with dose adjustments. ^{1 6 7 8 9}

How is the drug CDK4/6 inhibitors with endocrine therapy unique for breast cancer treatment?

CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib, when combined with endocrine therapy, offer a unique approach by specifically targeting proteins (CDK4 and CDK6) that help cancer cells grow, leading to improved progression-free survival in hormone receptor-positive, HER2-negative advanced breast cancer. This combination therapy is taken orally and has become a new standard of care, showing significant benefits over endocrine therapy alone. ^{1 2 4 5 10}

Research Team

Katherine Clifton, MD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

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 am 18 years old or older.

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. [2020]

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

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

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

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

5. England pubmed.ncbi.nlm.nih.gov

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors: existing and emerging differences. [2023]

6. 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]

7. Germany pubmed.ncbi.nlm.nih.gov

Palbociclib-The First of a New Class of Cell Cycle Inhibitors. [2018]

8. England pubmed.ncbi.nlm.nih.gov

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

9. England pubmed.ncbi.nlm.nih.gov

CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities. [2020]

10. United States 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. [2020]