DNA-Guided Adjuvant Therapy for Breast Cancer

(DARE Trial)

Recruiting at 13 trial locations

Overseen By Julee Hartwell

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Criterium, Inc.

Must be taking: Aromatase inhibitors, Tamoxifen

Must not be taking: Fulvestrant, CDK4/6 inhibitors

Disqualifiers: Invasive cancer, HER2 positive, others

Stay on Your Current Meds You can continue your current medications while participating

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

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 2 years

70 Participants Needed

Trial Summary

What is the purpose of this trial?

A randomized, Phase II trial of circulating tumor DNA-guided second line Adjuvant therapy for high Residual risk, Estrogen Receptor positive, HER-2 negative breast cancer (DARE)

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

The trial does not specify if you need to stop your current medications, but it does allow patients who are currently taking an aromatase inhibitor or tamoxifen as adjuvant endocrine therapy. However, you cannot be on a CDK4/6 inhibitor or certain other medications that interact with trial drugs. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of Fulvestrant and Palbociclib for breast cancer?

Research shows that the combination of Palbociclib and Fulvestrant improves progression-free survival (PFS) in women with advanced estrogen receptor-positive breast cancer. Early changes in circulating tumor DNA (ctDNA) levels can predict how well patients respond to this drug combination. ^{1 2 3 4 5}

Is DNA-guided adjuvant therapy for breast cancer safe?

The combination of palbociclib (Ibrance) and fulvestrant (Faslodex) has been approved for treating certain types of advanced breast cancer and is generally well-tolerated. Common side effects include low white blood cell counts, infections, tiredness, nausea, and anemia, but these are manageable in most cases. ^{1 4 6 7 8}

How is DNA-Guided Adjuvant Therapy for Breast Cancer different from other treatments?

This treatment is unique because it uses DNA markers to guide therapy decisions, potentially allowing for more personalized treatment plans based on the genetic profile of the tumor, unlike standard treatments that do not typically use such specific genetic information. ^{1 2 4 5 9}

Research Team

Lajos Pusztai, MD

Principal Investigator

Yale University

Eligibility Criteria

This trial is for men and women with stage II-III, HER2 negative, ER positive breast cancer who have been on hormone therapy for 6 months to 7 years. They must not show signs of cancer spread and agree to use contraception. Those with high recurrence risk or ctDNA positivity are eligible. Exclusions include intolerance to the drugs being tested, severe health issues, living outside the US, certain cancer histories, or taking specific medications.

Inclusion Criteria

My breast cancer is stage II or III, HER2 negative, and ER positive.

My scans show no cancer spread to other parts of my body.

I agree to use birth control during and after the trial if I am a woman who can still have children or a man.

Exclusion Criteria

I haven't had cancer in the last 5 years, except for skin cancer.

I am on medication that strongly affects liver enzyme levels and cannot switch.

I have been treated with fulvestrant, a CDK4/6 inhibitor, or was in the PENELOPE/PALLAS trials.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Up to 7 years

Routine follow-up clinic visits every 4 to 6 months

Surveillance/ctDNA Screening

Assess the incidence of ctDNA detection in patients with ER positive HER2- breast cancer receiving standard of care adjuvant endocrine therapy

Enrollment period

Treatment

Randomized patients receive either palbociclib plus fulvestrant or continue standard of care endocrine therapy

Up to 2 years

Regular visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Treatment Details

Interventions

• Fulvestrant
• Palbociclib

Trial Overview The DARE trial tests if adding Palbociclib and Fulvestrant (second line adjuvant therapies) can benefit patients with a high residual risk of breast cancer after initial treatment. It's randomized: some will get standard care while others receive the new combination; decisions are made by chance.

Participant Groups

Group I: Arm A Experimental Treatment 2 Interventions

Palbociclib/Fulvestrant Combination

Group II: Arm B Active Control 1 Intervention

Adjuvant Therapy

Who Is Running the Clinical Trial?

Criterium, Inc.

Lead Sponsor

Trials

18

Recruited

730+

Findings from Research

In a study of 459 patients with estrogen receptor-positive breast cancer, high levels of circulating tumor DNA (ctDNA) were linked to worse progression-free survival (PFS) on both palbociclib plus fulvestrant and placebo plus fulvestrant, indicating that ctDNA can serve as a potential biomarker for early progression risk.

Specific genomic alterations, such as TP53 mutations and FGFR1 amplifications, were also associated with poorer PFS, suggesting that patients with these markers may require more aggressive treatment strategies despite receiving CDK4/6 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer. O'Leary, B., Cutts, RJ., Huang, X., et al.[2023]

In a study of 201 patients with hormone receptor-positive/HER2-negative metastatic breast cancer, the presence of circulating tumor DNA (ctDNA), particularly TP53 mutations, was linked to poorer progression-free survival (PFS) and overall survival (OS), indicating its potential as a prognostic biomarker.

Dynamic changes in ctDNA levels during treatment could predict treatment efficacy, with higher ctDNA suppression observed in patients treated with capecitabine, suggesting that monitoring ctDNA could help assess how well a treatment is working.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Mutations and ctDNA Dynamics as Prognostic and Predictive Factors in ER-Positive/HER2-Negative Metastatic Breast Cancer Patients. Pascual, J., Gil-Gil, M., Proszek, P., et al.[2023]

In a study of 280 patients with HR+/HER2- breast cancer treated with CDK4/6 inhibitors and endocrine therapy, factors like modified Scarff-Bloom-Richardson (SBR) scores and lack of PR expression were linked to shorter progression-free survival (PFS), highlighting their potential as biomarkers for treatment response.

Gene expression analyses revealed that changes in cell cycle and estrogen receptor signaling during treatment were significant, with certain gene sets associated with shorter PFS, suggesting that understanding these biological features could improve treatment strategies for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determinants of response to CDK4/6 inhibitors in the real-world setting. Witkiewicz, AK., Schultz, E., Wang, J., et al.[2023]

In a study of 61 women with ER+ HER2- metastatic breast cancer, early changes in circulating tumor DNA (ctDNA) levels were found to be predictive of the effectiveness of the combination therapy of palbociclib and fulvestrant, with ctDNA clearance at day 30 associated with significantly longer progression-free survival (PFS).

Patients who showed an increase in ctDNA levels at day 30 had a higher risk of disease progression, indicating that monitoring ctDNA can provide valuable insights into treatment response before traditional radiological evaluations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients. Darrigues, L., Pierga, JY., Bernard-Tessier, A., et al.[2022]

In the PALOMA-3 study involving women with advanced estrogen receptor-positive breast cancer, changes in circulating tumor DNA (ctDNA) levels after 15 days of treatment with the CDK4/6 inhibitor palbociclib and fulvestrant were found to strongly predict progression-free survival, indicating a potential biomarker for treatment response.

The study revealed that while ESR1 mutations can be present in tumor subclones, their ctDNA dynamics were less effective in predicting clinical outcomes, suggesting that monitoring ctDNA levels could be more reliable for assessing treatment efficacy in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. O'Leary, B., Hrebien, S., Morden, JP., et al.[2022]

Oral palbociclib is an effective treatment for HR-positive, HER2-negative advanced or metastatic breast cancer, significantly prolonging progression-free survival when used with letrozole or fulvestrant in clinical trials involving postmenopausal women.

The most common side effect was neutropenia, which was manageable and rarely led to serious complications, indicating that palbociclib can be safely administered without significantly compromising its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer. Kim, ES., Scott, LJ.[2022]

In a study involving 1723 women with HR+/HER2- advanced or metastatic breast cancer, palbociclib combined with aromatase inhibitors or fulvestrant showed low dose-reduction rates (18.9% and 12.3%, respectively), indicating good tolerability.

The treatment demonstrated favorable progression-free rates (PFR) at 12 months, with 88.1% for palbociclib + AI and 79.8% for palbociclib + fulvestrant, along with high survival rates (97.3% and 97.5%, respectively), suggesting its effectiveness in real-world clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world treatment of patients with palbociclib for HR+/HER2-advanced/metastatic breast cancer: the Europe IRIS study. Mycock, K., Zhan, L., Hart, K., et al.[2022]

Palbociclib, when combined with fulvestrant, significantly improves progression-free survival in women with hormone receptor-positive, HER2-negative advanced breast cancer, showing a median PFS of 9.5 months compared to 4.6 months with placebo, based on a study of 521 women.

The safety profile of palbociclib includes common adverse reactions such as neutropenia and infections, which were observed in over 20% of patients, confirming its known side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval of Palbociclib in Combination with Fulvestrant for the Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer. Walker, AJ., Wedam, S., Amiri-Kordestani, L., et al.[2022]

In a study of 56 patients with advanced breast cancer, a significant reduction in cell-free DNA (cfDNA) mutations was observed after 15 days of treatment with palbociclib and fulvestrant, indicating a biological response to the therapy.

However, this reduction in cfDNA mutations did not correlate with improved progression-free survival, suggesting that while cfDNA changes may reflect treatment effects, they do not necessarily predict clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in cell-free DNA after short-term palbociclib and fulvestrant treatment for advanced or metastatic hormone receptor-positive and human epidermal growth factor 2-negative breast cancer. Iwamoto, T., Niikura, N., Watanabe, K., et al.[2023]

References

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

Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer. [2023]

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

Baseline Mutations and ctDNA Dynamics as Prognostic and Predictive Factors in ER-Positive/HER2-Negative Metastatic Breast Cancer Patients. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Determinants of response to CDK4/6 inhibitors in the real-world setting. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients. [2022]

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

Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. [2022]

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

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Real-world treatment of patients with palbociclib for HR+/HER2-advanced/metastatic breast cancer: the Europe IRIS study. [2022]

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

FDA Approval of Palbociclib in Combination with Fulvestrant for the Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Changes in cell-free DNA after short-term palbociclib and fulvestrant treatment for advanced or metastatic hormone receptor-positive and human epidermal growth factor 2-negative breast cancer. [2023]