Pre-op Radiation + Abemaciclib + Letrozole for Breast Cancer

Overseen By Mridula George, MD

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Rutgers, The State University of New Jersey

Must be taking: CDK4/6 inhibitors

Must not be taking: CDK4/6 inhibitors, Aromatase inhibitors

Disqualifiers: Metastatic disease, Uncontrolled hypertension, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

15 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on CDK4/6 inhibitors or aromatase inhibitors, you cannot participate in the trial.

What data supports the effectiveness of the drug combination of Abemaciclib and Letrozole for breast cancer?

Research shows that Abemaciclib, when combined with Letrozole, significantly improves progression-free survival in patients with advanced ER-positive, HER2-negative breast cancer. Additionally, Abemaciclib with endocrine therapy reduces the risk of recurrence in early breast cancer with a high risk of recurrence. ^{1 2 3 4 5}

Is the combination of Abemaciclib and Letrozole safe for breast cancer treatment?

Abemaciclib, when combined with endocrine therapy like Letrozole, has been shown to have an acceptable and manageable safety profile in breast cancer treatment, with common side effects including diarrhea, infections, and low white blood cell counts. ^{1 2 3 5 6}

How is the drug combination of Abemaciclib and Letrozole unique for breast cancer treatment?

This drug combination is unique because it combines Abemaciclib, a CDK4/6 inhibitor that helps stop cancer cell growth, with Letrozole, an endocrine therapy that reduces estrogen levels, potentially enhancing the effectiveness of pre-operative radiation in treating hormone receptor-positive, HER2-negative breast cancer. ^{1 2 3 5 6}

What is the purpose of this trial?

This phase 1b study investigates the safety and feasibility of combining pre-operative radiation therapy with Cyclin-Dependent Kinase 4 (CDK4/6) inhibitors in participants with hormone receptor positive/HER2 negative (HR+/HER2-) breast cancer. The study aims to assess the benefits of concurrent use of these treatments in a specific participant population, focusing on their safety and tolerability. The hypothesis is that the combination therapy will be well-tolerated, providing valuable insights into its effectiveness for future clinical applications.

Research Team

Mridula George, MD

Principal Investigator

Cancer Institute of New Jersey Rutgers

Eligibility Criteria

This trial is for individuals with HR+/HER2- breast cancer who can take oral meds, are surgery candidates (lumpectomy or mastectomy), have a tumor size of at least 1.5 cm, and meet specific hormone receptor criteria. They must not be suspected of having metastatic disease, should have an ECOG performance status ≤2, and certain blood levels must be within specified ranges.

Inclusion Criteria

My breast cancer recurrence score is below 25.

My cancer has not spread to other parts of my body.

I am a candidate for surgery to remove my breast cancer.

Exclusion Criteria

I need chemotherapy before surgery.

I have had breast cancer in the same breast before.

I have had radiation therapy on the same side as my current breast cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Participants receive Abemaciclib and Letrozole for three cycles prior to radiation therapy

12 weeks

Regular visits for monitoring and on-treatment biopsy between cycle 3, day 16, and cycle 4, day 1

Treatment Part B

Continuation of Abemaciclib and Letrozole with the addition of radiation therapy

4 weeks

Regular visits for radiation therapy administration

Treatment Part C

Two additional cycles of Abemaciclib and Letrozole

8 weeks

Surgery

Participants undergo surgery following treatment cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Follow-up visits every six months

Treatment Details

Interventions

• Abemaciclib
• Letrozole

Trial Overview The RADIANT study tests the safety and potential benefits of combining pre-op radiation therapy with Abemaciclib and Letrozole in treating early-stage breast cancer. It's designed to see if this combo is tolerable and could inform future treatment effectiveness.

Participant Groups

Group I: Combined Pre-Operative Therapy with Abemaciclib, Letrozole, and Radiation in HR+/HER2- Breast Cancer Experimental Treatment 2 Interventions

Part A: * 28-day treatment cycle based on abemaciclib * Abemaciclib 150mg BID (twice a day). * Letrozole 2.5mg daily and Abemaciclib 150mg twice a day for three cycles prior to undergoing radiation therapy. * On-treatment biopsy conducted between cycle 3, day 16, and cycle 4, day 1. * This occurs two weeks prior to transitioning to Part B. Dose Level 0 150mg Twice daily with at least 6 hours between doses Dose Level 1 100mg Twice daily with at least 6 hours between doses Dose Level 2 50mg Twice daily with at least 6 hours between doses Part B: * Continue treatment from Part A, 28-day cycle based on abemaciclib. * Abemaciclib 150mg BID (twice a day) with letrozole 2.5mg daily. * Part B focuses on the administration of radiation therapy following the three cycles of combined abemaciclib and letrozole. * Targeted radiation treatment. Part C: * Two cycles of abemaciclib, 150mg twice a day. * Letrozole 2.5mg daily. Part D: Surgery

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?

Rutgers, The State University of New Jersey

Lead Sponsor

Trials

471

Recruited

81,700+

Mridula George, MD

Lead Sponsor

Trials

3

Recruited

60+

Findings from Research

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 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]

Letrozole can be safely administered alongside radiotherapy in postmenopausal women with early-stage breast cancer, with no significant increase in severe skin-related toxic effects observed between concurrent and sequential treatment groups during the study.

Both treatment groups experienced similar rates of acute skin toxicity, with dermatitis being the most common issue, indicating that combining letrozole with radiotherapy does not exacerbate skin side effects significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial. Azria, D., Belkacemi, Y., Romieu, G., et al.[2022]

In the neoMONARCH study, postmenopausal women with HR+/HER2- breast cancer showed significant decreases in Ki67 expression and achieved higher rates of complete cell-cycle arrest when treated with abemaciclib alone or in combination with anastrozole compared to anastrozole alone.

The combination therapy not only inhibited cancer cell growth but also enhanced immune activation, suggesting a dual mechanism of action that could improve treatment outcomes, while the most common side effects were manageable gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2- Breast Cancer. Hurvitz, SA., Martin, M., Press, MF., et al.[2023]

In a pooled analysis of 1152 patients from the MONARCH 2 and MONARCH 3 studies, abemaciclib combined with endocrine therapy showed a consistent improvement in progression-free survival (PFS) across all age groups, indicating its efficacy in treating HR+, HER2- advanced breast cancer regardless of age.

Older patients experienced higher rates of clinically relevant side effects, such as diarrhea and nausea, but these were manageable with dose adjustments, suggesting that while safety concerns exist, the treatment remains effective for older populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials. Goetz, MP., Okera, M., Wildiers, H., et al.[2022]

In a phase II study involving 16 postmenopausal women with locally advanced or metastatic HR+/HER2- breast cancer, the combination of bosutinib and letrozole showed significant treatment-related adverse events, with 15 out of 16 participants experiencing side effects, primarily diarrhea and liver enzyme elevations.

Due to a high incidence of dose-limiting toxicities and an unfavorable risk-benefit ratio, the study concluded that further investigation of bosutinib plus letrozole as a treatment option was not warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib in combination with the aromatase inhibitor letrozole: a phase II trial in postmenopausal women evaluating first-line endocrine therapy in locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer. Moy, B., Neven, P., Lebrun, F., et al.[2021]

References

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

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

2. France pubmed.ncbi.nlm.nih.gov

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

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

Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial. [2022]

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

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2- Breast Cancer. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Bosutinib in combination with the aromatase inhibitor letrozole: a phase II trial in postmenopausal women evaluating first-line endocrine therapy in locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer. [2021]