Early Treatment Switch Strategies for Advanced Breast Cancer

Overseen By Frances Valdes-Albini, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Miami

Must be taking: LHRH analogues

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Secondary cancer, CDK4/6i exposure, others

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: 1

500 Participants Needed

Trial Summary

What is the purpose of this trial?

The majority of patients (pts) with breast cancer have hormone receptor positive (HR+) disease, and this holds true for pts with advanced breast cancer (ABC). Currently frontline therapy for pts with HR+ ABC is antihormonal therapy with an aromatase inhibitor or selective estrogen receptor degrader plus a CDK4/6i. The proposed trial is a randomized study to further evaluate the potential benefit of switching a frontline regimen at the time that a molecular signal, ctDNA, suggests progression prior to detection of clinical progression using standard methods. The purpose of this study is to determine whether switching treatment earlier in the disease process, based on molecular progression, will increase the amount of time that a patient's metastatic breast cancer is controlled compared to patients with metastatic breast cancer who receive treatment later based on diagnostic imaging results or other methods currently used in medical practice.

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 cannot have had prior systemic anticancer therapy for metastatic or advanced disease, and you should not be on medications that are known to be cytochrome (CYP) 3A4 inhibitors or inducers within 7 days before starting the trial.

What evidence supports the effectiveness of the drug combination of AI+CDK4/6i for advanced breast cancer?

Research shows that combining CDK4/6 inhibitors with aromatase inhibitors (AI) significantly improves progression-free survival in hormone receptor-positive advanced breast cancer. Studies like MONARCH2 and PALOMA-1 have demonstrated that these combinations can also help overcome resistance to hormone treatments. ^{1 2 3 4 5}

What safety data exists for CDK4/6 inhibitors in breast cancer treatment?

CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib, when combined with aromatase inhibitors or fulvestrant, have shown to be generally safe and effective in treating hormone receptor-positive, HER2-negative advanced breast cancer. However, they have different side effects, such as liver function test abnormalities and QTc prolongation (a heart rhythm issue) with ribociclib, which should be monitored. These treatments have been approved and are used in clinical practice, indicating a recognized safety profile. ^{1 3 6 7 8}

What makes the Early Treatment Switch Strategies for Advanced Breast Cancer unique?

This treatment strategy is unique because it explores various combinations of drugs targeting different pathways, such as CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors, to overcome resistance in advanced hormone receptor-positive breast cancer. These combinations aim to improve progression-free survival and address resistance mechanisms that occur with standard endocrine therapies. ^{1 2 3 9 10}

Research Team

Frances Valdes-Albini, MD

Principal Investigator

University of Miami

Eligibility Criteria

This trial is for men and women over 18 with advanced breast cancer that can't be cured by surgery. They must have hormone receptor positive, HER2- metastatic breast cancer, no prior treatment for advanced disease, and their body should be functioning well enough to participate. Patients who've had certain other cancers or treatments recently aren't eligible.

Inclusion Criteria

My cancer has not spread to my organs in a way that threatens my life immediately.

I am fully active or restricted in physically strenuous activity but can do light work.

I am a woman who is postmenopausal, has suppressed ovarian function, or is premenopausal and willing to undergo hormone therapy for the trial.

Exclusion Criteria

I was treated with CDK4/6 inhibitors less than a year ago.

My breast cancer is advanced but can still be treated with the goal of curing it.

My electrolyte levels are stable and do not affect heart rhythm medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Step 1: ctDNA Monitoring

Participants undergo ctDNA monitoring with blood samples collected at specified timepoints until a rise in ctDNA is detected.

Up to 36 months

Cycle 1 day 1, Day 30, Day 60, and every 8-9 weeks

Step 2: Treatment

Participants either continue current therapy or switch to an alternate therapy based on ctDNA results.

14 months

Step 3: Optional Treatment

Optional treatment for participants experiencing clinical progression, allowing a switch to alternative therapies.

Up to 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• AI+CDK4/6i
• Chemotherapy
• mTOR inhibitor + AI
• mTOR inhibitor + Selective estrogen receptor modulator
• mTOR inhibitor + SERD
• PI3K inhibitor + AI
• PI3K inhibitor + SERD
• SERD+CDK4/6i

Trial Overview The study tests if switching breast cancer treatments when a blood marker (ctDNA) indicates the disease is progressing—before it's visible on scans—helps control the cancer longer. It compares early switchers to those who change treatments later based on standard methods like imaging results.

Participant Groups

Group I: Step 3: Optional Treatment for Patients in Arm 1 Experimental Treatment 9 Interventions

Optional for participants who were randomized to Step 2 Arm 1 and experience clinical progression. Participants may change from their AI+CDK4/6i to SERD+CDK4/6i, or from SERD+CDK4/6i treatment to alternative endocrine therapy or chemotherapy. Therapy options for Step 3 are the same as listed for participants randomized to Step 2 Arm 2 and is administered standard of care. For those patients who decline to crossover into Step 3, further treatment and disease management will occur at their treating physician's discretion.

Group II: Step 2 Arm 2: Early Switch in Therapy Experimental Treatment 9 Interventions

Participants in Step 2 Arm 2 undergo an early switch in standard of care therapy received in Step 1: * From AI+CDK4/6i in Step 1 to one of the following alternate endocrine therapies (ET) or chemotherapy: * SERD+CDK4/6i * mTOR Inhibitor + AI * mTOR Inhibitor+SERD * mTOR inhibitor + Selective estrogen receptor modulator * PI3K inhibitor + SERD * oral SERD * Chemotherapy * From SERD+CDK4/6i in Step 1 to one of the following alternate ET or chemotherapy: * mTOR Inhibitor + AI * mTOR Inhibitor+SERD * mTOR inhibitor + Selective estrogen receptor modulator * PI3K inhibitor + AI * PI3K inhibitor + SERD * oral SERD * Chemotherapy Participants will receive this therapy for approximately 14 months.

Group III: Step 2 Arm 1: No Modification of Therapy Experimental Treatment 2 Interventions

Participants in Step 2 Arm 1 will first undergo ctDNA monitoring in Step 1, providing blood samples for ctDNA testing at the following timepoints until a rise in ctDNA leading to a ratio (ctDNA result at time of assessment/ctDNA level at baseline) greater than (\>) 1 occurs: * Cycle 1 day 1 (C1D1), * Day 30 (D30) post-treatment initiation (±3 days), * Day 60 (D60) post-treatment initiation (±3 days), and then * every 8-9 weeks (±1 week). Participants will have no change in standard of care therapy administered in Step 1.

AI+CDK4/6i is already approved in United States, European Union for the following indications:

Approved in United States as AI + CDK4/6i for:

• Hormone receptor-positive, HER2-negative advanced or metastatic breast cancer

Approved in European Union as AI + CDK4/6i for:

• Hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer

Who Is Running the Clinical Trial?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

Findings from Research

The PI3K/AKT/mTOR pathway is frequently activated in estrogen receptor-positive (ER+) breast cancer, making it a key target for new therapies, including the recently approved alpelisib and capivasertib, which are used in combination with fulvestrant for advanced cases.

The development of multiple inhibitors targeting this pathway, alongside CDK4/6 inhibitors, presents a complex landscape for personalizing treatment strategies in ER+ advanced breast cancer, necessitating careful consideration of genomic contexts for optimal efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer. Alves, CL., Ditzel, HJ.[2023]

Data from multiple clinical trials (MONARCH2, PALOMA-1, and TREnd) indicate that combining CDK4/6 inhibitors with standard endocrine therapy significantly improves progression-free survival in patients with advanced ER-positive breast cancer.

The use of CDK4/6 inhibitors may also help to overcome acquired resistance to hormone treatments, enhancing the overall effectiveness of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating ER+ Breast Cancer with CDK4/6 Inhibitors. [2021]

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]

New combinations of endocrine therapy (ET) for hormone receptor-positive (HR+) advanced breast cancer, such as fulvestrant plus anastrozole or palbociclib plus letrozole, have shown improved progression-free survival, especially in ET-naïve patients.

While these combinations are generally safe, they carry risks of serious toxicities, necessitating careful monitoring and patient education, and the use of circulating tumor DNA as a biomarker may help tailor treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancing Endocrine Therapy Combination Strategies for the Treatment of Postmenopausal HR+/HER2- Advanced Breast Cancer. Pritchard, KI., Chia, SK., Simmons, C., et al.[2018]

Aromatase inhibitors like anastrozole, letrozole, and exemestane are key treatments for estrogen receptor-positive metastatic breast cancer, but many patients develop resistance and experience disease progression within months.

Recent research has identified new drug combinations targeting pathways like mTOR, PI3K, and CDK4/6, which show promise in overcoming resistance and improving treatment outcomes for hormone-sensitive metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cotargeting of CYP-19 (aromatase) and emerging, pivotal signalling pathways in metastatic breast cancer. Daldorff, S., Mathiesen, RM., Yri, OE., et al.[2018]

In a Phase III clinical trial (CAPItello-291), the combination of the AKT inhibitor capivasertib and the SERD fulvestrant improved progression-free survival (PFS) in HR+ breast cancer patients who had previously been treated with aromatase inhibitors, indicating a promising treatment strategy for this population.

Despite some reduction in efficacy due to prior CDK4/6 inhibitor treatment, both RB+ and RB- palbociclib-resistant breast cancer cells still responded to the combination therapy, suggesting that targeting both AKT and estrogen receptor pathways can be effective even in resistant models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining the AKT inhibitor capivasertib and SERD fulvestrant is effective in palbociclib-resistant ER+ breast cancer preclinical models. Hopcroft, L., Wigmore, EM., Williamson, SC., et al.[2023]

Ribociclib, when combined with letrozole or fulvestrant, has shown improved progression-free survival and overall survival in postmenopausal women with hormone receptor-positive breast cancer, based on a Phase III study involving 668 participants.

While ribociclib is effective, it has a higher risk of liver function abnormalities and can cause QTc prolongation, making it less suitable for patients with certain cardiac conditions; alternative CDK 4/6 inhibitors like palbociclib or abemaciclib may be safer options in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection. Parati, MC., Pedersini, R., Perego, G., et al.[2022]

CDK4/6 inhibitors, when used with aromatase inhibitors or fulvestrant, provide an effective treatment option for hormone receptor-positive, HER2-negative breast cancer patients, leading to longer progression-free survival.

In a two-year clinical experience study, the side effects and tumor responses to palbociclib and ribociclib were consistent with existing data, indicating their promising role in breast cancer therapy, although the choice of aromatase inhibitor may influence outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First clinical experience with CDK4/6 inhibitors in breast cancer therapy. Cobec, IM., Moleriu, L., Moatar, AE., et al.[2021]

CDK4/6 inhibitors combined with endocrine therapy significantly improve survival rates in advanced hormone receptor-positive, HER2-negative breast cancer, but there is limited data on treatment options after disease progression with these inhibitors.

Resistance to CDK4/6 inhibitors often involves mutations in PIK3CA and ESR1, with PIK3CA mutations being actionable due to the recent approval of targeted therapies like alpelisib, highlighting the importance of genomic sequencing for guiding further treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical Treatment Strategies and Future Directions After Progression While Receiving CDK4/6 Inhibition and Endocrine Therapy in Advanced HR+/HER2- Breast Cancer. Sammons, S., Shastry, M., Dent, S., et al.[2021]

Endocrine-based treatments are standard for women with hormone receptor-positive/HER2-negative metastatic breast cancer, but about 50% develop resistance, prompting research into new therapies.

Novel treatments like CDK4/6 and PI3K/AKT/mTOR inhibitors have improved outcomes for patients who progress after endocrine therapy, enhancing progression-free survival and overall survival, but identifying predictors of response is crucial for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2- Metastatic Breast Cancer: Biological Mechanisms and New Treatments. Presti, D., Quaquarini, E.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer. [2023]

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

Treating ER+ Breast Cancer with CDK4/6 Inhibitors. [2021]

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

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

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

Enhancing Endocrine Therapy Combination Strategies for the Treatment of Postmenopausal HR+/HER2- Advanced Breast Cancer. [2018]

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

Cotargeting of CYP-19 (aromatase) and emerging, pivotal signalling pathways in metastatic breast cancer. [2018]

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

Combining the AKT inhibitor capivasertib and SERD fulvestrant is effective in palbociclib-resistant ER+ breast cancer preclinical models. [2023]

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

Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection. [2022]

8. Greece pubmed.ncbi.nlm.nih.gov

First clinical experience with CDK4/6 inhibitors in breast cancer therapy. [2021]

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

Practical Treatment Strategies and Future Directions After Progression While Receiving CDK4/6 Inhibition and Endocrine Therapy in Advanced HR+/HER2- Breast Cancer. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2- Metastatic Breast Cancer: Biological Mechanisms and New Treatments. [2023]