Subtype-Targeted Therapeutics for Breast Cancer

Overseen By Allison Zhang

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stanford University

Disqualifiers: Pregnancy, Prior breast cancer therapy, 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

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

Compensation: Varies

Number of Visits: 2

Duration: 2-3 weeks

19 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug that targets specific genetic changes found in some breast cancers. It aims to slow down tumor growth more effectively than standard treatments. The study focuses on patients with certain types of breast cancer that have these genetic features.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you have had prior breast cancer-directed therapy, you cannot have received it within the last 6 months, except for surgery.

What data supports the effectiveness of the drug Alpelisib in treating breast cancer?

Alpelisib has shown promising results in treating hormone receptor-positive metastatic breast cancer with PIK3CA mutations, as highlighted in the Phase III SOLAR-1 trial, which led to its FDA approval. ^{1 2 3 4 5}

What safety data exists for treatments like Alpelisib, Letrozole, and Tamoxifen in breast cancer?

Alpelisib has been studied for safety in hormone receptor-positive metastatic breast cancer, showing promising results. Letrozole, a type of aromatase inhibitor, generally has a favorable safety profile compared to Tamoxifen, with fewer blood clotting issues but may affect bone health. Tamoxifen has been a standard treatment for years, but newer treatments like aromatase inhibitors are considered safer in some aspects. ^{3 6 7 8 9}

What makes the drug combination of Alpelisib, Amcenestrant, Fulvestrant, Infigratinib, Letrozole, Tamoxifen, and Zotatifin unique for breast cancer?

This drug combination targets specific subtypes of breast cancer by using a mix of hormone therapies and targeted agents, which may offer a more personalized treatment approach compared to standard therapies that often focus on a single target or pathway. ^{4 10 11 12 13}

Research Team

Jennifer Caswell-Jin

Principal Investigator

Stanford Universiy

Eligibility Criteria

This trial is for adults with ER-positive, HER2-negative breast cancer that hasn't been treated yet. The tumor must be at least 1 cm and could be a new case or a local recurrence in the breast. Participants need to have certain gene changes in their tumors and meet specific health criteria.

Inclusion Criteria

You have breast cancer that is estrogen receptor-positive and HER2-negative, confirmed by a biopsy. The tumor must be at least 1 centimeter in size and located in the breast. You must be at least 18 years old and able to understand and sign a consent form.

My breast tumor is a specific type based on lab tests and has a growth rate of at least 10%.

Exclusion Criteria

I haven't had breast cancer treatment before, except surgery for a local recurrence.

I am allergic to the medication or its ingredients used in this study.

Pregnant woman, as confirmed by positive serum hCG test prior to initiating study treatment. Nursing (lactating) woman also not allowed.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive integrative subtype targeted therapeutics for 14 days

2-3 weeks

1 visit (in-person) for initial treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-3 weeks

1 visit (in-person) for follow-up assessment

Treatment Details

Interventions

• Alpelisib
• Amcenestrant
• Fulvestrant
• Infigratinib
• Letrozole
• Tamoxifen
• Zotatifin

Trial Overview The study tests if adding targeted drugs like Alpelisib, Tamoxifen, Zotatifin, or Fulvestrant before surgery can slow tumor growth better than standard hormone therapy alone. Each drug targets different genetic changes in the tumors.

Participant Groups

Group I: IC8:Zotatifin in combination with Fulvestrant Experimental Treatment 2 Interventions

Integrative subtype 8, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Group II: IC7:Zotatifin in combination with Fulvestrant Experimental Treatment 2 Interventions

Integrative subtype 7, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Group III: IC6:Zotatifin in combination with Fulvestrant Experimental Treatment 2 Interventions

Integrative subtype 6, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Group IV: IC4:Zotatifin in combination with Fulvestrant Experimental Treatment 2 Interventions

Integrative subtype 4, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Group V: IC3:Zotatifin in combination with Fulvestrant Experimental Treatment 2 Interventions

Integrative subtype 3, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Group VI: IC2:Zotatifin in combination with Fulvestrant Experimental Treatment 2 Interventions

Integrative subtype 2, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Group VII: IC1:Alpelisib in combination with Tamoxifen (closed to enrollment) Experimental Treatment 2 Interventions

Integrative subtype IC1, Treatment (14 days, - 2 or + 7 days): Take assigned alpelisib pills, 300 mg (two 150 mg tablets) with food, once daily by mouth. Tamoxifen pills, 20 mg once daily by mouth

Group VIII: IC1:Tamoxifen (closed to enrollment) Active Control 1 Intervention

Integrative subtype 1, Treatment (14 days, -2 to +7 days): Take assigned tamoxifen pills, 20 mg once daily by mouth

Group IX: IC2:Fulvestrant Active Control 1 Intervention

Integrative subtype 2, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Group X: IC3:Fulvestrant Active Control 1 Intervention

Integrative subtype 3, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1. on Day 1.

Group XI: IC4:Fulvestrant Active Control 1 Intervention

Integrative subtype 4, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1..

Group XII: IC6:Fulvestrant Active Control 1 Intervention

Integrative subtype 6, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Group XIII: IC7:Fulvestrant Active Control 1 Intervention

Integrative subtype 7, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Group XIV: IC8:Fulvestrant Active Control 1 Intervention

Integrative subtype 8, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.

Alpelisib is already approved in United States, European Union for the following indications:

Approved in United States as Piqray for:

• Hormone receptor-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen

Approved in European Union as Piqray for:

• Hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer in combination with fulvestrant

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

In the FLIPPER trial, the combination of palbociclib and fulvestrant significantly improved progression-free survival (PFS) in postmenopausal women with HR+/HER2- advanced breast cancer compared to placebo and fulvestrant.

Patient-reported outcomes indicated that while global health status and quality of life (QoL) were maintained during treatment with palbociclib/fulvestrant, the time to deterioration in QoL was longer with placebo/fulvestrant, suggesting that palbociclib/fulvestrant is a beneficial treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. Tibau, A., Martínez, MT., Ramos, M., et al.[2023]

In the MONALEESA-3 trial, the addition of ribociclib to fulvestrant significantly improved median progression-free survival (PFS) from 12.8 months to 20.5 months in patients with hormone receptor-positive, HER2-negative advanced breast cancer, indicating its efficacy as a treatment option.

The SANDPIPER trial showed that taselisib combined with fulvestrant extended PFS in patients with PIK3CA mutations, but it also resulted in a higher rate of severe adverse events (32% vs 9%), highlighting the need to balance efficacy with safety in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ASCO 2018 highlights: metastatic breast cancer. Rinnerthaler, G., Gampenrieder, SP., Greil, R.[2020]

Alpelisib (PIQRAY®) is the first PI3K inhibitor approved for treating hormone receptor-positive metastatic breast cancer with PIK3CA mutations, showing promising clinical results that support its use in overcoming endocrine resistance.

The review highlights the pharmacodynamic and pharmacokinetic properties of alpelisib, along with safety and efficacy data from the Phase III SOLAR-1 trial, which led to its FDA approval, indicating its potential as a tailored treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations. Mavratzas, A., Marmé, F.[2021]

Letrozole significantly outperformed tamoxifen in delaying disease progression and treatment failure in postmenopausal women with advanced breast cancer, with median times of 9.4 months versus 6.0 months, respectively.

While the overall survival (OS) was slightly better for letrozole (34 months) compared to tamoxifen (30 months), this difference was not statistically significant; however, letrozole did show improved survival rates during the first two years of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. Mouridsen, H., Gershanovich, M., Sun, Y., et al.[2022]

Third-generation aromatase inhibitors (AIs) like anastrozole, letrozole, and exemestane have emerged as effective alternatives to tamoxifen for treating postmenopausal breast cancer, particularly in hormone receptor-positive cases, as shown in the ATAC trial with over five years of follow-up.

Fulvestrant, a new type of estrogen receptor antagonist with no partial agonist activity, represents a promising option in breast cancer treatment, and the review discusses future sequencing strategies for using AIs earlier in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the treatment of postmenopausal breast cancer. Howell, A.[2018]

The combination of buparlisib and letrozole was found to be safe for patients with metastatic ER-positive breast cancer, with a maximum-tolerated dose of 100 mg/day and manageable side effects like hyperglycemia and fatigue.

In this phase Ib study involving 51 patients, the treatment showed a clinical benefit rate of 31%, indicating some patients experienced significant disease control, regardless of their PIK3CA mutation status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Mayer, IA., Abramson, VG., Isakoff, SJ., et al.[2021]

References

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ASCO 2018 highlights: metastatic breast cancer. [2020]

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