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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether adding a new drug before surgery can slow breast cancer growth more effectively than standard anti-hormone treatments. The drug targets specific genetic changes in breast tumors, and treatments like Alpelisib (Piqray) will be tested based on these changes. Suitable candidates for this trial include individuals with ER-positive, HER2-negative breast cancer, with a tumor at least 1 cm in size and still in the breast. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that the combination of zotatifin and fulvestrant has a favorable safety profile, indicating it was generally well-tolerated by patients. The FDA granted this drug combination a fast track designation, signaling its potential safety and effectiveness.

Research has shown that alpelisib is already approved for treating certain types of breast cancer. This approval indicates it is considered safe for human use, though patients should be aware of possible side effects. Alpelisib is often used with tamoxifen, and both drugs have been used in breast cancer treatment with established safety data.

Overall, these drugs have been studied and used with some understanding of their safety. It is important for patients to discuss any concerns with healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they target specific breast cancer subtypes with promising combinations. The use of Alpelisib combined with Tamoxifen offers a unique approach by integrating a PI3K inhibitor with a well-known selective estrogen receptor modulator, potentially enhancing efficacy against certain cancer subtypes. Meanwhile, Zotatifin paired with Fulvestrant introduces an innovative mechanism by using an eIF4A inhibitor to disrupt protein synthesis, potentially inhibiting cancer growth in a new way. These treatments aim to address the limitations of existing options by offering targeted, potentially more effective solutions for specific breast cancer subtypes.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research has shown that combining Alpelisib with Tamoxifen, a treatment option in this trial, may help treat certain types of breast cancer. In earlier studies, patients responded to this treatment for an average of about 5.77 months. Similarly, the combination of Zotatifin and Fulvestrant, another treatment option in this trial, has shown positive results. Zotatifin, when used with Fulvestrant, helped shrink tumors in patients who had tried other treatments before. Both treatment combinations target specific genetic changes in breast cancer, offering hope for more personalized and effective treatments. ^{5 6 7 8 9}

Who Is on the Research Team?

Jennifer Caswell-Jin

Principal Investigator

Stanford Universiy

Are You a Good Fit for This Trial?

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Effector Therapeutics

Industry Sponsor

Trials

11

Recruited

600+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9631302/

Real world outcomes with alpelisib in metastatic hormone ... The median duration of response was 5.77 months (range: 5.54, 8.98). At the time of this report, 8/27 (29.6%) patients had died, and all deaths were attributed ...

2. uspharmacist.com uspharmacist.com/article/breast-cancer-screening-and-treatment-update-1

Breast Cancer Screening and Treatment Update In the Mammary Prevention 3 trial, exemestane reduced the reslative incidence of invasive breast cancers by 65% compared with placebo. The NCCN ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10416257/

A review of FDA approved drugs and their formulations for ... Vinorelbine alone or in combination is an effective and safe treatment for pre-treated locally advanced, metastatic, or secondary breast cancer patients. When ...

4. mayo.edu mayo.edu/research/clinical-trials/tests-procedures/hormone-therapy-for-breast-cancer

Hormone Therapy For Breast Cancer Clinical Trials This phase IIb trial studies how well low-dose tamoxifen citrate works in reducing breast cancer risk in radiation-induced cancer survivors.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1368764615000552

Treatment strategies for advanced hormone receptor ... This review will examine the treatment options available for patients with HR-positive/HER2-negative breast cancer, with an emphasis on the role of treatment ...

6. ema.europa.eu ema.europa.eu/fr/media/48505

Alpelisib EU Safety Risk Management Plan Have prescribed Piqray (alpelisib) ideally in at least 1 advanced breast cancer patient. Milestones: Final report submission: 31-May-2025.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2019/212526Orig1s000MultidisciplineR.pdf

212526Orig1s000 - accessdata.fda.gov Alpelisib (PIQRAY) is indicated for the treatment of postmenopausal women, and men, with hormone receptor. (HR)-positive, HER2-negative, ...

8. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK596653/

Clinical Review - Alpelisib (Piqray) - NCBI - NIH The most common cause of on-treatment death was breast cancer (3.6% in the alpelisib group and 4.1% in the placebo group) and other causes of on-treatment death ...

9. hhs.texas.gov hhs.texas.gov/sites/default/files/documents/jan-2024-durb-agenda-item5q.pdf

Oncology Oral Breast Cancer TCR There are no safety or efficacy data for abemaciclib, alpelisib, elacestrant, exemestane, lapatinib, letrozole, neratinib, palbociclib ...