Alpelisib + Trastuzumab + Pertuzumab for Breast Cancer

(EPIK-B2 Trial)

Not currently recruiting at 47 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must be taking: Taxane, Trastuzumab, Pertuzumab

Disqualifiers: Diabetes, Pancreatitis, Heart disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new maintenance treatment for individuals with advanced HER2-positive breast cancer, specifically targeting those with the PIK3CA genetic mutation. Researchers are testing a combination of alpelisib (Piqray), trastuzumab, and pertuzumab to determine its effectiveness compared to a placebo. The trial consists of two parts: the first assesses the safety of different alpelisib doses, and the second evaluates the treatment's effectiveness. Individuals previously treated with certain chemotherapy drugs and possessing the PIK3CA mutation in their tumors may be suitable candidates for this study. As a Phase 3 trial, this study serves as the final step before FDA approval, offering participants the chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that combining alpelisib, trastuzumab, and pertuzumab is safe for individuals with HER2-positive breast cancer. Earlier studies found that the side effects of this combination were similar to those observed in previous research on alpelisib, indicating expected outcomes. Most patients may experience common side effects from these drugs, but they are typically manageable. Alpelisib has been used in similar contexts before, so doctors understand how the body reacts to it.

The trial is in an advanced stage, indicating that the treatment has already passed earlier safety tests. Extensive safety data supports this, providing confidence in trying the treatment in the trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for breast cancer?

Researchers are excited about the combination of Alpelisib with Trastuzumab and Pertuzumab for breast cancer because it targets cancer growth in a new way. Unlike standard therapies that focus mainly on HER2 receptors, Alpelisib specifically inhibits the PI3K pathway, which is often activated in breast cancer, leading to tumor growth. This dual-action approach not only targets the cancer cells more precisely but also addresses resistance issues associated with other treatments. By combining these drugs, there is potential to enhance the overall effectiveness and provide a more comprehensive treatment strategy for patients.

What evidence suggests that this trial's treatments could be effective for HER2-positive advanced breast cancer?

Research has shown promising results for using a combination of three drugs—alpelisib, trastuzumab, and pertuzumab—to treat HER2-positive advanced breast cancer with a PIK3CA mutation. In this trial, participants will receive different dosages of alpelisib alongside trastuzumab and pertuzumab, or a placebo version of alpelisib with trastuzumab and pertuzumab. Studies have found that patients receiving this combination therapy have better overall survival rates. For example, one study found that 62.9% of patients lived longer after one year when treated with these drugs. Early data also suggest that this treatment could offer significant benefits. This combination targets specific pathways in cancer cells, potentially increasing the treatment's effectiveness. These findings provide hope for better outcomes in managing advanced breast cancer. ^{2 4 6 7 8}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for HER2-positive advanced breast cancer patients with a PIK3CA mutation who completed up to 8 cycles of taxane-based therapy. They must have good performance status and organ function, no inflammatory breast cancer, uncontrolled heart issues, history of severe skin reactions or lung disease, diabetes type I or uncontrolled type II.

Inclusion Criteria

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

I've had up to 8 treatments with specific drugs for my cancer, or stopped at 4-5 due to side effects.

My bone marrow and organs are functioning well.

Exclusion Criteria

I have been diagnosed with type I diabetes or my type II diabetes is not under control.

I have been diagnosed with inflammatory breast cancer.

I have serious heart problems that are not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part 1: Safety Run-in

Open-label safety run-in to confirm the recommended phase 3 dose of alpelisib in combination with trastuzumab and pertuzumab

6 weeks

Multiple visits for dose escalation and monitoring

Part 2: Randomized Treatment

Randomized, double-blind, placebo-controlled phase to assess efficacy and safety of alpelisib in combination with trastuzumab and pertuzumab

Up to approximately 38 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Alpelisib
• Pertuzumab
• Trastuzumab

Trial Overview The study tests the effectiveness and safety of Alpelisib in combination with Trastuzumab and Pertuzumab as maintenance therapy post-taxane induction. It's a two-part study: an initial phase to confirm safe dosage followed by a randomized comparison with placebo.

How Is the Trial Designed?

Group I: Part 2: Alpelisib + Trastuzumab + Pertuzumab Experimental Treatment 3 Interventions

Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200mg alpelisib, with potential for intra-participant dose escalation to 250 mg

Group II: Part 1: Alpelisib + Trastuzumab + Pertuzumab Experimental Treatment 3 Interventions

In the Part 1, up to 3 alpelisib dose levels may be sequentially tested in 3 cohorts of subjects: Cohort A: Alpelisib 300mg + trastuzumab (6mg/kg) + pertuzumab (420 mg) Cohort B: Alpelisib 250 mg+ trastuzumab (6mg/kg) + pertuzumab (420 mg) Cohort C: Alpelisib 200mg + trastuzumab (6mg/kg) + pertuzumab (420 mg)

Group III: Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab Placebo Group 3 Interventions

Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200 mg alpelisib matching placebo, with potential for intra-participant dose escalation to 250 mg

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead 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

Published Research Related to This Trial

The novel anti-HER2 antibody 5G9 showed significantly stronger synergistic effects with trastuzumab in inhibiting cell growth compared to pertuzumab, achieving an 85% inhibition rate versus 55% (P<0.001).

In animal models, the combination of 5G9 and trastuzumab demonstrated greater antitumor efficacy than the pertuzumab and trastuzumab combination, suggesting that 5G9 could be a more effective treatment option for HER2-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic antitumor activity. Ding, X., Gu, W., Zhong, Y., et al.[2021]

A study involving 808 patients with HER-2 positive breast cancer showed that adding pertuzumab to trastuzumab and docetaxel significantly improved overall survival, with a 3-year survival rate increase of 10% to 15%.

While pertuzumab did not worsen cardiac toxicity in patients with low cardiovascular risk, it was associated with increased side effects such as severe diarrhea and skin disorders, indicating the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]

Pertuzumab is an effective anti-HER2 monoclonal antibody that works by preventing HER2 from forming heterodimers, which reduces tumor cell growth and survival, particularly in HER2-positive metastatic breast cancer.

In the phase III CLEOPATRA trial involving a combination of pertuzumab, trastuzumab, and docetaxel, patients experienced significantly improved progression-free survival and overall survival compared to those receiving placebo, with an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab: a review of its use for first-line combination treatment of HER2-positive metastatic breast cancer. McCormack, PL.[2021]

A comprehensive analysis of 14,707 adverse events related to pertuzumab from the FDA Adverse Event Reporting System revealed significant safety concerns, including potential risks of myelosuppression, cardiotoxicity, and other serious conditions occurring in 12 organ systems.

Most adverse events, particularly cardiac-related issues, were reported within the first month of therapy, highlighting the need for careful monitoring and preparedness for emergency interventions, especially in elderly patients and those with pre-existing cardiovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A disproportionality analysis of adverse events associated to pertuzumab in the FDA Adverse Event Reporting System (FAERS). Zou, SP., Yang, HY., Ouyang, ML., et al.[2023]

Pertuzumab, a new monoclonal antibody targeting HER2, has shown improved patient outcomes in clinical trials for early-stage and metastatic HER2-positive breast cancer, especially when used in combination with chemotherapy and trastuzumab.

The review highlights that while trastuzumab has improved survival for HER2-positive breast cancer, there is still a need for better treatment options, which pertuzumab aims to address, particularly for patients who continue to relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab in human epidermal growth-factor receptor 2-positive breast cancer: clinical and economic considerations. Lamond, NW., Younis, T.[2021]

In a study of 57 patients with HER2-positive breast cancer receiving neoadjuvant treatment with doxorubicin and cyclophosphamide followed by trastuzumab and pertuzumab, only 3.5% developed severe heart failure, indicating a relatively low cardiac event rate.

The study found no increased risk of cardiotoxicity from the combination of trastuzumab and pertuzumab after doxorubicin-based chemotherapy, suggesting that this treatment regimen is cardiac safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer. Yu, AF., Singh, JC., Wang, R., et al.[2018]

Alpelisib (Piqray) is effective for treating advanced or metastatic breast cancer that is HR-positive, HER2-negative, and has PIK3CA mutations, targeting specific genetic alterations to improve treatment outcomes.

Polatuzumab vedotin-piiq (Polivy) is used for diffuse large B-cell lymphoma, while eculizumab (Soliris) is indicated for neuromyelitis optica spectrum disorder, highlighting the development of targeted therapies for specific cancer types and autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. Choy, M.[2020]

In a study of 55 women with HER2-positive metastatic breast cancer, the combination of trastuzumab and pertuzumab with chemotherapy resulted in a median progression-free survival (PFS) of 10 months, indicating significant efficacy in this treatment approach.

The treatment was generally safe, with common side effects including neutropenia (40%), leukopenia (34.5%), and thrombocytopenia (32.7%), but serious adverse reactions were relatively low, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab plus pertuzumab in combination with chemotherapy in metastatic HER2-positive breast cancer: a retrospective single-armed cohort study in China. Qian, Y., Peng, Y., Zhou, H., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10673796/

Real-World Treatment Patterns and Outcomes Following First ... A recent analysis using a prospective observational registry (SystHERs) showed that 75% of the patients with HER2+ mBC received pertuzumab and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12445173/

Complete Response With Alpelisib and Trastuzumab in a ... Those treated with targeted therapy after multidisciplinary tumor board discussion (n = 30) demonstrated improved 1-year overall survival (62.9% ...

3. aacrjournals.org aacrjournals.org/cancerres/article/83/7_Supplement/4926/722307/Abstract-4926-Alpelisib-in-combination-with

Abstract 4926: Alpelisib in combination with trastuzumab and ... Preliminary efficacy data suggest promising clinical benefit with ALP ... breast cancer: EPIK-B2 Study Part 1 safety and efficacy results.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04208178

NCT04208178 | Study of Alpelisib (BYL719) in ... The purpose of this two part multicenter, randomized, double-blind, placebo-controlled, Phase III study is to evaluate the efficacy and safety of alpelisib.

5. everyone.org everyone.org/explore/compare?id1=308&id2=361

Piqray (alpelisib) vs Phesgo (pertuzumab, trastuzumab, ... The results demonstrated non-inferior levels of pertuzumab and trastuzumab in the blood, suggesting that Phesgo is as effective as the separate administrations ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9640784/

Targeting HER2-positive breast cancer - PubMed Central Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1040842825000125

Challenges and prospects in HER2-positive breast cancer ... Moreover, alpelisib combined with trastuzumab achieved an apparent remission rate of 29 % among HER2-positive breast cancer patients with PIK3CA mutation (Pérez ...

8. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-02351

Study of Alpelisib (BYL719) in Combination With ... The purpose of this two part multicenter, randomized, double-blind, placebo-controlled, Phase III study is to evaluate the efficacy and safety of alpelisib.