Alpelisib + Trastuzumab + Pertuzumab for Breast Cancer

(EPIK-B2 Trial)

Recruiting at 43 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

19 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tested a combination of drugs for patients with advanced breast cancer that has a specific genetic mutation. The goal was to see if this combination could better control the cancer by blocking growth signals. The study was stopped due to changes in treatment approaches, not because of safety issues.

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.

What data supports the effectiveness of the drug combination Alpelisib, Trastuzumab, and Pertuzumab for breast cancer?

Research shows that combining trastuzumab and pertuzumab with chemotherapy can improve survival rates in patients with HER2-positive breast cancer. Pertuzumab and trastuzumab work well together because they target different parts of the HER2 protein, which is often overactive in certain breast cancers. ^{1 2 3 4 5}

What safety data exists for the combination of Alpelisib, Trastuzumab, and Pertuzumab in breast cancer treatment?

Pertuzumab, when added to Trastuzumab and chemotherapy, has been shown to increase survival in breast cancer patients without worsening heart-related side effects, although it may cause severe diarrhea, skin issues, and fever with low white blood cell count. Trastuzumab and Pertuzumab are generally safe for the heart, but ongoing monitoring of Pertuzumab's safety is recommended. ^{3 4 5 6 7}

How does the drug combination of Alpelisib, Trastuzumab, and Pertuzumab differ from other breast cancer treatments?

This drug combination is unique because it targets the HER2 protein in breast cancer cells using two different antibodies, Trastuzumab and Pertuzumab, which bind to different sites on the HER2 receptor, potentially enhancing their effectiveness. Alpelisib, a PI3K inhibitor, is added to this combination to further inhibit cancer cell growth by targeting a different pathway, making this approach potentially more effective for certain patients compared to standard treatments. ^{3 4 5 8 9}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

References

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

Pharmaceutical Approval Update. [2020]

2. China 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. [2022]

3. France pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

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

Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer. [2018]

7. England pubmed.ncbi.nlm.nih.gov

A disproportionality analysis of adverse events associated to pertuzumab in the FDA Adverse Event Reporting System (FAERS). [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic antitumor activity. [2021]

9. Australia pubmed.ncbi.nlm.nih.gov

Efficacy of late line pertuzumab with trastuzumab and chemotherapy in HER2-positive metastatic breast cancer: An Australian case series. [2020]