Triple Drug Therapy for HER2 Positive Breast Cancer

Overseen By Monica Rocha

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Jonsson Comprehensive Cancer Center

Must not be taking: Anticoagulants, Corticosteroids, CYP3A4 inducers

Disqualifiers: Other malignancy, Hypertension, Heart disease, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 23

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib/II trial studies the side effects and best dose of ribociclib, tucatinib, and trastuzumab for the treatment of HER2 positive breast cancer that has spread to other parts of the body (metastatic), and then compares the effect of ribociclib, tucatinib, trastuzumab with or without fulvestrant to docetaxel, carboplatin, trastuzumab, and pertuzumab (standard of care) for the treatment of early stage breast cancer before surgery (neoadjuvant therapy). Ribociclib and tucatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Trastuzumab is a form of targeted therapy because it attaches itself to specific molecules (receptors) on the surface of tumor cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the tumor cell may be marked for destruction by the body's immune system. Pertuzumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Estrogen can cause the growth of breast tumor cells. Fulvestrant blocks the use of estrogen by the tumor cells. Chemotherapy drugs, such as docetaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib, tucatinib, and trastuzumab with or without fulvestrant before surgery may make the tumor smaller and may reduce the amount of normal tissue that needs to be removed.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it mentions that participants cannot be on certain non-protocol anti-cancer therapies and must stop using specific medications like raloxifene, tamoxifen, or aromatase inhibitors at least 28 days before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What evidence supports the effectiveness of the triple drug therapy for HER2-positive breast cancer?

Research shows that drugs targeting HER2, like trastuzumab and tucatinib, have significantly improved outcomes for patients with HER2-positive breast cancer, which is a particularly aggressive form of the disease. These drugs have been shown to prolong survival and improve prognosis, especially when used in combination with other therapies. ^{1 2 3 4 5}

Is the triple drug therapy for HER2-positive breast cancer safe?

Ribociclib (Kisqali) has been studied for safety in breast cancer, with common side effects including low white blood cell counts, nausea, and fatigue. Trastuzumab (Herceptin and its biosimilars) is widely used for HER2-positive breast cancer and is generally considered safe, though it can cause heart problems in some cases. Tucatinib (Tukysa) has shown safety in early trials, particularly for brain metastases in HER2-positive breast cancer. ^{6 7 8 9 10}

How does the triple drug therapy for HER2-positive breast cancer differ from other treatments?

This triple drug therapy combines oral vinorelbine, capecitabine, and trastuzumab, offering a unique oral chemotherapy option alongside trastuzumab, which is typically used in combination with other chemotherapy drugs. This approach may provide a different administration route and potentially improved convenience for patients compared to standard intravenous treatments. ^{5 11 12 13 14}

Research Team

Nicholas P McAndrew, M.D.

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Eligibility Criteria

Adults with HER2 positive metastatic breast cancer or early stage breast cancer pre-surgery can join. They need a normal heart function, blood counts within specific ranges, and proper liver and kidney function. Pregnant women can't participate; others must use effective contraception. Excluded are those with recent other cancers, uncontrolled conditions like hypertension, major surgery within the last month, certain drug therapies, infections or heart issues.

Inclusion Criteria

My kidney function, measured by creatinine clearance, is adequate.

I may receive blood transfusions, G-CSF, and hydration as part of the study.

Your calcium levels in your blood are normal or can be adjusted to normal before starting the trial.

Exclusion Criteria

I am on medication for seizures.

You have a history of having a longer than normal QT interval in your heart.

I cannot swallow pills or have a stomach condition that affects medication absorption.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ib Treatment

Patients receive ribociclib, tucatinib, and trastuzumab. Cycles repeat every 28 days for up to 4 cycles.

16 weeks

Weekly visits for IV administration

Phase II Treatment

Patients receive different combinations of ribociclib, tucatinib, trastuzumab, fulvestrant, docetaxel, carboplatin, and pertuzumab based on hormone receptor status. Cycles repeat every 21-28 days for up to 6 cycles.

18-24 weeks

Every 21-28 days for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Ribociclib
• Trastuzumab
• Tucatinib

Trial Overview The trial is testing ribociclib and tucatinib's effectiveness in stopping tumor growth when combined with trastuzumab for metastatic cases. It also compares this combo to standard chemotherapy before surgery in early-stage cases. The study will determine the best dose of these drugs and their impact on tumor size reduction.

Participant Groups

Group I: Phase Ib (ribociclib, tucatinib, trastuzumab) Experimental Treatment 4 Interventions

Patients receive ribociclib PO QD on days 1-21, tucatinib PO BID on days 1-28, and trastuzumab IV over 30-90 minutes every 7 days. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Phase II,Arm A(ribociclib,tucatinib, trastuzumab, fulvestrant) Experimental Treatment 4 Interventions

Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28, trastuzumab IV over 30-90 minutes every 7 days and fulvestrant subcutaneously (SC) on days 1 and 15 of cycle 1 and day 1 of every subsequent cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group III: Phase II, Arm C (ribociclib, tucatinib, trastuzumab) Experimental Treatment 4 Interventions

Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28, and trastuzumab IV over 30-90 minutes every 7 days. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group IV: Phase II,Arm B(docetaxel,carboplatin,trastuzumab,pertuzumab) Active Control 5 Interventions

Patients receive docetaxel IV over 1 hour on day 1, carboplatin IV on day 1, trastuzumab IV over 30-90 minutes on day 1, and pertuzumab IV over 1 hour on day 1. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

Seagen Inc.

Industry Sponsor

Trials

212

Recruited

73,800+

Founded

1997

Headquarters

Bothell, USA

Known For

Antibody-Drug Conjugates

Top Products

Adcetris (brentuximab vedotin), Tukysa (tucatinib), Padcev (enfortumab vedotin-ejfv), Tivdak (tisotumab vedotin-tftv)

Dr. Roger Dansey

Seagen Inc.

Chief Medical Officer since 2018

MD from University of Witwatersrand

David R. Epstein

Seagen Inc.

Chief Executive Officer since 2022

BSc in Pharmacy from Rutgers University, MBA from Columbia University

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Findings from Research

HER2-positive breast cancer, which historically had a poor prognosis, can now be effectively treated with a variety of anti-HER2 therapies, significantly improving patient survival rates.

Newly developed treatments, including trastuzumab deruxtecan and trastuzumab emtansine, along with ongoing clinical trials, are expanding options for patients with advanced HER2-positive breast cancer, raising important questions about the best treatment sequences and combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-HER2 Drugs for the Treatment of Advanced HER2 Positive Breast Cancer. Stanowicka-Grada, M., Senkus, E.[2023]

HER2-positive breast cancer, which affects about 20% of cases, has seen improved treatment outcomes with therapies like trastuzumab and pertuzumab, making it crucial to tailor treatment strategies based on disease progression and patient needs.

Current first-line treatment for HER2+ metastatic breast cancer involves a combination of taxane, trastuzumab, and pertuzumab, while trastuzumab deruxtecan is preferred in the second line, especially for patients with central nervous system involvement, highlighting the importance of evolving treatment protocols and ongoing research into new therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic HER2-Positive Breast Cancer: Is There an Optimal Sequence of Therapy? Dempsey, N., Sandoval, A., Mahtani, R.[2023]

HER2 overexpression is a significant factor in 20% of breast cancers, leading to poor patient prognosis, but targeted therapies like trastuzumab, lapatinib, and pertuzumab have been shown to significantly improve outcomes for HER2-positive patients.

The FDA has recently approved the combination of trastuzumab, pertuzumab, and docetaxel as a first-line treatment for metastatic breast cancer, along with trastuzumab emtansine (T-DM1), highlighting the ongoing advancements in HER2-targeted therapies and the need to address challenges like drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HER2-directed therapy for metastatic breast cancer. Jelovac, D., Emens, LA.[2014]

The definition of HER2-positive breast cancer is evolving to include a 'HER2-low' category, which may respond to new antibody drug conjugates (ADCs), offering potential treatment options for patients previously considered HER2-negative.

Resistance to HER2-targeted therapies is a significant challenge, but combining treatments that target downstream signaling pathways, like PI3K and AKT/mTOR, may help overcome this resistance and improve outcomes for patients with HER2-positive and HER2-low tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Human Epidermal Growth Factor Receptor Family in Breast Cancer beyond HER2. Riecke, K., Witzel, I.[2023]

HER2-targeted therapies, such as trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1), have significantly improved survival rates for patients with HER2-positive breast cancer, both in early and advanced stages, without increasing toxicity.

Despite these advancements, resistance to HER2-targeted treatments is common, highlighting the need for further research into the mechanisms of resistance and the development of biomarkers to personalize therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updates on the treatment of human epidermal growth factor receptor type 2-positive breast cancer. Kim, M., Agarwal, S., Tripathy, D.[2020]

Ribociclib, a CDK 4/6 inhibitor, significantly improves median progression-free survival (PFS) in women with HR+/HER2- metastatic breast cancer when used in combination with endocrine therapy, with PFS ranging from 8 to 13 months across three phase III trials.

The treatment is well tolerated, particularly in elderly patients, and while it has some dose-limiting toxicities like neutropenia and QTc prolongation, it maintains health-related quality of life and reduces pain scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. Rascon, K., Flajc, G., De Angelis, C., et al.[2020]

A feasibility study of a non-taxane triple therapy (pertuzumab, trastuzumab, and eribulin mesylate) for advanced HER2-positive breast cancer showed promising results, with no Grade 4 or 5 adverse events reported among the 10 enrolled patients.

The therapy led to significant increases in the CD8+ T cell/CD4+Foxp3+ regulatory T cell ratio, suggesting an immune response, and showed an improving trend in quality of life as measured by the FACT-B score at 3 months, indicating potential efficacy and safety for patients who cannot tolerate taxanes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers. Tono, Y., Ishihara, M., Miyahara, Y., et al.[2019]

In a phase I study involving 41 patients with HER2-positive brain metastases, the combination of tucatinib and trastuzumab was found to be tolerable, with a maximum tolerated dose of 300 mg twice daily or 750 mg once daily, and common side effects including elevated liver enzymes.

The treatment showed preliminary efficacy, with a clinical benefit rate of 35% in the twice-daily cohort and 53% in the once-daily cohort, indicating potential effectiveness in managing brain metastases in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases. Metzger Filho, O., Leone, JP., Li, T., et al.[2021]

Trastuzumab biosimilars, including MYL-1401O, CT-P6, SB3, PF-05280014, and ABP980, have been approved by the FDA for treating HER2-positive breast cancer, offering potential cost savings and improved access to targeted therapies.

The review highlights the importance of clinical data supporting these biosimilars, suggesting that their adoption in clinical practice will rely on healthcare providers' confidence in the evidence of their efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biosimilars for breast cancer: a review of HER2-targeted antibodies in the United States. Miller, EM., Schwartzberg, LS.[2020]

Ribociclib, approved by the FDA for treating advanced breast cancer, significantly improves progression-free survival when combined with letrozole compared to a placebo, as shown in a study of 668 patients.

The overall response rate for patients receiving ribociclib plus letrozole was 52.7%, compared to 37.1% for those on placebo, indicating its efficacy, although common side effects included neutropenia and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. Shah, A., Bloomquist, E., Tang, S., et al.[2019]

Trastuzumab effectively targets HER-2, a protein overexpressed in about 20% of breast cancers, and has shown clinical benefits when used alone or with chemotherapy, particularly in patients with HER-2 amplification.

Combining trastuzumab with docetaxel, a powerful chemotherapy drug, has demonstrated significant efficacy in treating HER-2-positive breast cancer, making these combinations some of the most effective therapies available for both metastatic and early-stage patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel/trastuzumab combination therapy for the treatment of breast cancer. Nabholtz, JM., Gligorov, J.[2019]

In a phase II trial involving 50 patients with HER2-positive metastatic breast cancer, the combination of oral vinorelbine, capecitabine, and trastuzumab resulted in a high objective response rate of 77% and a clinical benefit rate of 93%.

The treatment demonstrated a median overall survival of 47 months and a manageable safety profile, with the most common severe side effects being neutropenia (71%) and hand-foot syndrome (20%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of a triple combination of oral vinorelbine, capecitabine and trastuzumab as first-line treatment in HER2-positive metastatic breast cancer. Chan, A., Conte, PF., Petruzelka, L., et al.[2018]

Adjuvant chemotherapy significantly reduces breast cancer mortality by one-third, but the individual benefits can vary based on tumor characteristics and patient health, making the decision to use it a careful balance of risks and benefits.

For HER2-positive breast cancer, trastuzumab is crucial as it greatly enhances prognosis, while the most effective chemotherapy regimen for aggressive types includes both an anthracycline and a taxane.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Medical treatment of breast cancer: chemotherapy and tailored therapy]. Dalenc, F.[2014]

Trastuzumab (Herceptin) combined with endocrine therapy is a promising treatment for women with less aggressive, estrogen receptor/HER2-positive metastatic breast cancer, while for aggressive HER2-positive cases, it significantly improves survival when used with chemotherapy, particularly taxanes.

Trastuzumab has a favorable safety profile, adding little toxicity to taxane chemotherapy, and enhances quality of life compared to chemotherapy alone, making it a viable option for patients who may not tolerate cytotoxic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maximizing clinical benefit with trastuzumab. Bell, R., Verma, S., Untch, M., et al.[2019]

References

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

Anti-HER2 Drugs for the Treatment of Advanced HER2 Positive Breast Cancer. [2023]

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

Metastatic HER2-Positive Breast Cancer: Is There an Optimal Sequence of Therapy? [2023]

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

HER2-directed therapy for metastatic breast cancer. [2014]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting the Human Epidermal Growth Factor Receptor Family in Breast Cancer beyond HER2. [2023]

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

Updates on the treatment of human epidermal growth factor receptor type 2-positive breast cancer. [2020]

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

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. [2020]

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

Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Biosimilars for breast cancer: a review of HER2-targeted antibodies in the United States. [2020]

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

FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Docetaxel/trastuzumab combination therapy for the treatment of breast cancer. [2019]

12. Greece pubmed.ncbi.nlm.nih.gov

Phase II study of a triple combination of oral vinorelbine, capecitabine and trastuzumab as first-line treatment in HER2-positive metastatic breast cancer. [2018]

13. France pubmed.ncbi.nlm.nih.gov

[Medical treatment of breast cancer: chemotherapy and tailored therapy]. [2014]

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

Maximizing clinical benefit with trastuzumab. [2019]