Alpelisib + Tucatinib for Breast Cancer

Recruiting at 5 trial locations

Overseen By Soumaya Chappidi

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Criterium, Inc.

Must be taking: Fulvestrant

Must not be taking: CYP3A4, CYP2C8 inhibitors

Disqualifiers: Pregnancy, Diabetes, Infections, others

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: Unknown

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two medications, Alpelisib (Piqray) and Tucatinib (Tukysa, ONT-380, or ARRY-380), to evaluate their effectiveness for individuals with a specific type of breast cancer that has spread and exhibits certain genetic traits. The goal is to determine the safest and most effective doses for those with HER2-positive metastatic breast cancer that also has a PIK3CA mutation. It suits individuals with this advanced breast cancer who have already tried at least two targeted treatments and meet specific health conditions. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use certain medications that strongly affect liver enzymes (CYP3A4 and CYP2C8) within a specific time before starting the trial. It's best to discuss your current medications with the trial team.

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

Research has shown that the combination of alpelisib and tucatinib is generally well-tolerated. Studies have found this treatment to be safe at certain doses, with patients responding well and experiencing no major safety issues. Most side effects were manageable and did not necessitate stopping the treatment. This suggests the treatment could be a viable option for individuals with PIK3CA-mutant HER2-positive metastatic breast cancer. However, it is important to consult a doctor about potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Alpelisib and Tucatinib for breast cancer because it targets cancer cells in a novel way. While standard treatments often focus on hormone receptors or HER2 proteins individually, this duo takes on both PI3K and HER2 pathways simultaneously, potentially enhancing effectiveness. Alpelisib specifically inhibits the PI3K pathway, which plays a role in cancer cell growth, while Tucatinib targets the HER2 protein, crucial in many aggressive breast cancers. This dual-action approach could offer a more comprehensive attack on cancer cells, providing hope for better outcomes in patients with HR+/HER2+ metastatic breast cancer.

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

This trial will evaluate the combination of alpelisib and tucatinib for treating HER2-positive breast cancer with PIK3CA mutations. Research has shown that this combination is effective, with earlier studies indicating that three out of five patients experienced a partial response, meaning their tumors got smaller. This combination is not only effective but also well-tolerated, allowing patients to undergo treatment without severe side effects. Tucatinib specifically targets and reduces activity in cancer cells with excessive HER2, a protein that promotes cancer cell growth. Alpelisib blocks a specific pathway (PI3K) that cancer cells use to multiply. Together, these drugs show promise in stopping cancer growth in patients with this specific type of breast cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Elena Shagisultanova

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for adults with HER2-positive metastatic breast cancer that has a specific mutation (PIK3CA). Participants must understand the study and be willing to follow its procedures. They should have an ECOG performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. People with severe medical conditions, recent anti-cancer therapy, pregnancy, certain drug hypersensitivities, or inability to swallow pills cannot join.

Inclusion Criteria

You have a disease that can be measured or evaluated using specific criteria.

My tumor has a PIK3CA mutation.

Ability to understand and the willingness to sign a written informed consent and comply with the study scheduled visits, treatment plans, laboratory tests and other procedures

Exclusion Criteria

I haven't taken any forbidden medications recently.

I haven't had any cancer treatment or surgery in the last 14 days.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ib Treatment

Tolerability of tucatinib and alpelisib combination is confirmed and maximum tolerated dose determined. Therapy administered in 28-day cycles.

10 months

Monthly visits (in-person)

Phase II Treatment

Expansion of drug combination testing at maximum tolerated dose to determine progression-free survival rate.

20 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Alpelisib
• Tucatinib

Trial Overview The trial is testing the combination of Alpelisib and Tucatinib with Fulvestrant in patients who have PIK3CA-Mutant HER2+ metastatic breast cancer. It's designed to see how safe this combo is and how well it works compared to standard treatments.

How Is the Trial Designed?

Group I: Ib Safety Cohort /II Expansion Cohort Experimental Treatment 3 Interventions

In phase Ib, the tolerability of tucatinib and alpelisib combination will be confirmed and maximum tolerated dose determined. Therapy will be administered in 28 day cycles of tucatinib 300 mg PO BID and alpelisib 250 mg PO daily (dose level 1). Treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. Fulvestrant will also be administered in patients with HR+/HER2+ metastatic breast cancer. Once RP2D is determined, the study will be continued to phase II, and new patients will enroll at RP2D. All patients in phase IB part, who are remaining on study at the time of initiation of phase II, will be rolled over to phase II. At that time, their study drug doses will be modified as follows: (1) if a patient is on the drug doses lower than RP2D, doses will not be increased; (2) if a patient is on a higher doses compared to RP2D, doses of study drugs will be changed to RP2D.

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?

Criterium, Inc.

Lead Sponsor

Trials

18

Recruited

730+

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

Published Research Related to This Trial

Alpelisib is an approved PI3K inhibitor that effectively treats metastatic estrogen receptor-positive breast cancers with specific PIK3CA hotspot mutations, as shown in clinical trials.

Recent findings suggest that patients with non-hotspot PIK3CA mutations also benefit from alpelisib, expanding its potential use in clinical practice beyond the initially defined mutation hotspots.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib Efficacy without Cherry-PI3King Mutations. Tau, S., Miller, TW.[2023]

Tucatinib, approved by the FDA for advanced HER2-positive breast cancer, significantly improved progression-free survival (PFS) and overall survival (OS) compared to placebo, particularly benefiting patients with brain metastases, who comprised 48% of the study population.

The HER2CLIMB trial demonstrated a favorable benefit-risk profile for tucatinib, although it is associated with safety concerns such as diarrhea and hepatotoxicity, which are important to monitor during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer. Shah, M., Wedam, S., Cheng, J., et al.[2022]

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]

Alpelisib received accelerated FDA approval for treating severe PIK3CA-related overgrowth spectrum (PROS) in patients aged 2 years and older, based on real-world data from a study involving 37 patients, where 27% showed a significant radiologic response after 24 weeks.

Among those who responded to treatment, 60% maintained their response for at least 12 months, indicating potential long-term benefits, although common side effects included diarrhea, stomatitis, and hyperglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Alpelisib for PIK3CA-related Overgrowth Spectrum (PROS). Singh, S., Bradford, D., Li, X., et al.[2023]

The combination of alpelisib and infigratinib can be safely administered at full doses in patients with PIK3CA-mutant advanced solid tumors, although 71% of patients experienced treatment interruptions or dose reductions due to toxicity.

Despite the safety of the drug combination, the trial did not show clear evidence of enhanced efficacy or synergistic activity in patients with concurrent PIK3CA and FGFR alterations, indicating that further research is needed to optimize treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined PIK3CA and FGFR Inhibition With Alpelisib and Infigratinib in Patients With PIK3CA-Mutant Solid Tumors, With or Without FGFR Alterations. Hyman, DM., Tran, B., Paz-Ares, L., et al.[2022]

Alpelisib (Piqray™) is an oral PI3K inhibitor specifically targeting PI3Kα, showing efficacy in treating hormone receptor-positive, HER2-negative breast cancer in patients with a PIK3CA mutation.

The drug has been approved in the USA for use in combination with fulvestrant, marking a significant milestone in its development for breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib: First Global Approval. Markham, A.[2020]

The PI3Kα inhibitor alpelisib demonstrated a 58.2% disease control rate in patients with solid tumors that have PIK3CA alterations, indicating its potential efficacy in this specific cancer population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PI3Kα Inhibitor Alpelisib Has Activity in PIK3CA-altered Tumors. [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]

In a real-life study of 233 patients with advanced breast cancer who had PIK3CA mutations, treatment with alpelisib and fulvestrant resulted in a median progression-free survival (PFS) of 5.3 months, indicating its efficacy even after multiple prior treatments.

However, 39.1% of patients discontinued alpelisib due to adverse events, highlighting the importance of monitoring for side effects in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program. Bello Roufai, D., Gonçalves, A., De La Motte Rouge, T., et al.[2023]

In a study of 76 women with hormone receptor-positive, HER2-negative metastatic breast cancer, alpelisib combined with endocrine therapy demonstrated a median progression-free survival of 5.2 months, indicating its effectiveness in a real-world setting.

However, about 31.6% of patients had to permanently discontinue alpelisib due to adverse events, with hyperglycemia being the most common serious side effect, highlighting the need for careful monitoring of patients on this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Cohort Study of the Antitumor Efficacy and Toxicity Profile of Alpelisib for Metastatic or Locally Advanced HR+, HER2- Breast Cancer: A Single-Institution Experience. Sarfraz, H., Bari, S., Whiting, J., et al.[2023]

Citations

1. aacrjournals.org aacrjournals.org/clincancerres/article/31/12_Supplement/P5-03-10/753975/Abstract-P5-03-10-Safety-and-Preliminary-Efficacy

Abstract P5-03-10: Safety and Preliminary Efficacy of Tucatinib ... The combination of tucatinib and alpelisib is tolerable at DL1 and shows remarkable antitumor activity with partial responses in 3 out of 5 evaluable patients.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11302197/

Enhanced anti-tumor effects by combination of tucatinib and ... Tucatinib reduces the metabolic activity in HER2-overexpressing cell lines and enhances radiation effects. Breast cancer. Data of BC cell lines ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05230810

NCT05230810 | Clinical Trial of Alpelisb and Tucatinib in ... Phase IB/II clinical trial of Alpelisb and Tucatinib in patients with PIK3CA-Mutant HER2-positive metastatic breast cancer. Detailed Description. This study is ...

4. docwirenews.com docwirenews.com/post/the-combination-of-tucatinib-and-alpelisib-shows-efficacy-in-patients-with-her2-positive-metastatic-breast-cancer

The Combination of Tucatinib and Alpelisib Shows Efficacy ... The combination of tucatinib and alpelisib is both tolerable and effective at treating patients with HER2-positive (HER2+) PIK3CA-mutated metastatic breast ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1526820925001673

Sequential Therapy With HER2 Tyrosine Kinase Inhibitors ... Interim safety analysis of phase IB trial of HER2 inhibitor tucatinib combined with PI3Kα inhibitor alpelisib in HER2+ PIK3CA-mutated metastatic breast cancer.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e13021

Interim safety analysis of phase IB trial of HER2 inhibitor ... Conclusions: Tucatinib and alpelisib combination is tolerable at DL1 and demonstrates promising antitumor activity, including responses in pts ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05230810

NCT05230810 | Clinical Trial of Alpelisb and Tucatinib in ... Phase IB/II clinical trial of Alpelisb and Tucatinib in patients with PIK3CA-Mutant HER2-positive metastatic breast cancer. Detailed Description. This study is ...

8. conference-correspondent.com conference-correspondent.com/highlights/sabcs/1274:trial-to-assess-alpelisib-in-combination-with-tucatinib-in-pik3ca-mutated-her2-positive-metastatic-breast-cancer

Trial to Assess Alpelisib in Combination with Tucatinib ... Clinical trial assessing alpelisib plus tucatinib in HER2-positive mBC with PIK3CA mutations is currently enrolling patients.

9. cancertherapyadvisor.com cancertherapyadvisor.com/news/breast-cancer-clinical-trial-tucatinib-alpelisib-pik3ca-her2/

Clinical Trial: Tucatinib Plus Alpelisib in PIK3CA-Mutant, ... The primary outcomes are the safety and tolerability of the combination in phase 1b and progression-free survival in phase 2. Secondary outcomes ...