Alpelisib + Tucatinib for Breast Cancer

Recruiting in Palo Alto (17 mi)

+5 other locations

Overseen by Elena Shagisultanova

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Criterium, Inc.

Must be taking: Fulvestrant

Must not be taking: CYP3A4, CYP2C8 inhibitors

Disqualifiers: Pregnancy, Diabetes, Infections, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a combination of two drugs, tucatinib and alpelisib, in patients with a specific type of advanced breast cancer. These patients have a genetic mutation and a type of cancer that may not respond well to standard treatments. The drugs work by blocking signals that help cancer cells grow. Alpelisib is approved for treating certain types of advanced breast cancer.

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.

What data supports the effectiveness of the drug combination Alpelisib and Tucatinib for breast cancer?

Alpelisib has shown effectiveness in treating certain types of breast cancer, particularly those with a specific genetic mutation (PIK3CA), when used with another drug called fulvestrant. Tucatinib has been effective in treating breast cancer that has spread to the brain. These findings suggest that the combination of Alpelisib and Tucatinib could be beneficial for breast cancer treatment. ^{1 2 3 4 5}

What safety information is available for Alpelisib and Tucatinib in humans?

Alpelisib has been associated with side effects like diarrhea and high blood sugar, while Tucatinib has been linked to diarrhea and liver issues. Both drugs have been approved for use in certain types of breast cancer, indicating they have been evaluated for safety in humans. ^{1 3 6 7 8}

What makes the drug combination of Alpelisib and Tucatinib unique for breast cancer treatment?

The combination of Alpelisib and Tucatinib is unique because Alpelisib targets a specific mutation (PIK3CA) in breast cancer cells, while Tucatinib is known for its activity against HER2-positive breast cancer, potentially offering a novel approach for patients with specific genetic profiles. ^{1 3 4 9 10}

Research Team

Elena Shagisultanova

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Alpelisib (PI3K Inhibitor)
• Tucatinib (HER2 Inhibitor)

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.

Participant Groups

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.

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

Findings from Research

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]

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]

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]

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 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]

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 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 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]

References

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

Alpelisib: First Global Approval. [2020]

2. 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]

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

Pharmaceutical Approval Update. [2020]

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

The PI3Kα Inhibitor Alpelisib Has Activity in PIK3CA-altered Tumors. [2019]

5. England 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. [2023]

6. Switzerland 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. [2023]

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

FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer. [2022]

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

FDA Approval Summary: Alpelisib for PIK3CA-related Overgrowth Spectrum (PROS). [2023]

9. United States 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. [2022]

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

Alpelisib Efficacy without Cherry-PI3King Mutations. [2023]