Alpelisib for Overgrowth Spectrum

(EPIK-P2 Trial)

Not currently recruiting at 58 trial locations

Overseen By Novartis Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Novartis Pharmaceuticals

Must not be taking: PI3K inhibitors, CYP3A4 inducers

Disqualifiers: Malignancy, Heart disease, Diabetes, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether alpelisib, a medication, can effectively treat individuals with PIK3CA-related overgrowth spectrum (PROS), a condition causing abnormal growths that impact daily life. Researchers aim to assess the safety and effectiveness of alpelisib for both children and adults with these growths. The trial includes several groups receiving either alpelisib or a placebo (a non-active substance) to compare results. Suitable candidates for this trial are those with PROS who have noticeable growths affecting daily activities and a confirmed PIK3CA gene mutation. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial requires you to stop taking strong inducers of CYP3A4 or inhibitors of breast cancer resistance protein (BCRP) at least 7 days before starting the treatment. Other medications are not specifically mentioned, so consult with the trial team for more details.

Will I have to stop taking my current medications?

The trial requires that you stop taking strong inducers of CYP3A4 or inhibitors of breast cancer resistance protein (BCRP) at least 7 days before starting the treatment. If you are on these medications, you will need to discontinue them before participating.

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

Research shows that alpelisib is generally well-tolerated, though some side effects require attention. In earlier studies, about 5% of patients lowered their dose due to side effects, and 11% temporarily paused their treatment. Common side effects include elevated blood sugar levels, which is expected with this medication type. Notably, no severe lab issues were reported, offering reassurance for those considering this treatment. Overall, the safety of alpelisib is deemed acceptable, especially given the serious conditions it targets. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for overgrowth?

Researchers are excited about Alpelisib because it specifically targets the PI3K pathway, which is linked to overgrowth conditions. Unlike standard treatments that might not target this precise pathway, Alpelisib is designed to directly inhibit this mechanism, potentially providing a more effective option for managing overgrowth disorders. Additionally, Alpelisib offers flexible dosing in both granule and tablet forms, making it adaptable for different age groups, from infants to adults, enhancing its usability across various patient needs. This targeted approach and versatile delivery make it a promising candidate for those with limited treatment options.

What evidence suggests that this trial's treatments could be effective for PIK3CA-related overgrowth spectrum?

Research has shown that alpelisib effectively treats PIK3CA-related overgrowth spectrum (PROS). In this trial, participants will enter different treatment arms, with some receiving alpelisib and others a placebo. One study found that patients experienced significant improvements, such as reduced overgrowth. The FDA approved alpelisib because many patients responded positively by week 24. Alpelisib targets a specific enzyme linked to PROS, offering a new way to manage the condition. These findings suggest that alpelisib could be a promising treatment option for people with PROS. ^{6 7 8 9 10}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for pediatric and adult patients with PIK3CA-related Overgrowth Spectrum (PROS) who have at least one measurable lesion over 2 cm confirmed by MRI. Participants must be able to provide a tissue sample, have stable blood sugar levels, and not have had previous treatment with alpelisib or similar drugs. Those with isolated macrodactyly, skin nevus/nevi, macroencephaly without other lesions, recent radiation or surgery in the area of interest are excluded.

Inclusion Criteria

Signed informed consent and assent (when applicable) from the patient, parent, legal authorized representative or guardian prior to any study related screening procedures are performed

For China only: Tissue sample collection and biomarker assessments are not applicable.

I have PROS with worsening symptoms and a confirmed measurable lesion.

Exclusion Criteria

I have not had major surgery within the last 3 months.

I have only large fingers/toes, skin moles, or an enlarged head without other PROS-related issues.

I have not been treated with alpelisib or similar drugs for more than 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

6 weeks

Core Treatment

Participants undergo a 16-week randomized, double-blind, placebo-controlled treatment period

16 weeks

Regular visits as per protocol

Extension Period

Participants continue treatment in an open-label setting for an additional 24 weeks

24 weeks

Long-term Extension

Participants may continue treatment for up to approximately 5 years

Up to 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Alpelisib
• Placebo

Trial Overview The study tests the effectiveness and safety of Alpelisib compared to a placebo in treating PROS. Initially, there's a 16-week blind phase where neither doctors nor participants know who gets Alpelisib or placebo. After that period, all may receive Alpelisib during extension periods while monitoring how their bodies absorb the drug.

How Is the Trial Designed?

Group I: Pediatric cohort (group 5: 6-17 years old)-Alpelisib FCT Experimental Treatment 1 Intervention

Pediatric participants (6 to 17 year old) will receive 125 mg alpelisib film-coated (FCT) once daily, in an open-label setting.

Group II: Pediatric cohort (group 4: 2 to 5 years old)- Alpelisib FCT Experimental Treatment 1 Intervention

Pediatric participants (2 to 5 years old) will receive 50 mg of alpelisib film-coated tablets (FCT) once daily in an open-label setting.

Group III: Pediatric cohort (group 3: 0 to 5 years old)- Alpelisib granules Experimental Treatment 1 Intervention

Pediatric participants (0 to 5 years old) will receive alpelisib granules formulation with an age-dependent starting dose (\<1 month: 20 mg every other day; 1 to \<6 months: 20 mg daily; 6 to \<2 years: 40 mg daily; 2 to \<6 years: 50 mg daily).

Group IV: Pediatric cohort (group 2: 6 to 17 years old) -Alpelisib Experimental Treatment 1 Intervention

During double-blind randomized study period (from baseline up to Week 16, pediatric participants (6 to 17 years old) will be randomized to receive alpelisib (50 mg, oral, once daily). After Week 16, participants will continue their active treatment at the same dose level.

Group V: Adult cohort (group 1)- Alpelisib Experimental Treatment 1 Intervention

During double-blind randomized study period (from baseline up to Week 16), adult participants will be randomized to receive alpelisib (125 mg, oral, once daily). After Week 16, participants will continue their active treatment at the same dose level.

Group VI: Adult cohort (group 1)- Placebo Placebo Group 2 Interventions

During double-blind randomized study period (from baseline up to Week 16), adult participants will be randomized to receive placebo. After Week 16, participants will be switched to active treatment with alpelisib at the placebo dose level received at the end of the placebo period.

Group VII: Pediatric cohort (group 2: 6 to 17 years old)-Placebo Placebo Group 2 Interventions

During double-blind randomized study period (from baseline up to Week 16), pediatric participants (6 to 17 years old) will be randomized to receive Placebo. After Week 16, participants will be switched to active treatment with alpelisib at the placebo dose level received at the end of the placebo period.

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?

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

An automated platform tested the sensitivity of 602 human tumor-derived cell lines to various selective kinase inhibitors, revealing that an ALK inhibitor effectively suppressed growth in a specific subset of tumors, including anaplastic large cell lymphomas, non-small-cell lung cancers, and neuroblastomas.

The effectiveness of the ALK inhibitor was strongly linked to specific genomic alterations in ALK, such as chromosomal translocations and gene amplification, suggesting that patients with these genetic changes may benefit from targeted ALK inhibition in their treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. McDermott, U., Iafrate, AJ., Gray, NS., 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]

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]

In a study using genome-wide CRISPR activation screens on neuroblastoma cell lines, PIM1 was identified as a resistance gene that, when overexpressed, is linked to poor survival outcomes in patients with ALK-positive neuroblastoma.

Combining the ALK inhibitor ceritinib with the PIM1 inhibitor AZD1208 significantly enhances anti-tumor efficacy in patient-derived xenografts, suggesting that targeting both ALK and PIM1 could be an effective treatment strategy for high-risk neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status. Trigg, RM., Lee, LC., Prokoph, N., et al.[2021]

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]

A rare LOC388942-ALK fusion in a patient with ALK-positive non-small cell lung cancer (NSCLC) was sensitive to crizotinib, demonstrating the importance of targeted therapies in treating specific genetic alterations.

The patient developed resistance to sequential treatments with ceritinib and alectinib, and ultimately acquired the ALK G1202R mutation after long-term treatment with anlotinib, highlighting the need for dynamic monitoring of genetic changes during treatment to inform ongoing therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Classical ALK G1202R resistance mutation was identified in a lung adenocarcinoma patient with rare LOC388942-ALK fusion after sequential treatment with ALK-TKIs and anlotinib: a case report. Zhai, X., Liu, Y., Liang, Z., et al.[2022]

In a study of 521 lung cancer specimens, 14 cases (2.7%) were found to have ALK gene fusions, with a significant number (42.9%) of these patients presenting with advanced stage IV disease, leading to poor survival outcomes without targeted therapy.

The study identified overexpression of the SPP1 protein in ALK-positive lung cancer, which is linked to poor patient outcomes, suggesting that targeting the PI3K/AKT/SPP1 signaling pathway could be a promising strategy for treating aggressive lung cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy. Ji, X., Liu, Y., Mei, F., et al.[2022]

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 PI3K&#945; Inhibitor Alpelisib Has Activity in PIK3CA-altered Tumors. [2019]

In a real-world study of 62 women with hormone-receptor-positive, PIK3CA-mutated metastatic breast cancer, longer exposure to alpelisib (over 90 days) was associated with significantly delayed cancer progression compared to shorter exposure (77 days vs. 187 days).

Adverse events were the main reason for early discontinuation of alpelisib, while disease progression was the most common reason for stopping the drug overall, highlighting the importance of managing side effects to maintain treatment duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors leading to alpelisib discontinuation in patients with hormone receptor positive, human epidermal growth factor receptor-2 negative breast cancer. Cheung, YM., Cromwell, GE., Tolaney, SM., et al.[2022]

Alpelisib (PIQRAY®) is the first PI3K inhibitor approved for treating hormone receptor-positive metastatic breast cancer with PIK3CA mutations, showing promising clinical results that support its use in overcoming endocrine resistance.

The review highlights the pharmacodynamic and pharmacokinetic properties of alpelisib, along with safety and efficacy data from the Phase III SOLAR-1 trial, which led to its FDA approval, indicating its potential as a tailored treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations. Mavratzas, A., Marmé, F.[2021]

In Portugal, 54.6% of institutions perform reflex molecular testing for ALK-positive non-small-cell lung carcinoma (NSCLC), with next-generation sequencing (NGS) being the preferred method in 90.9% of cases, allowing for timely diagnosis within 14-21 days.

Alectinib is the most commonly used first-line treatment for ALK-positive NSCLC, especially favored for patients with brain metastases, indicating that the treatment practices align with international guidelines and provide access to effective therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis and Treatment of Advanced ALK Rearrangement-Positive Non-Small-Cell Lung Cancer in Portugal: Results of a National Questionnaire. Figueiredo, A., Rodrigues, A., Gaspar, C., et al.[2023]

In a study of 51 older breast cancer patients (median age 71), alpelisib was associated with significant adverse events, particularly hyperglycemia, which affected 37 patients and led to hospitalizations for 5.

Despite the adverse effects, there is potential for older patients to benefit from alpelisib if the management of these side effects, especially hyperglycemia, can be improved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Observations with alpelisib in older patients (≥ 65 year of age) with breast cancer in a non-clinical trial setting. Almodallal, Y., Le-Rademacher, JG., Cook, KD., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37634128/

Alpelisib for treatment of patients with PIK3CA-related ... EPIK-P1 provides real-world evidence of alpelisib effectiveness and safety in patients with PROS and confirms PI3Kα as a valid therapeutic target for PROS ...

2. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-pik3ca-related-overgrowth-spectrum

FDA approves alpelisib for PIK3CA-related overgrowth ... The major efficacy outcome measure was the proportion of patients with radiological response at week 24 as determined by blinded independent ...

3. nature.com nature.com/articles/s41431-025-01885-y

First report of successful pregnancies after treatment with ... We report the successful outcomes of three pregnancies in three primiparous PROS patients who underwent prolonged treatment with alpelisib.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04285723

NCT04285723 | Retrospective Chart Review Study of ... Improvement in PIK3CA Related Overgrowth Spectrum (PROS) signs and symptoms was defined based on Common Toxicity Criteria (CTC) grade reduction or resolution of ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1098360023009851

Alpelisib for treatment of patients with PIK3CA-related ... Alpelisib, a PI3Kα-selective inhibitor, targets the underlying etiology of PROS, offering a novel therapeutic approach to current management strategies.

6. vijoice-hcp.com vijoice-hcp.com/products/vijoice/pik3ca-related-overgrowth-spectrum/safety-profile/full-safety-profile

Full Safety Profile | VIJOICE® (alpelisib) tablets | HCP Additional safety data · 5% of patients required dose reductions due to ARs. · Dose interruption due to an AR occurred in 11% of patients.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10841299/

Alpelisib for PIK3CA-related Overgrowth Spectrum (PROS) The safety profile of alpelisib is acceptable in view of the severe and potentially life-threatening nature of PROS as a rare disease and the lack of FDA- ...

8. piqray-hcp.com piqray-hcp.com/metastatic-breast-cancer/safety-profile

Safety & Adverse Reactions | PIQRAY® (alpelisib) tablets No grade 4 laboratory abnormalities were reported. Glucose increase is an expected laboratory abnormality of PI3K inhibition. · - Ketoacidosis was reported in ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S2405844024035606

A real-world disproportionality analysis of FDA adverse ... Our research scrutinizes the FDA database to assess alpelisib 's safety. We retrospectively analyzed data from April 2019 to June 2023 using ...

10. clinicaltrials.gov clinicaltrials.gov/study/NCT04589650

NCT04589650 | Study Assessing the Efficacy, Safety and ... Also called a data ... Study Assessing the Efficacy, Safety and PK of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum ( ...