Alpelisib for Lymphatic Malformations

(EPIK-L1 Trial)

Recruiting at 61 trial locations

Overseen By Novartis Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Novartis Pharmaceuticals

Must not be taking: PI3K inhibitors

Disqualifiers: PROS, Central Conducting Lymphatic Anomaly, 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

Compensation: Varies

Number of Visits: Unknown

232 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests alpelisib, a medication, to determine if it can reduce symptoms and improve the condition of individuals with lymphatic malformations (LyM) that have a specific genetic mutation in the PIK3CA gene. Participants will receive either alpelisib or a placebo to compare results. The trial suits those diagnosed with LyM, who have the PIK3CA mutation, and are not considering surgery or other non-drug treatments during the trial. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potential advancements in treatment.

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.

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

A previous study showed that alpelisib produced promising results in treating conditions related to the PIK3CA gene. Research indicates that alpelisib reduced the size of certain damaged tissue areas in patients, though some side effects occurred. In another study, 16.7% of patients showed improvement in their condition.

Alpelisib is generally well-tolerated, but some people have experienced side effects like high blood sugar and diarrhea. The FDA has approved alpelisib for other conditions, indicating that its safety is well-understood. This knowledge helps researchers assess potential risks and benefits. Understanding these findings can assist in making an informed decision about joining this trial. ^{1 2 3 4 5}

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

Researchers are excited about Alpelisib for lymphatic malformations because it targets a genetic mutation known as the PIK3CA pathway, which is believed to play a crucial role in the development of these malformations. Unlike current treatments that often involve surgery or sclerotherapy, which can be invasive and have varying success rates, Alpelisib offers a targeted approach by specifically inhibiting the PI3K enzyme involved in cell growth. This specificity could potentially lead to more effective management of the condition with fewer side effects, offering hope for both pediatric and adult patients.

What evidence suggests that this trial's treatments could be effective for lymphatic malformations?

Research has shown that alpelisib, which participants in this trial may receive, can help shrink abnormal growths and improve symptoms in people with PIK3CA-related conditions. One study found that patients experienced reduced growth of these abnormal areas and felt better overall, with fewer symptoms. In both animal tests and human patients, alpelisib led to smaller lymphatic growths. Patients also reported less pain and swelling after starting treatment with alpelisib. These findings suggest that alpelisib could be a helpful treatment for lymphatic growths. ^{1 2 6 7 8}

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 lymphatic malformations (LyM) that are linked to a PIK3CA gene mutation. Participants must be willing to follow the study's schedule, have a confirmed diagnosis of LyM, not be candidates for or unwilling to undergo local treatments like sclerotherapy until after 24 weeks, and have at least one measurable LyM lesion.

Inclusion Criteria

My cancer has a PIK3CA gene mutation.

I am willing to stay at the clinical site as needed and follow the study rules.

My doctor has confirmed I have lymphoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stage 1 Treatment

Participants receive alpelisib in an open-label fashion for dose selection over 24 weeks

24 weeks

Stage 2 Treatment

Participants receive alpelisib or placebo in a double-blind, placebo-controlled manner for 24 weeks

24 weeks

Open-label Extension

Participants may continue receiving alpelisib in an open-label extension phase

Long-term

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 trial is testing the effectiveness of Alpelisib compared to a placebo in treating lymphatic malformations. The focus is on observing changes in radiological response and symptom severity between the two groups.

How Is the Trial Designed?

Group I: Pediatric participants (6-17 years of age), alpelisib dose 3 (Stage 1) Experimental Treatment 1 Intervention

Pediatric participants 6-17 years of age who will receive dose 3 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1).

Group II: Pediatric participants (6-17 years of age), alpelisib dose 2 (Stage 1) Experimental Treatment 1 Intervention

Pediatric participants 6-17 years of age who will receive dose 2 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1)

Group III: Pediatric participants (6-17 years of age), alpelisib (Stage 2) Experimental Treatment 1 Intervention

Pediatric participants (6-17 years of age) who will receive alpelisib at the dose selected for confirmatory phase in pediatric participants (Stage 2)

Group IV: Pediatric participants (0-5 years of age), alpelisib (Stage 2) Experimental Treatment 1 Intervention

Pediatric participants of 0-5 years who will dose 3 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier

Group V: Adult participants, alpelisib dose 2 (Stage 1) Experimental Treatment 1 Intervention

Adult participants (≥18 years of age) who will receive dose 2 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1).

Group VI: Adult participants, alpelisib dose 1 (Stage 1) Experimental Treatment 1 Intervention

Adult participants (≥18 years of age) who will receive dose 1 of alpelisib an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1)

Group VII: Adult participants, alpelisib (Stage 2) Experimental Treatment 1 Intervention

Adult participants (≥18 years of age) who will receive alpelisib at the dose selected for confirmatory phase in adult participants (Stage 2)

Group VIII: Adult participants, placebo (Stage 2) Placebo Group 1 Intervention

Adult participants (≥18 years of age) who will receive matching placebo

Group IX: Pediatric participants (6-17 years of age), placebo (Stage 2) Placebo Group 1 Intervention

Pediatric participants (6-17 years of age) who will receive matching placebo

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

A genetic mouse model of PIK3CA-related lymphatic malformations showed that alpelisib, a PIK3CA inhibitor, effectively prevents the occurrence of these malformations and improves survival rates.

In a small clinical trial with six patients, including three children, alpelisib treatment led to a significant 48% reduction in the volume of lymphatic malformations over six months, along with decreased pain and inflammation, although some patients experienced mild adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib administration reduced lymphatic malformations in a mouse model and in patients. Delestre, F., Venot, Q., Bayard, C., et al.[2022]

Alpelisib, a PIK3CA inhibitor, was successfully used to treat two infants with life-threatening conditions related to PIK3CA-related overgrowth spectrum (PROS), showing significant clinical improvements after 12 months.

The treatment was well-tolerated with no reported adverse events, indicating that low-dose alpelisib is a feasible and safe option for managing severe symptoms and complications associated with PROS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of two infants with PIK3CA-related overgrowth spectrum by alpelisib. Morin, G., Degrugillier-Chopinet, C., Vincent, M., et al.[2022]

Alpelisib, a selective inhibitor of the PIK3CA pathway, showed significant clinical benefits in a case series of 19 patients with PIK3CA-related overgrowth syndrome (PROS), including those with life-threatening complications, and had few adverse effects.

In a specific case of a patient with CLOVES syndrome, alpelisib treatment after surgery led to a notable reduction in lymphangioma size and prevented further tissue overgrowth, indicating its potential as a safe and effective pharmacological option for managing PROS disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib to treat CLOVES syndrome, a member of the PIK3CA-related overgrowth syndrome spectrum. Garreta Fontelles, G., Pardo Pastor, J., Grande Moreillo, C.[2022]

In a study of three patients with TIE-2 receptor mutations, treatment with alpelisib for 6 months led to significant improvements in pain control, gait, and reduction in the size of venous malformations.

Alpelisib also dramatically improved coagulopathy, highlighting its potential as a novel therapy for patients with treatment-resistant venous malformations, although dosing should be individualized based on patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: Preliminary pharmacokinetics and pharmacodynamic data. Remy, A., Tran, TH., Dubois, J., et al.[2022]

RNA sequencing of blood samples from 10 lymphatic malformation (LM) patients revealed 421 genes that differentiate LM from healthy individuals, highlighting novel pathway alterations involved in LM, including oxidative phosphorylation and Wnt/β-catenin pathways.

The study suggests potential new therapies for LM through computational drug repositioning, indicating that existing drugs like sirolimus could be repurposed, which may lead to safer and more effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations. Kim, T., Tafoya, E., Chelliah, MP., et al.[2020]

In a study of 27 children with intractable head and neck lymphatic malformations, sirolimus therapy was effective in reducing lesion volume, particularly in macrocystic types, with 23 out of 27 participants showing improvement.

The treatment was generally well-tolerated, with only mild adverse effects reported, primarily upper respiratory infections, indicating that sirolimus is a safe option for managing these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Initial Sirolimus Therapy for 27 Patients with Intractable Lymphatic Malformations. Zhang, X., Wang, S., Guo, Y., et al.[2021]

A recurrent gain-of-function mutation in the ARAF gene was identified in a 12-year-old boy with severe lymphatic disease, leading to increased ERK1/2 activity and abnormal lymphatic growth, which was not responsive to standard treatment.

Treatment with the MEK inhibitor trametinib resulted in significant clinical improvement for the patient, including resolution of lymphatic edema and improved pulmonary function, demonstrating the potential of targeted therapies based on genetic findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. Li, D., March, ME., Gutierrez-Uzquiza, A., 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]

Citations

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sciencedirect.com

sciencedirect.com/science/article/pii/S1098360022008917

Alpelisib for the treatment of PIK3CA-related head and ...

Individuals with head and neck PROS treated with alpelisib had decreased malformation size and locoregional overgrowth, improved function and symptoms, and ...

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clinicaltrials.gov

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NCT05948943 | Alpelisib in Pediatric and Adult Patients ...

A Two-stage Double-blind, Randomized, Placebo-controlled Study to Assess the Efficacy, Safety and Pharmacokinetics of Alpelisib in Pediatric and Adult Patients ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12322174/

First report of successful pregnancies after treatment with ...

After initiating alpelisib, she showed good clinical response including pain reduction, cessation of inflammatory flares and bleeding, and a ...

4.

nature.com

nature.com/articles/s41598-023-37468-4

Targeted treatment of severe vascular malformations ...

Alpelisib administration reduced lymphatic malformations in a mouse model and in patients. Sci. Transl. Med. https://doi.org/10.1126 ...

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clinicaltrials.ucsf.edu

clinicaltrials.ucsf.edu/trial/NCT05948943

Alpelisib in Pediatric and Adult Patients With Lymphatic ...

The main purpose of this study in participants with PIK3CA-mutated LyM is to assess the change in radiological response and symptom severity upon treatment ...

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novartis.com

novartis.com/us-en/news/media-releases/novartis-announces-findings-from-real-world-study-alpelisib-demonstrating-clinical-benefit-people-pik3ca-related-overgrowth-spectrum-pros

Novartis announces findings from a real-world study of ...

Results from EPIK-P1 showed alpelisib effectively reduced volume of clinically significant PROS-related lesions and improved signs and symptoms ...

7.

ashpublications.org

ashpublications.org/blood/article/144/Supplement%201/5512/527723/Epik-P2-A-Phase-2-Study-of-Alpelisib-ALP-in

Epik-P2: A Phase 2 Study of Alpelisib (ALP) in Pediatric and ...

The primary objective was not met; confirmed objective response with ALP (any time) was achieved in 16.7% (9/54; 97.5% CI: 7.0%-31.1%) and 23.2% ...

8.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11667470/

A phase II double-blind multicentre, placebo-controlled trial to ...

Current data on alpelisib efficacy and safety in MCAP patients solely come from compassionate use, which fails to demonstrate a clear ...