Alpelisib for Lymphatic Malformations

(EPIK-L1 Trial)

Recruiting at 33 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

Trial Summary

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 Alpelisib safe for humans?

In a study involving patients with lymphatic malformations, Alpelisib was generally well-tolerated, but some patients experienced mild side effects like mucositis (inflammation of the mouth) and diarrhea. ^{1 2 3 4 5}

How is the drug Alpelisib unique in treating lymphatic malformations?

Alpelisib is unique because it targets the PIK3CA gene mutations that cause lymphatic malformations, offering a new approach where no approved medical therapies exist. It has shown promising results in reducing the size of these malformations and alleviating symptoms in patients who did not respond to other treatments like surgery or sirolimus. ^{1 4 6 7 8}

What is the purpose of this trial?

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 with alpelisib film-coated tablets (FCT) as compared to placebo.

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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]

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, 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]

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]

References

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

Alpelisib administration reduced lymphatic malformations in a mouse model and in patients. [2022]

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

Efficacy of Initial Sirolimus Therapy for 27 Patients with Intractable Lymphatic Malformations. [2021]

3. United States 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. [2020]

4. United States 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. [2022]

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

ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. [2022]

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

Treatment of two infants with PIK3CA-related overgrowth spectrum by alpelisib. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Alpelisib to treat CLOVES syndrome, a member of the PIK3CA-related overgrowth syndrome spectrum. [2022]

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

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