Alpelisib for Overgrowth Spectrum Disorders

(EPIK-P3 Trial)

Recruiting at 8 trial locations

Overseen By Novartis Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Novartis Pharmaceuticals

Must be taking: Alpelisib

Disqualifiers: Uncontrolled diabetes, GI impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

41 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a prospective interventional Phase II multi center study, open label, preceded by a retrospective non-interventional period, to assess the long-term safety and efficacy of alpelisib, in pediatric and adult participants with PROS.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Alpelisib for treating overgrowth spectrum disorders?

Research shows that Alpelisib, a drug targeting the PIK3CA gene, was effective in reducing the size of overgrowth lesions in 27% of patients with PIK3CA-related overgrowth spectrum disorders. Additionally, 60% of those who responded to the treatment maintained their improvement for at least 12 months. ^{1 2 3 4 5}

Is Alpelisib safe for humans?

Alpelisib has been approved by the FDA for treating certain overgrowth disorders and has been studied in both children and adults. Common side effects include diarrhea, mouth sores, and high blood sugar, but some patients have used it without significant adverse effects. ^{1 2 3 5 6}

How is the drug Alpelisib unique for treating overgrowth spectrum disorders?

Alpelisib is unique because it specifically targets the PI3K pathway, which is often involved in overgrowth disorders, offering a more targeted approach compared to other treatments that may not address this specific pathway. ^{7 8 9 10 11}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for pediatric and adult patients with PIK3CA-Related Overgrowth Spectrum (PROS) who were previously in the EPIK-P1 study. They must have taken at least one dose of alpelisib after March 9, 2020, and give informed consent. People can't join if they stopped taking alpelisib due to severe side effects or have certain medical conditions like uncontrolled diabetes.

Inclusion Criteria

Participant is treated with at least one dose of alpelisib after the EPIK-P1 study data cut-off date of 09-Mar-2020

Participants who had previously participated in the study EPIK-P1

Signed informed consent form and assent (when applicable) from the participant, parent, or guardian must be obtained prior to any study related screening procedures being performed

Exclusion Criteria

I stopped taking alpelisib due to severe side effects or uncontrolled diabetes.

For participants in the retrospective period: All EPIK-P1 participants who permanently discontinued the investigational drug on or prior to the cut-off date 09-Mar-2020

Timeline

Retrospective Period

Non-interventional period where key safety and efficacy information is collected from medical charts

From 10-Mar-2020 to Day -1

Prospective Period

Interventional period where participants receive alpelisib and safety and efficacy data are collected

Up to 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days after last dose

Treatment Details

Interventions

• Alpelisib

Trial Overview The study is testing the long-term safety and effectiveness of a drug called Alpelisib in treating PROS. It's an open-label Phase II trial where all participants know they're getting Alpelisib, following up on earlier research from the EPIK-P1 study.

Participant Groups

Group I: Alpelisib Experimental Treatment 1 Intervention

All participants will receive alpelisib once a day

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

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]

In a phase 1 study involving 44 pediatric patients with refractory solid tumors and ALCL, the recommended phase 2 dose (RP2D) of crizotinib in combination with topotecan and cyclophosphamide was determined to be 215 mg/m2/dose taken twice daily, showing it can be safely tolerated at this dosage.

The study found that while the oral solution of crizotinib was not well tolerated due to palatability issues, the crizotinib formulated capsules were more acceptable, although they led to increased toxicity that requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children's Oncology Group phase 1 consortium study (ADVL1212). Greengard, E., Mosse, YP., Liu, X., et al.[2021]

PF-06463922 is a next-generation ALK inhibitor that shows significantly higher potency than crizotinib against various ALK mutations, including those that confer resistance, such as F1174L and F1245C.

In preclinical studies, PF-06463922 induced complete tumor regression in both crizotinib-resistant and sensitive neuroblastoma models, suggesting it could be a promising treatment option for children with ALK-mutated neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. Infarinato, NR., Park, JH., Krytska, K., et al.[2022]

References

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

Clinical Response to PI3K-α Inhibition in a Cohort of Children and Adults With PIK3CA-Related Overgrowth Spectrum Disorders. [2022]

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

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

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

Response to Alpelisib in Clinically Distinct Pediatric Patients With PIK3CA -related Disorders. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing. [2020]

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

Alpelisib for treatment of patients with PIK3CA-related overgrowth spectrum (PROS). [2023]

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

New Drug Treats Rare Genetic Overgrowth Disorder. [2022]

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

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status. [2021]

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

New therapeutic strategies in neuroblastoma: combined targeting of a novel tyrosine kinase inhibitor and liposomal siRNAs against ALK. [2018]

9. Germany pubmed.ncbi.nlm.nih.gov

Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children's Oncology Group phase 1 consortium study (ADVL1212). [2021]

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

Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma. [2022]

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

The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. [2022]