Alpelisib for Overgrowth Spectrum

(EPIK-P2 Trial)

Recruiting at 50 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

205 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a prospective Phase II multi-center study with an initial 16-week, randomized, double-blind, placebo-controlled period, followed by two extension periods to assess the efficacy, safety and pharmacokinetics (PK) of alpelisib in pediatric and adult patients with PIK3CA-related overgrowth spectrum (PROS)

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.

What data supports the idea that Alpelisib for Overgrowth Spectrum is an effective drug?

The available research shows that Alpelisib was approved by the FDA for treating PIK3CA-related Overgrowth Spectrum (PROS) based on a study where 27% of patients had a significant reduction in the size of their growths after 24 weeks. Additionally, 60% of those who responded to the treatment maintained their improvement for at least 12 months. This suggests that Alpelisib can be effective in managing symptoms of PROS. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Alpelisib for treating PIK3CA-related overgrowth spectrum (PROS)?

Alpelisib has been shown to be effective for PIK3CA-related overgrowth spectrum (PROS), with 27% of patients experiencing a significant reduction in lesion size after 24 weeks, and 60% of those responders maintaining the benefit for at least 12 months. ^{1 2 3 4 5}

What safety data is available for Alpelisib?

Alpelisib, also known as Piqray, has been evaluated for safety in various settings. In the treatment of PIK3CA-related overgrowth spectrum (PROS), common adverse reactions (≥10%) included diarrhea, stomatitis, and hyperglycemia. In breast cancer patients, particularly older ones, it has shown an unusual adverse event profile. Factors such as drug exposure duration and maximum-tolerated dose can vary, affecting clinical response and safety outcomes. ^{2 3 5 6 7}

Is Alpelisib safe for humans?

Alpelisib has been approved for use in breast cancer and PIK3CA-related overgrowth spectrum (PROS), with common side effects including diarrhea, mouth sores, and high blood sugar. It has been studied in both clinical trials and real-world settings, showing some adverse reactions but generally considered safe for its approved uses. ^{2 3 5 6 7}

Is the drug Alpelisib (Piqray) a promising treatment for Overgrowth Spectrum?

The provided research articles do not contain information about Alpelisib (Piqray) or its effectiveness for Overgrowth Spectrum, so we cannot determine if it is a promising treatment based on this data. ^{8 9 10 11 12}

How is the drug Alpelisib unique for treating Overgrowth Spectrum?

Alpelisib (Piqray) is unique because it specifically targets the PI3K pathway, which is often involved in overgrowth conditions, offering a targeted approach that differs from more general treatments. This drug is typically used in cancer treatments, but its application in Overgrowth Spectrum is novel, as there are no standard treatments for this condition. ^{8 9 10 11 12}

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 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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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]

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]

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]

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]

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]

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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Observations with alpelisib in older patients (≥ 65 year of age) with breast cancer in a non-clinical trial setting. [2022]

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

Alpelisib: First Global Approval. [2020]

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

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

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

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

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

Pharmaceutical Approval Update. [2020]

7. Netherlands 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

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

9. Switzerland 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. [2023]

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

Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. [2021]

11. China 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. [2022]

12. England pubmed.ncbi.nlm.nih.gov

SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy. [2022]