Avapritinib for Pediatric Solid Cancers

Recruiting at 25 trial locations

Overseen By Lindsey Hoffman, DO

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Blueprint Medicines Corporation

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Uncontrolled cardiovascular disease, Seizure disorder, others

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

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: 8

37 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1/2, multicenter, open-label trial of avapritinib in participants 2 to \< 18 years of age with advanced relapsed/refractory (R/R) solid tumors, including central nervous system (CNS) tumors, that harbor a PDGFRA and/or KIT mutation (including non-synonymous point mutations, insertions, and deletions) or amplification, or DMG-H3K27a who have no available curative treatment options. This is a single-arm trial in which all participants will receive avapritinib. The study consists of 2 parts: dose confirmation, safety, and PK (Part 1) and initial efficacy, safety, and PK at the Part 2 recommended dose (Part 2).

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that participants cannot take certain drugs that strongly affect liver enzymes (CYP3A inhibitors or inducers) within 28 days before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What safety data exists for Avapritinib in humans?

Avapritinib, also known as Ayvakit or BLU-285, has been approved for use in adults with certain types of gastrointestinal tumors, and post-marketing data is being collected to monitor adverse events (side effects). However, there is limited large-scale data on its safety, and more research is needed to fully understand its safety profile in humans. ^{1 2 3 4 5}

What makes the drug Avapritinib unique for treating pediatric solid cancers?

Avapritinib is unique because it targets specific genetic mutations in cancer cells, offering a precision medicine approach that is not commonly available for pediatric solid tumors. This drug is designed to inhibit certain proteins that drive cancer growth, making it a novel option compared to traditional chemotherapy. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for children and teenagers aged 2 to less than 18 with advanced solid tumors, including brain tumors that have specific genetic changes (mutations in KIT or PDGFRA) or a type of glioma called DMG-H3K27a. They should have tried standard treatments without success and not be eligible for other curative options. Participants need to be stable on certain medications, able to perform daily activities at least minimally, and agree to use contraception.

Inclusion Criteria

Participant agrees to utilize contraception consistent with local regulations.

My brain disease treatment with steroids has been stable or reduced for a week.

My diagnosis is DMG-H3K27a and standard treatments have not worked or are not available.

Exclusion Criteria

My platelet count is low and I haven't had a transfusion in the last 14 days.

Participant has International normalized ratio or prothrombin time (PT) > ULN.

My liver enzymes are high, but not over five times the normal limit if my cancer affects my liver.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Confirmation and Safety (Part 1)

Participants receive avapritinib to confirm dose, assess safety, and pharmacokinetics

28 days

4 visits (in-person)

Initial Efficacy and Safety (Part 2)

Participants receive avapritinib at the recommended dose to assess initial efficacy and safety

28 days

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Avapritinib

Trial Overview The study tests avapritinib, a medication targeting cancers with certain genetic mutations. It's an open-label trial where all participants receive the drug. The first part confirms the dose and assesses safety; the second part looks at how effective it is at a recommended dose while continuing safety assessments.

Participant Groups

Group I: avapritinib Experimental Treatment 1 Intervention

Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles.

Avapritinib is already approved in United States, European Union for the following indications:

Approved in United States as Ayvakit for:

• Unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations
• Advanced systemic mastocytosis
• Indolent systemic mastocytosis

Approved in European Union as Ayvakit for:

• Unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations
• Advanced systemic mastocytosis
• Indolent systemic mastocytosis

Who Is Running the Clinical Trial?

Blueprint Medicines Corporation

Lead Sponsor

Trials

31

Recruited

6,000+

Findings from Research

Avapritinib is a selective tyrosine kinase inhibitor specifically targeting PDGFRA and KIT mutations, and it has been approved in the USA for treating gastrointestinal stromal tumors (GIST) with PDGFRA exon 18 mutations, including the D842V variant.

The drug is currently under regulatory review in the USA as a 4th-line treatment for GIST and is also being evaluated in the EU for the same indication, highlighting its potential as a significant treatment option for patients with advanced GIST.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avapritinib: First Approval. Dhillon, S.[2021]

A total of 3120 adverse event cases related to avapritinib were reported to the FDA, with 44% occurring within the first 30 days of treatment, highlighting the importance of monitoring patients closely during this period.

The study found that elderly male patients are at a higher risk for serious adverse events, indicating that clinicians should exercise caution when prescribing avapritinib to this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. Rong, L., Xie, M., Jiang, M., et al.[2023]

Ceritinib, at a recommended dose of 500 mg/m2 once daily, demonstrated promising antitumor activity in pediatric patients with ALK-positive malignancies, particularly in inflammatory myofibroblastic tumors (IMT) and anaplastic large cell lymphoma (ALCL), as well as in some cases of neuroblastoma.

The safety profile of ceritinib was manageable, with 81% of patients experiencing grade 3 or 4 adverse events, primarily increases in liver enzymes, indicating that while the treatment can have serious side effects, it is consistent with what has been observed in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study. Fischer, M., Moreno, L., Ziegler, DS., et al.[2022]

The OncoKids panel is a next-generation sequencing assay that effectively detects various diagnostic, prognostic, and therapeutic markers in pediatric cancers, using only 20 ng of DNA and RNA from diverse sample types.

Validated on 192 clinical samples, the OncoKids panel demonstrated strong analytical sensitivity and reproducibility, supporting its use for routine clinical testing in a wide range of pediatric malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OncoKids: A Comprehensive Next-Generation Sequencing Panel for Pediatric Malignancies. Hiemenz, MC., Ostrow, DG., Busse, TM., et al.[2019]

References

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

Avapritinib: First Approval. [2021]

2. England pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. [2023]

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

Clinical Benefit of Avapritinib in KIT-Mutant Gastrointestinal Stromal Tumors: A Post Hoc Analysis of the Phase I NAVIGATOR and Phase I/II CS3007-001 Studies. [2023]

4. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Use of crizotinib for refractory ALK-positive lymphomas]. [2018]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of Anti-Angiogenic Drugs in Pediatric Patients with Solid Tumors: A Systematic Review and Meta-Analysis. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Near complete response to ceritinib in a pediatric patient with metastatic ALK-rearranged lung adenocarcinoma. [2023]

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

Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study. [2022]

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

An update on genomic-guided therapies for pediatric solid tumors. [2022]

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

Discovery of actionable genetic alterations with targeted panel sequencing in children with relapsed or refractory solid tumors. [2021]

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

OncoKids: A Comprehensive Next-Generation Sequencing Panel for Pediatric Malignancies. [2019]