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Validação do Alvo e Eficácia da Metformina em Doentes com Ependimoma do Grupo A da Fossa Posterior (PFA) (PNOC041)

5 de novembro de 2026 atualizado por: University of California, San Francisco

Um Estudo de Validação de Alvo e Eficácia da Metformina em Doentes com Ependimoma do Grupo A da Fossa Posterior (PFA) Recorrente ou Progressivo

This is a multi-site study of the pharmacodynamic effects and efficacy of metformin in children and young adults with recurrent or progressive Posterior Fossa Group A (PFA) ependymoma.

Visão geral do estudo

Status

Recrutamento

Condições

Intervenção / Tratamento

Descrição detalhada

PRIMARY OBJECTIVES:

I. To assess pharmacodynamic effect on PFA tumor cells of metformin in participants with recurrent or progressive PFA undergoing surgical resection of the tumor by determining change in H3K27me3 and/or EZHIP expression in tumor nuclei compared to pre-treatment levels (TV Phase)

II. To measure disease stabilization rate by Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria (complete (CR), partial (PR) response; ≥50% reduction in size but <CR), and Stable (SD); < 50% reduction in size but not meeting criteria for progressive disease) in participants with recurrent or progressive PFA ependymoma following metformin treatment (Efficacy Phase).

EXPLORATORY OBJECTIVES:

I. Estimate the 1-year progression-free survival and overall-survival of participants with recurrent or progressive PFA treated with single agent metformin (Efficacy Phase).

II. To assess pharmacokinetics (PK) of metformin by measuring plasma, CSF and intra-tumoral concentration of metformin, the latter two obtained at the time of surgery or at the time of further disease progression on study in consenting participants (Both cohorts).

III. Evaluate the feasibility of using MR spectroscopy (MRS) imaging to study oncometabolite profile of recurrent or progressive PFA ependymoma pre-and post-treatment with metformin.

OUTLINE:

This will be a two-part study: a TV phase and an efficacy phase. Participants will be initially enrolled in the TV phase and receive treatment prior to planned surgery. Participants already enrolled on the TV phase may continue to the efficacy phase of the study if they have measurable disease post-surgery. Participants in the efficacy phase will receive daily oral metformin until disease progression or till there are unacceptable adverse event(s). Long term/survival follow-up procedures are to be captured under the Pediatric Neuro-Oncology Consortium (PNOC) Protocol for Children and Young Adults Diagnosed with a Central Nervous System (CNS) Tumor to Assess Cognitive, Quality of Life (QOL), and Comprehensive Effects of Therapies protocol (COMP). Participants will be followed under the PNOC COMP protocol until death or withdrawal from study.

Tipo de estudo

Intervencional

Inscrição (Estimado)

30

Estágio

  • Fase 2

Contactos e Locais

Esta seção fornece os detalhes de contato para aqueles que conduzem o estudo e informações sobre onde este estudo está sendo realizado.

Contato de estudo

  • Nome: PNOC Operations Office
  • Número de telefone: 415-502-1600
  • E-mail: PNOC041@ucsf.edu

Locais de estudo

  • Brasil
    • São Paulo
      • São Paulo, São Paulo, Brasil, 04039-001
        • Ainda não está recrutando
        • GRAACC - Grupo de Apoio ao Adolescente e a Crianca com Cancer
        • Contato:
        • Contato:
  • Estados Unidos
    • Alabama
      • Birmingham, Alabama, Estados Unidos, 35233
        • Recrutamento
        • University of Alabama at Birmingham
        • Contato:
        • Contato:
    • California
      • San Francisco, California, Estados Unidos, 94143
        • Recrutamento
        • University of California, San Francisco
        • Investigador principal:
          • Sabine Mueller, MD, PhD
        • Contato:
          • PNOC Operations Office
          • Número de telefone: 415-502-1600
          • E-mail: PNOC041@ucsf.edu
    • District of Columbia
      • Washington D.C., District of Columbia, Estados Unidos, 20010
    • Indiana
      • Indianapolis, Indiana, Estados Unidos, 46202
        • Ainda não está recrutando
        • Riley Hospital for Children at Indiana University Health
        • Contato:
          • Brian Weiss, MD
          • Número de telefone: 317-944-8784
          • E-mail: weissbd@iu.edu
        • Contato:
          • Alex Lion, DO, MPH
          • Número de telefone: 317-944-8784
          • E-mail: alion@iu.edu
    • Maryland
      • Baltimore, Maryland, Estados Unidos, 21287
        • Recrutamento
        • Johns Hopkins University
        • Contato:
          • Kenneth Cohen, MD, MBA
          • Número de telefone: 410-614-5055
          • E-mail: kcohen@jhmi.edu
        • Contato:
          • Robyn Gartrell, MD
          • Número de telefone: 410-614-5055
          • E-mail: rgartre1@jh.edu
    • Michigan
      • Ann Arbor, Michigan, Estados Unidos, 48109
        • Ainda não está recrutando
        • University of Michigan
        • Contato:
        • Contato:
    • Missouri
      • St Louis, Missouri, Estados Unidos, 63110
        • Recrutamento
        • Washington University
        • Contato:
        • Contato:
    • New Jersey
      • Hackensack, New Jersey, Estados Unidos, 07601
        • Ainda não está recrutando
        • Hackensack Meridian Health
        • Contato:
        • Contato:
    • North Carolina
      • Durham, North Carolina, Estados Unidos, 27710
    • Tennessee
      • Memphis, Tennessee, Estados Unidos, 38105
        • Ainda não está recrutando
        • St. Jude Children's Research Hospital
        • Contato:
        • Contato:
    • Utah
      • Salt Lake City, Utah, Estados Unidos, 84113
    • Washington

Critérios de participação

Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.

Critérios de elegibilidade

Idades elegíveis para estudo

1 ano a 39 anos (Filho, Adulto)

Aceita Voluntários Saudáveis

Não

Gêneros Elegíveis para o Estudo

Tudo

Descrição

Inclusion Criteria:

  1. Participants must have recurrent or progressive posterior fossa A (PFA) ependymoma following surgery AND radiation treatment (RT).

  2. Participants must have a diagnosis of PFA ependymoma. Any number of previous recurrences are permissible provided the participant meets other enrollment criteria.

  3. Participants must have adequate tumor tissue available from initial diagnosis or from pre- trial enrollment. Formalin-fixed paraffin-embedded (FFPE) material (1 full block) should be provided. If FFPE material is not available, 10 unstained slides with an accompanying hematoxylin and eosin (H&E) report should be provided.

    Target Validation (TV) Phase:

    o Participants are candidates to undergo elective surgery for removal of all or a portion of their recurrent/progressive tumor.

    Efficacy Phase:

    • Participant must have measurable disease; this will be defined as lesions that can be accurately measured in two dimensions (longest diameter to be recorded) The size threshold is met if both in-plane diameters are ≥10 mm or both in-plane diameters are at least two times the MRI slice thickness, plus the interslice gap with a minimum size of no less than double the slice thickness on MRI.
    • Participants with an isolated local progression of the tumor following RT (or stereotactic radiosurgery, SRS) must be > 6 months from completion of RT to the lesion to rule out pseudo progression or must have tissue confirmation of progression prior to enrollment.
    • Previously irradiated lesions are considered non-measurable except in cases of documented progression of the lesion since the completion of radiation therapy as outlined above.

  4. Prior Therapy: Participants must not be receiving metformin for other medical indications or previous exposure to metformin following their diagnosis of PFA ependymoma. However, participants treated on the TV phase, but did not continue onto maintenance therapy will be allowed to enroll on the efficacy phase with future recurrences or progression of their disease.

  5. Age: 1 -39 years at the time of enrollment.

  6. Performance Score: Karnofsky >= 50 for participants > 16 years of age and Lansky >=50 for participants <=16 years of age. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

  7. Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.

  8. Organ Function Requirements

    1. Peripheral absolute neutrophil count (ANC) >= 1000/mm^3.
    2. Platelet count >=100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
    3. Serum creatinine < 1.5 Upper Limit normal (ULN) based on age and gender
    4. Total bilirubin <= 1.5 x ULN for age; in presence of Gilbert's syndrome, total bilirubin < 3 x ULN or direct bilirubin < 1.5 x ULN
    5. alanine aminotransferase (ALT) <= 3 x ULN.
    6. aspartate aminotransferase (AST) <=3 x ULN.

  9. Participants with seizure disorder may be enrolled if well controlled and are on stable dose of anti-seizure medication for > 72 hours prior to enrollment. Participants who have neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration.

  10. Participants must enroll on PNOC COMP if PNOC COMP is open to accrual at the enrolling institution.

  11. A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.

Exclusion Criteria:

  1. Participants with a history of diabetes mellitus or those meeting criteria for pre-diabetes are excluded. Pre-diabetes is defined per American Diabetes Association criteria as any of the following: fasting plasma glucose (FPG) 100-125 mg/dL (5.6-6.9 mmol/L); 2-hour plasma glucose (OGTT) 140-199 mg/dL (7.8-11.0 mmol/L); or hemoglobin A1c (HbA1c) 5.7%-6.4% (39-47 mmol/mol).
  2. Participants without any measurable disease.
  3. Participants who have had chemotherapy or have received radiotherapy to the non-target lesion within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
  4. Participants must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur. Such participants should also be discussed with study chairs.
  5. Participants with rapidly progressive symptoms that require urgent surgery that in the investigators assessment cannot be safely deferred for 6 weeks are excluded from target validation phase of the study
  6. Participants who are receiving any other investigational agents.
  7. Concurrent radiation therapy in any form is not permitted while on the study drug
  8. History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin.
  9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection.
  10. Women of childbearing potential must not be pregnant or breast-feeding.
  11. Human immunodeficiency virus- (HIV) positive participants will be ineligible if HIV therapy regimen has not been stable for at least 4 weeks or there is intent to change the regimen within 8 weeks following enrollment, or if they are severely immunocompromised.

Plano de estudo

Esta seção fornece detalhes do plano de estudo, incluindo como o estudo é projetado e o que o estudo está medindo.

Como o estudo é projetado?

Detalhes do projeto

  • Finalidade Principal: Tratamento
  • Alocação: Não randomizado
  • Modelo Intervencional: Atribuição sequencial
  • Mascaramento: Nenhum (rótulo aberto)

Armas e Intervenções

Grupo de Participantes / Braço
Intervenção / Tratamento
Experimental: Target Validation (TV) Phase (Metformin)

Participants will each receive daily oral metformin with a weekly schedule starting at 250 mg/m^2 twice a day (BID) for the first week, then increasing to 500 mg/m^2 BID for week 2, 1000 mg/m^2 BID for week 3, and then 1666 mg/m^2 BID for week 4-6 prior to planned surgery. Participants with no measurable disease following surgical intervention may either go off treatment or continue metformin at the physician's discretion. Participants have the option of continuing on the efficacy phase of the study without undergoing planned surgery no demonstrated progressive disease on pre-surgery MRI AND if the family opts to continue treatment with metformin without undergoing surgical resection of the tumor. Participants with measurable tumor by RAPNO criteria following surgery may continue onto efficacy phase and receive maintenance metformin until disease progression or till there are unacceptable adverse event(s).
Procedimento: Magnetic Resonance Imaging (MRI)

Undergo MRI imaging

Outros nomes:
  • Ressonância magnética
Medicamento: Metformin

Given orally (PO)

Outros nomes:
  • Glucófago
Procedimento: Planned Surgical Resection

Undergo planned surgery as part of regular care

Outros nomes:
  • Ressecção Cirúrgica
Procedimento: Specimen Collection

Tumor Tissue, blood, and cerebral spinal fluid (CSF) may be collected for correlative analysis.

Outros nomes:
  • Recolha de Amostras de Espécime
Procedimento: MR spectroscopy (MRS)

Undergo MRS imaging

Outros nomes:
  • SRA
Experimental: Efficacy Phase (Metformin)

Participants with recurrent or progressive PFA ependymoma that have failed upfront surgery and radiation will receive daily oral metformin until disease progression or till there are unacceptable adverse event(s). Disease response will be assessed by MRI imaging using RAPNO criteria. Participants already enrolled on the TV phase may enroll in this phase if they have measurable disease post-surgery. Treatment may continue until disease progression or until there are unacceptable adverse event(s).
Procedimento: Magnetic Resonance Imaging (MRI)

Undergo MRI imaging

Outros nomes:
  • Ressonância magnética
Medicamento: Metformin

Given orally (PO)

Outros nomes:
  • Glucófago
Procedimento: Planned Surgical Resection

Undergo planned surgery as part of regular care

Outros nomes:
  • Ressecção Cirúrgica
Procedimento: Specimen Collection

Tumor Tissue, blood, and cerebral spinal fluid (CSF) may be collected for correlative analysis.

Outros nomes:
  • Recolha de Amostras de Espécime
Procedimento: MR spectroscopy (MRS)

Undergo MRS imaging

Outros nomes:
  • SRA

O que o estudo está medindo?

Medidas de resultados primários

Medida de resultado
Descrição da medida
Prazo
Proportion of participants with changes in biomarkers between the pre-and post-metformin treated samples (Target Validation Phase)
Prazo: From initiation of study treatment until surgical resection of tumor, approximated 6 weeks

Proportion of participants with a 10% reduction in Enhancer of Zeste Inhibitory Protein (EZHIP) and/or a 10% increase in the epigenetic modification to the DNA packaging protein histone H3, with tri-methylation of lysine 27 on histone H3 (H3K27me3) between the pre- and post-metformin treated samples by Immunohistochemistry (IHC).
From initiation of study treatment until surgical resection of tumor, approximated 6 weeks
Disease Stabilization Rate (Efficacy Phase)
Prazo: From initiation of study treatment until discontinuation of treatment, up to 2 years

The primary endpoint of the efficacy phase is the disease stabilization rate by RAPNO criteria (complete (CR), partial (PR); response >50% reduction in size < CR, and stable (SD) which is a < 50% reduction in size and not meeting the definition for progressive disease) tumor responses), CR+PR+SD.
From initiation of study treatment until discontinuation of treatment, up to 2 years

Colaboradores e Investigadores

É aqui que você encontrará pessoas e organizações envolvidas com este estudo.

Patrocinador

University of California, San Francisco

Colaboradores

Pediatric Neuro-Oncology Consortium
The Lilabean Foundation, Inc.

Investigadores

  • Investigador principal: Sabine Mueller, MD, PhD, University of California, San Francisco
  • Cadeira de estudo: Santhosh A Upadhyaya, MD, University of Michigan, C. S. Mott Children's Hospital

Datas de registro do estudo

Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados ​​pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.

Datas Principais do Estudo

Início do estudo (Real)

5 de maio de 2026

Conclusão Primária (Estimado)

30 de abril de 2028

Conclusão do estudo (Estimado)

31 de março de 2030

Datas de inscrição no estudo

Enviado pela primeira vez

6 de novembro de 2025

Enviado pela primeira vez que atendeu aos critérios de CQ

6 de novembro de 2025

Primeira postagem (Real)

10 de novembro de 2025

Atualizações de registro de estudo

Última Atualização Postada (Real)

9 de novembro de 2026

Última atualização enviada que atendeu aos critérios de controle de qualidade

5 de novembro de 2026

Última verificação

1 de novembro de 2026

Mais Informações

Termos relacionados a este estudo

Termos MeSH relevantes adicionais

Outros números de identificação do estudo

  • 25087
  • NCI-2025-08332 (Identificador de registro: NCI Clinical Trials Reporting Program (CTRP))

Plano para dados de participantes individuais (IPD)

Planeja compartilhar dados de participantes individuais (IPD)?

SIM

Descrição do plano IPD

De-identified datasets may be shared with research collaborators during the course of the study.

Tipo de informação de suporte de compartilhamento de IPD

  • PROTOCOLO DE ESTUDO
  • SEIVA
  • CIF

Informações sobre medicamentos e dispositivos, documentos de estudo

Estuda um medicamento regulamentado pela FDA dos EUA

Sim

Estuda um produto de dispositivo regulamentado pela FDA dos EUA

Não

produto fabricado e exportado dos EUA

Sim

Essas informações foram obtidas diretamente do site clinicaltrials.gov sem nenhuma alteração. Se você tiver alguma solicitação para alterar, remover ou atualizar os detalhes do seu estudo, entre em contato com register@clinicaltrials.gov. Assim que uma alteração for implementada em clinicaltrials.gov, ela também será atualizada automaticamente em nosso site .

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