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Zielvalidierung und Wirksamkeit von Metformin bei Patienten mit Ependymom der hinteren Schädelgrube Gruppe A (PFA) (PNOC041)

5. November 2026 aktualisiert von: University of California, San Francisco

Eine Zielvalidierungs- und Wirksamkeitsstudie von Metformin bei Patienten mit rezidivierendem oder progressivem Ependymom der Gruppe A (PFA) der hinteren Schädelgrube

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.

Studienübersicht

Status

Rekrutierung

Bedingungen

Intervention / Behandlung

Detaillierte Beschreibung

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.

Studientyp

Interventionell

Einschreibung (Geschätzt)

30

Phase

  • Phase 2

Kontakte und Standorte

Dieser Abschnitt enthält die Kontaktdaten derjenigen, die die Studie durchführen, und Informationen darüber, wo diese Studie durchgeführt wird.

Studienkontakt

  • Name: PNOC Operations Office
  • Telefonnummer: 415-502-1600
  • E-Mail: PNOC041@ucsf.edu

Studienorte

  • Brasilien
    • São Paulo
      • São Paulo, São Paulo, Brasilien, 04039-001
        • Noch keine Rekrutierung
        • GRAACC - Grupo de Apoio ao Adolescente e a Crianca com Cancer
        • Kontakt:
        • Kontakt:
  • Vereinigte Staaten
    • Alabama
      • Birmingham, Alabama, Vereinigte Staaten, 35233
        • Rekrutierung
        • University of Alabama at Birmingham
        • Kontakt:
        • Kontakt:
    • California
      • San Francisco, California, Vereinigte Staaten, 94143
        • Rekrutierung
        • University of California, San Francisco
        • Hauptermittler:
          • Sabine Mueller, MD, PhD
        • Kontakt:
    • District of Columbia
      • Washington D.C., District of Columbia, Vereinigte Staaten, 20010
    • Indiana
      • Indianapolis, Indiana, Vereinigte Staaten, 46202
        • Noch keine Rekrutierung
        • Riley Hospital for Children at Indiana University Health
        • Kontakt:
        • Kontakt:
          • Alex Lion, DO, MPH
          • Telefonnummer: 317-944-8784
          • E-Mail: alion@iu.edu
    • Maryland
      • Baltimore, Maryland, Vereinigte Staaten, 21287
        • Rekrutierung
        • Johns Hopkins University
        • Kontakt:
          • Kenneth Cohen, MD, MBA
          • Telefonnummer: 410-614-5055
          • E-Mail: kcohen@jhmi.edu
        • Kontakt:
    • Michigan
      • Ann Arbor, Michigan, Vereinigte Staaten, 48109
        • Noch keine Rekrutierung
        • University of Michigan
        • Kontakt:
        • Kontakt:
    • Missouri
      • St Louis, Missouri, Vereinigte Staaten, 63110
        • Rekrutierung
        • Washington University
        • Kontakt:
        • Kontakt:
    • New Jersey
      • Hackensack, New Jersey, Vereinigte Staaten, 07601
        • Noch keine Rekrutierung
        • Hackensack Meridian Health
        • Kontakt:
        • Kontakt:
    • North Carolina
      • Durham, North Carolina, Vereinigte Staaten, 27710
    • Tennessee
      • Memphis, Tennessee, Vereinigte Staaten, 38105
    • Utah
      • Salt Lake City, Utah, Vereinigte Staaten, 84113
    • Washington

Teilnahmekriterien

Forscher suchen nach Personen, die einer bestimmten Beschreibung entsprechen, die als Auswahlkriterien bezeichnet werden. Einige Beispiele für diese Kriterien sind der allgemeine Gesundheitszustand einer Person oder frühere Behandlungen.

Zulassungskriterien

Studienberechtigtes Alter

1 Jahr bis 39 Jahre (Kind, Erwachsene)

Akzeptiert gesunde Freiwillige

Nein

Studienberechtigte Geschlechter

Alle

Beschreibung

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.

Studienplan

Dieser Abschnitt enthält Einzelheiten zum Studienplan, einschließlich des Studiendesigns und der Messung der Studieninhalte.

Wie ist die Studie aufgebaut?

Designdetails

  • Hauptzweck: Behandlung
  • Zuteilung: Nicht randomisiert
  • Interventionsmodell: Sequenzielle Zuweisung
  • Maskierung: Keine (Offenes Etikett)

Waffen und Interventionen

Teilnehmergruppe / Arm
Intervention / Behandlung
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).
Verfahren: Magnetic Resonance Imaging (MRI)

Undergo MRI imaging

Andere Namen:
  • MRT
Arzneimittel: Metformin

Given orally (PO)

Andere Namen:
  • Glucophage
Verfahren: Planned Surgical Resection

Undergo planned surgery as part of regular care

Andere Namen:
  • Chirurgische resektion
Verfahren: Specimen Collection

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

Andere Namen:
  • Probenentnahme
Verfahren: MR spectroscopy (MRS)

Undergo MRS imaging

Andere Namen:
  • FRAU
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).
Verfahren: Magnetic Resonance Imaging (MRI)

Undergo MRI imaging

Andere Namen:
  • MRT
Arzneimittel: Metformin

Given orally (PO)

Andere Namen:
  • Glucophage
Verfahren: Planned Surgical Resection

Undergo planned surgery as part of regular care

Andere Namen:
  • Chirurgische resektion
Verfahren: Specimen Collection

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

Andere Namen:
  • Probenentnahme
Verfahren: MR spectroscopy (MRS)

Undergo MRS imaging

Andere Namen:
  • FRAU

Was misst die Studie?

Primäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
Proportion of participants with changes in biomarkers between the pre-and post-metformin treated samples (Target Validation Phase)
Zeitfenster: 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)
Zeitfenster: 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

Mitarbeiter und Ermittler

Hier finden Sie Personen und Organisationen, die an dieser Studie beteiligt sind.

Sponsor

University of California, San Francisco

Mitarbeiter

Pediatric Neuro-Oncology Consortium
The Lilabean Foundation, Inc.

Ermittler

  • Hauptermittler: Sabine Mueller, MD, PhD, University of California, San Francisco
  • Studienstuhl: Santhosh A Upadhyaya, MD, University of Michigan, C. S. Mott Children's Hospital

Studienaufzeichnungsdaten

Diese Daten verfolgen den Fortschritt der Übermittlung von Studienaufzeichnungen und zusammenfassenden Ergebnissen an ClinicalTrials.gov. Studienaufzeichnungen und gemeldete Ergebnisse werden von der National Library of Medicine (NLM) überprüft, um sicherzustellen, dass sie bestimmten Qualitätskontrollstandards entsprechen, bevor sie auf der öffentlichen Website veröffentlicht werden.

Haupttermine studieren

Studienbeginn (Tatsächlich)

5. Mai 2026

Primärer Abschluss (Geschätzt)

30. April 2028

Studienabschluss (Geschätzt)

31. März 2030

Studienanmeldedaten

Zuerst eingereicht

6. November 2025

Zuerst eingereicht, das die QC-Kriterien erfüllt hat

6. November 2025

Zuerst gepostet (Tatsächlich)

10. November 2025

Studienaufzeichnungsaktualisierungen

Letztes Update gepostet (Tatsächlich)

9. November 2026

Letztes eingereichtes Update, das die QC-Kriterien erfüllt

5. November 2026

Zuletzt verifiziert

1. November 2026

Mehr Informationen

Begriffe im Zusammenhang mit dieser Studie

Zusätzliche relevante MeSH-Bedingungen

Andere Studien-ID-Nummern

  • 25087
  • NCI-2025-08332 (Registrierungskennung: NCI Clinical Trials Reporting Program (CTRP))

Plan für individuelle Teilnehmerdaten (IPD)

Planen Sie, individuelle Teilnehmerdaten (IPD) zu teilen?

JA

Beschreibung des IPD-Plans

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

Art der unterstützenden IPD-Freigabeinformationen

  • STUDIENPROTOKOLL
  • SAFT
  • ICF

Arzneimittel- und Geräteinformationen, Studienunterlagen

Studiert ein von der US-amerikanischen FDA reguliertes Arzneimittelprodukt

Ja

Studiert ein von der US-amerikanischen FDA reguliertes Geräteprodukt

Nein

Produkt, das in den USA hergestellt und aus den USA exportiert wird

Ja

Diese Informationen wurden ohne Änderungen direkt von der Website clinicaltrials.gov abgerufen. Wenn Sie Ihre Studiendaten ändern, entfernen oder aktualisieren möchten, wenden Sie sich bitte an register@clinicaltrials.gov. Sobald eine Änderung auf clinicaltrials.gov implementiert wird, wird diese automatisch auch auf unserer Website aktualisiert .

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