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Topotecan in Treating Young Patients With Neoplastic Meningitis Due to Leukemia, Lymphoma, or Solid Tumors

29 juin 2011 mis à jour par: Pediatric Brain Tumor Consortium

A Phase I Pharmacokinetic Optimal Dosing Study of Intraventricular Topotecan for Children With Neoplastic Meningitis

RATIONALE: Drugs used in chemotherapy, such as topotecan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This phase I trial is studying the side effects, best way to give, and best dose of topotecan when given by intraventricular infusion in treating young patients with neoplastic meningitis due to leukemia, lymphoma, or solid tumors.

Aperçu de l'étude

Description détaillée

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose (MTD) of intraventricular topotecan in young patients with neoplastic meningitis secondary to leukemia, lymphoma, or solid tumors.
  • Determine the toxic effects and dose-limiting toxicity of this drug in these patients.
  • Determine whether the MTD of this drug is also the pharmacokinetic optimal dose, defined by the topotecan lactone concentration in the cerebral spinal fluid (CSF), in these patients.

Secondary

  • Determine, preliminarily, the antitumor activity of this drug in these patients.
  • Determine the pharmacokinetics of this drug in the CSF of these patients.
  • Correlate observed effects of post-treatment central review imaging (if feasible) with response to this drug in these patients.

OUTLINE: This is a non-randomized, dose-escalation, multicenter study.

  • Induction therapy (weeks 1-4): Patients receive topotecan intraventricularly* over 5 minutes on days 1-5 in weeks 1 and 3. Patients then proceed to consolidation therapy in week 5.

NOTE: *Patients who are willing, receive 1 intralumbar (instead of intraventricular) dose of topotecan on day 1 of week 3 only.

  • Consolidation therapy (weeks 5-10): Patients receive topotecan intraventricularly on days 1-5 in weeks 5 and 8. Patients then proceed to maintenance therapy in week 11.
  • Maintenance therapy (weeks 11-54): Patients receive topotecan intraventricularly on days 1-5 in weeks 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, and 51.

Cohorts of 3-6 patients receive escalating doses of intraventricular topotecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Once the MTD is determined, the cohort is expanded to 25 patients and the MTD is declared the pharmacokinetic optimal dose provided 23 of 25 patients treated at the MTD achieve the target pharmacokinetic parameter.

PROJECTED ACCRUAL: A total of 28-49 patients will be accrued for this study within 9-24 months.

Type d'étude

Interventionnel

Inscription (Réel)

19

Phase

  • La phase 1

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

    • California
      • San Francisco, California, États-Unis, 94115
        • UCSF Helen Diller Family Comprehensive Cancer Center
    • District of Columbia
      • Washington, District of Columbia, États-Unis, 20010-2970
        • Children's National Medical Center
    • Illinois
      • Chicago, Illinois, États-Unis, 60614
        • Children's Memorial Hospital - Chicago
    • Maryland
      • Bethesda, Maryland, États-Unis, 20892-1182
        • Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
    • Massachusetts
      • Boston, Massachusetts, États-Unis, 02115
        • Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
    • North Carolina
      • Durham, North Carolina, États-Unis, 27710
        • Duke Comprehensive Cancer Center
    • Pennsylvania
      • Philadelphia, Pennsylvania, États-Unis, 19104-4318
        • Children's Hospital of Philadelphia
      • Pittsburgh, Pennsylvania, États-Unis, 15213
        • Children's Hospital of Pittsburgh
    • Tennessee
      • Memphis, Tennessee, États-Unis, 38105
        • St. Jude Children's Research Hospital
    • Texas
      • Houston, Texas, États-Unis, 77030
        • Dan L. Duncan Cancer Center at Baylor College of Medicine
    • Washington
      • Seattle, Washington, États-Unis, 98105
        • Children's Hospital and Regional Medical Center - Seattle

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

3 ans à 21 ans (Enfant, Adulte)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

DISEASE CHARACTERISTICS:

  • Diagnosis of neoplastic meningitis secondary to leukemia, lymphoma (including AIDS-related lymphoma), or solid tumor (including primary CNS tumors or carcinomas of unknown primary site), defined by 1 of the following criteria:

    • Cerebral spinal fluid (CSF) cell count > 5/μL AND evidence of blast cells on cytospin or by cytology (for patients with leukemia or lymphoma)
    • Presence of tumor cells on cytospin or cytology OR unequivocal presence of meningeal disease by MRI (for patients with solid tumor)
  • No conventional therapy for neoplastic meningitis exists

    • Patients with CNS leukemia or lymphoma must be refractory to conventional therapy, including radiotherapy (i.e., second or greater relapse)
  • Patients with CNS leukemia or lymphoma must have had a negative bone marrow aspiration within the past 2 weeks
  • No clinical evidence of obstructive hydrocephalus
  • No compartmentalization of CSF flow by radioisotope indium In 111 or technetium Tc 99 DTPA flow study
  • No ventriculoperitoneal or ventriculoatrial shunt unless patient is completely shunt-independent
  • No impending spinal cord compression or other CNS involvement (e.g., acute visual loss secondary to optic nerve involvement) requiring emergent local radiotherapy

PATIENT CHARACTERISTICS:

Age

  • 3 to 21

Performance status

  • Lansky 60-100% (≤ 16 years of age) OR
  • Karnofsky 60-100% (> 16 years of age)

Life expectancy

  • Not specified

Hematopoietic

  • Not specified

Hepatic

  • Not specified

Renal

  • Calcium ≥ 7 mg/dL

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Sodium 125-150 mmol/L
  • Magnesium ≥ 0.7 mmol/L
  • Must have or be willing to have an intraventricular access device (i.e., Ommaya reservoir)
  • No uncontrolled infection

    • HIV-positive patients with AIDS-related lymphomatous meningitis are eligible
  • No other significant uncontrolled systemic medical illness that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • Recovered from prior biologic therapy or immunotherapy

Chemotherapy

  • Recovered from prior chemotherapy
  • At least 1 week since prior intra-colony stimulating factory (CSF) chemotherapy (2 weeks for liposomal cytarabine)
  • At least 3 weeks since prior systemic chemotherapy for leptomeningeal disease
  • Concurrent systemic chemotherapy to control systemic disease or bulk CNS disease allowed provided the systemic chemotherapy is not an investigational agent OR any of the following:

    • High-dose (> 1 g/m^2) methotrexate
    • High-dose (> 1 g/m^2) cytarabine
    • Fluorouracil
    • Capecitabine
    • Thiotepa
    • Nitrosoureas
    • Topotecan

Endocrine therapy

  • Not specified

Radiotherapy

  • See Disease Characteristics
  • At least 8 weeks since prior craniospinal radiotherapy and recovered
  • No concurrent CNS radiotherapy

    • Concurrent radiotherapy to extra-CNS sites (e.g., painful bone metastases not in the craniospinal axis) allowed

Surgery

  • Not specified

Other

  • More than 2 weeks since prior and no other concurrent investigational agents
  • No other concurrent intra-CSF or systemic therapy for leptomeningeal disease

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: N / A
  • Modèle interventionnel: Affectation à un seul groupe
  • Masquage: Aucun (étiquette ouverte)

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Délai
Estimate the maximum tolerated dose of intraventricular topotecan on this schedule
Délai: First 14 days of therapy
First 14 days of therapy
Number of patients with dose-limiting toxicity
Délai: First 14 days of therapy
First 14 days of therapy
Estimate the dose of intraventricular topotecan that will result in cerebrospinal fluid lactone concentrations exceeding 1 ng/mL for at least 8 hours after an intrathecal injection
Délai: Day 1 of Week 1
Day 1 of Week 1

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Number of patients with objective documentation of tumor response to intraventricular topotecan
Délai: Weeks 5, 11 and then every 12 weeks until off study
MRI of the brain and spine is obtained pre-consolidation, pre-maintenance, and then every 12 weeks in maintenance.
Weeks 5, 11 and then every 12 weeks until off study
Pharmacokinetics
Délai: Day 1 of Week 1
The cerebrospinal fluid (CSF) concentration-time profile for topotecan after intrathecal CSF administration will be modeled from the CSF samples collected on day 1 of week 1. Individual pharmacokinetic parameters estimated will include volume of central compartment, elimination rate constant, half-life, and clearance.
Day 1 of Week 1
Correlation of imaging parameters with tumor response
Délai: Pre-treatment, week 5, week 11, and then every 12 weeks until off study
MRI scans of the brain and spine is obtained pre-treament, pre-consolidation, pre-maintenance, and then every 12 weeks on maintenance.
Pre-treatment, week 5, week 11, and then every 12 weeks until off study

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Les enquêteurs

  • Chaise d'étude: Susan M. Blaney, MD, Baylor College of Medicine

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude

1 août 2005

Achèvement primaire (Réel)

1 août 2010

Dates d'inscription aux études

Première soumission

2 juin 2005

Première soumission répondant aux critères de contrôle qualité

2 juin 2005

Première publication (Estimation)

3 juin 2005

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Estimation)

30 juin 2011

Dernière mise à jour soumise répondant aux critères de contrôle qualité

29 juin 2011

Dernière vérification

1 juin 2011

Plus d'information

Termes liés à cette étude

Mots clés

Autres numéros d'identification d'étude

  • CDR0000430504
  • U01CA081457 (Subvention/contrat des NIH des États-Unis)
  • PBTC-019

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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