Study of Busulfan for Refractory Central Nervous System (CNS) Tumors

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2009 by Ann & Robert H Lurie Children's Hospital of Chicago.
Recruitment status was  Not yet recruiting
Sponsor:
Information provided by:
Ann & Robert H Lurie Children's Hospital of Chicago
ClinicalTrials.gov Identifier:
NCT00836628
First received: February 3, 2009
Last updated: NA
Last verified: February 2009
History: No changes posted
  Purpose

This protocol is aimed at establishing a maximum tolerated dose (MTD) for submyeloablative doses of Busulfex ® with the hope that a tolerable, submyeloablative dose can be established to test efficacy as alternative therapy for refractory pediatric brain tumors.


Condition Intervention Phase
Refractory Brain Tumors
Drug: Busulfan
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study Using Submyeloablative DOsing of Intravenous Busulfan (Busulfex) for Refractory Brain Tumors

Resource links provided by NLM:


Further study details as provided by Ann & Robert H Lurie Children's Hospital of Chicago:

Primary Outcome Measures:
  • maximum tolerated dose (MTD) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To describe the plasma pharmacokinetics in children with refractory barin tumors [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Event Free Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Progression Free Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Arms Assigned Interventions
Experimental: IV Busulfan
This is a single arm study. All subjects will receive the study medication at varying doses to be determined by dose escalation.
Drug: Busulfan
Busulfex ® will be administered every 4 weeks (28 days) as a continuous 24 hour infusion for up to 6 courses. Given the inter-patient variation in drug excretion and resultant plasma concentration, dose escalation will be based on plasma concentration. The starting Busulfex ® plasma concentration will be 300 ng/mL. There are a total of 7 dose levels (-1 to 5). This study will start at dose level 1.
Other Name: Busulfex

Detailed Description:

Pediatric brain tumors remain among the most common malignancies in childhood, second only to leukemia, representing 20% of all childhood cancers in the United States (1). Although significant strides have been made in therapies for other pediatric malignancies, mortality for patients with brain tumors remains high. The mainstay of therapy for CNS tumors has been a combination of surgery, chemotherapy, and radiation. High dose chemotherapy with stem cell transplant has been proposed as an alternative to radiation, in very young children and for relapsed patients. Stem cell transplantation however is not without significant side effects as well as transplant related mortality.

Busulfan is an alkylating agent and is able to exert its cytotoxic effects through hydrolysis and subsequent production of carbonium ions, directly alkylating DNA, interfering with its replication, and ultimately leading to cell death (2). Busulfan readily crosses the blood barrier, allowing for CNS levels nearly equal to those of plasma levels (5,6).

Primary Objectives:

To determine the maximum tolerated dose (MTD) of Busulfex ® in children with recurrent, progressive, or refractory primary brain tumors.

Secondary Objectives:

To obtain preliminary data regarding progression free survival (PFS) and event free survival (EFS) when Busulfex ® is used at submyeloablative doses in children with recurrent, progressive, or refractory primary brain tumors.

To describe the plasma pharmacokinetics of Busulfex ® in children with recurrent, progressive, or refractory primary brain tumors, using a continuous infusion.

  Eligibility

Ages Eligible for Study:   3 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Age: Age >2 year and ≤ 21 years Histologic Diagnosis Any histological proven (confirmed by institutional pathology report; pathology slides from outside referring outside institutions are not required.) recurrent or progressive CNS tumor. (optic pathway and brainstem gliomas allowed without histologic verification, but must have diagnostic imaging).

Life Expectancy Patients must have a life expectancy of ≥ 2 months. Prior Therapy There is no limit to the number of prior therapies a patient has received

  • Must be ≥ 3 weeks from myelosuppressive chemotherapy (6 weeks from nitrosoureas) and have demonstrated recovery (ANC ≥ 1000/uL) from their last course of chemotherapy
  • ≥ 6 months following allogeneic stem cell transplantation
  • ≥ 3 months following autologous stem cell transplantation
  • ≥ 3 months from craniospinal radiation
  • ≥ 4 weeks from focal radiation
  • ≥ 7 days from any past biologic/immunotherapy
  • ≥ 1 week from any hematopoietic growth factors Concomitant Medication
  • Patients taking Itraconazole or Phenytoin will be excluded. Patients must be off of these medications for at least 3 days prior to entering this trial. If the patient is taking phenytoin for seizures at the time of study enrollment, it must be stopped at least 3 days prior to starting therapy and Clonazepam will be substituted during the Busulfex ® infusions and for 24 hours following the infusion.
  • Patients on growth stimulating factors, such as GCSF, will be allowed to continue these medications only as indicated in the study.
  • Patients may be taking steroids while participating in this trial, but should be on a stable dose for >1 week prior to enrollment.
  • Medications interacting with the CYP3A4 substrate should also be avoided while the patient is on study.
  • Patients should also be on Pneumocystis prophylaxis while participating in this study. Pentamidine will be required, with a recommended dose of 4 mg/kg given intravenously every month. Pentamidine should continue throughout the duration of the trial.

Organ Function Requirements Adequate Bone Marrow Function Defined As

  • Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/ul (off growth factors x 48 hrs)
  • Platelet count greater than or equal to 100,000/uL (transfusion independent)
  • Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC transfusions) Adequate Renal Function Defined As
  • Serum creatinine less than or equal to 1.5 x upper limit of normal, or
  • Estimated creatinine clearance GFR greater than or equal to 70 ml/min/1.73 m² by the Schwartz formula Adequate Liver Function Defined As
  • Total bilirubin within normal range
  • SGPT (ALT) within normal range Adequate Pulmonary Function Defined As
  • Oxygen saturation >92% on room air Central Nervous System Function Defined As
  • Patients with seizure disorder may be enrolled; Patients MUST be on an anti-seizure medication upon enrollment, but this medication CANNOT be phenytoin or carbamezepine.
  • Patients must not be in status, coma or assisted ventilation prior to study enrollment.
  • Stable neurologic exam of at least 1 week duration Performance Level Karnofsky/ Lansky 50 or greater

Exclusion Criteria:

  • Pregnancy/Contraception: patients who are pregnant or breast-feeding will not be eligible.
  • Patients of childbearing potential must practice an effective method of birth control while participating on the study.
  • Females > 13 years of age or those who have achieved menarche must have a negative pregnancy test prior to study entry.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00836628

Contacts
Contact: Molly Fouts, BS, CCRP 773-880-8147 mefouts@childrensmemorial.org
Contact: Carrie Kempler, MPH, CCRP 773-883-6186 ckempler@childrensmemorial.org

Locations
United States, Illinois
Children's Memorial Hospital Not yet recruiting
Chicago, Illinois, United States, 60614
Contact: Molly Fouts, BS, CCRP    773-880-8147    mefouts@childrensmemorial.org   
Principal Investigator: Stewart Goldman, MD         
Sponsors and Collaborators
Ann & Robert H Lurie Children's Hospital of Chicago
Investigators
Principal Investigator: Stewart Goldman, MD Ann & Robert H Lurie Children's Hospital of Chicago
  More Information

No publications provided

Responsible Party: Stewart Goldman, MD, Director, Neuro-Oncology, Children's Memorial Hospital
ClinicalTrials.gov Identifier: NCT00836628     History of Changes
Other Study ID Numbers: CNS 1100
Study First Received: February 3, 2009
Last Updated: February 3, 2009
Health Authority: United States: Food and Drug Administration

Keywords provided by Ann & Robert H Lurie Children's Hospital of Chicago:
Progressive or Recurrent CNS Tumors
Progressive or Recurrent Brain Tumors
Progressive or Recurrent Ependymoma
Progressive or Recurrent High Grade Glioma
Progressive or Recurrent Astrocytoma
Progressive or Recurrent Medulloblastoma
Progressive or Recurrent Glioblastoma
Progressive or Recurrent Low Grade Glioma

Additional relevant MeSH terms:
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Busulfan
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists

ClinicalTrials.gov processed this record on August 28, 2014