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A Pilot Study of Dose-Intensified Procarbazine, CCNU, Vincristine (PCV) for Poor Prognosis Pediatric and Adult Brain Tumors Utilizing Fibronectin-Assisted, Retroviral-Mediated Modification of CD34+ Peripheral Blood Cells With O6-Methylguanine DNA Methyltransferase


Phase 1
5 Years
N/A
Open (Enrolling)
Both
Bone Marrow Suppression, Brain and Central Nervous System Tumors, Drug/Agent Toxicity by Tissue/Organ

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Trial Information

A Pilot Study of Dose-Intensified Procarbazine, CCNU, Vincristine (PCV) for Poor Prognosis Pediatric and Adult Brain Tumors Utilizing Fibronectin-Assisted, Retroviral-Mediated Modification of CD34+ Peripheral Blood Cells With O6-Methylguanine DNA Methyltransferase


OBJECTIVES: I. Determine the toxicity (detection of replication competent retrovirus)
associated with CD34+ cells transduced with a retroviral vector expressing human
O6-methylguanine DNA methyltransferase in adult and pediatric patients with poor prognosis
CNS tumors. II. Determine the safety of genetic modification of cells carried out in the
presence (ex vivo) of recombinant fibronectin (FN) fragment utilized to assist in retroviral
entry into mammalian cells. III. Determine any evidence of engraftment of cells exposed to
FN during retroviral transduction. IV. Determine any evidence of antibodies to FN following
infusion of cells exposed to FN during ex vivo retroviral transduction.

OUTLINE: Patients with surgically approachable lesions undergo maximal surgical debulking
that allows preservation of good neurologic functioning. Harvest: Patients receive
filgrastim (G-CSF) subcutaneously or IV beginning 4 days prior to initiation of first
leukapheresis and continuing until completion of harvest. Peripheral blood stem cells are
harvested and selected for CD34+ cells which are transduced with a fibronectin assisted
retroviral vector expressing human O6-methylguanine DNA methyltransferase. Intensification:
Patients receive oral lomustine and vincristine IV on day 0 and oral procarbazine on days
1-7. Treatment repeats every 4 weeks for 4 courses in the absence of disease progression or
unacceptable toxicity. Patients with newly diagnosed tumors may undergo involved field
radiotherapy (IF-RT) after completion of the third course of chemotherapy and may begin the
fourth course of chemotherapy after completion of IF-RT. Transplantation: Two-thirds of the
transduced CD34+ cells are reinfused on day 9 of the first course of chemotherapy. The
remaining portion (one-third) of the transduced CD34+ cells are reinfused on day 9 of the
second course of chemotherapy. Untransduced CD34+ cells are reinfused on day 9 of the last 3
courses of chemotherapy. Patients are followed every 3 months for 6 months, every 4 months
for 1 year, every 6 months through year 5, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 15-20 patients will be accrued for this study within 1
year.

Inclusion Criteria


DISEASE CHARACTERISTICS: Histologically proven newly diagnosed CNS tumors Eligible tumor
types: Glioblastoma multiforme (WHO grade IV) Anaplastic astrocytoma (WHO grade III)
Anaplastic oligodendroglioma (WHO grade III) Mixed anaplastic oligoastrocytoma (WHO grade
III) Incompletely resected ependymoma Diffusely intrinsic pontine or medullary glioma
Histology requirement waived OR Histologically proven recurrent or progressive CNS tumors
Eligible tumor types: Same as above plus oligodendroglioma (WHO grade II) No brainstem
tumors arising from the cervicomedullary region or midbrain without histologic proof of
malignancy No supratentorial low grade astrocytomas (WHO grade I or II)

PATIENT CHARACTERISTICS: Age: 5 and over Performance status: ECOG 0-2 Life expectancy: At
least 2 months Hematopoietic: Absolute neutrophil count greater than 1,000/mm3 Platelet
count greater than 100,000/mm3 (transfusion independent) Hemoglobin greater than 10 g/dL
at time of pulmonary function testing Hepatic: Bilirubin less than 1.2 mg/dL SGOT or SGPT
less than 3 times normal Renal: Creatinine less than 1.5 mg/dL OR Creatinine clearance or
radioisotope GFR greater than 70 mL/min Pulmonary: FEV1, FVC, and/or DLCO greater than 60%
predicted Children who are uncooperative with pulmonary function tests must have the
following: No evidence of dyspnea at rest No exercise intolerance Oxygen saturation (by
pulse oximetry) greater than 94% on room air Other: Minimum weight of 10 kg Not pregnant
or nursing No active infection

PRIOR CONCURRENT THERAPY: Biologic therapy: No growth factors after completion of study
chemotherapy Chemotherapy: No prior nitrosourea or procarbazine Endocrine therapy: No
concurrent dexamethasone as antiemetic Radiotherapy: No prior craniospinal radiotherapy
Surgery: Not specified

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the toxicity (detection of replication competent retrovirus) associated with CD34+ cells transduced with a retroviral vector expressing human O6-methylguanine DNA methyltransferase in adult and pediatric patients with poor prognosis CNS tumors.

Outcome Time Frame:

Year 2

Safety Issue:

Yes

Principal Investigator

James Croop, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Riley's Children Cancer Center at Riley Hospital for Children

Authority:

United States: Federal Government

Study ID:

9607-22

NCT ID:

NCT00005796

Start Date:

February 2000

Completion Date:

June 2012

Related Keywords:

  • Bone Marrow Suppression
  • Brain and Central Nervous System Tumors
  • Drug/Agent Toxicity by Tissue/Organ
  • recurrent adult brain tumor
  • adult brain stem glioma
  • adult ependymoma
  • adult medulloblastoma
  • adult glioblastoma
  • childhood high-grade cerebral astrocytoma
  • childhood oligodendroglioma
  • adult anaplastic astrocytoma
  • adult anaplastic oligodendroglioma
  • adult mixed glioma
  • drug/agent toxicity by tissue/organ
  • bone marrow suppression
  • untreated childhood brain stem glioma
  • recurrent childhood brain stem glioma
  • untreated childhood cerebellar astrocytoma
  • recurrent childhood cerebellar astrocytoma
  • recurrent childhood cerebral astrocytoma
  • recurrent childhood medulloblastoma
  • newly diagnosed childhood ependymoma
  • recurrent childhood ependymoma
  • adult giant cell glioblastoma
  • adult gliosarcoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Indiana University Cancer CenterIndianapolis, Indiana  46202-5265
Dana-Farber Cancer InstituteBoston, Massachusetts  02115