Combination Chemotherapy Plus Gene Therapy in Treating Patients With CNS Tumors

• ClinicalTrials.gov Identifier: NCT00005796
• Recruitment Status: Completed
• First Posted: April 28, 2004
• Last Update Posted: March 25, 2015
• Sponsor: Indiana University
• Collaborator: Indiana University Melvin and Bren Simon Cancer Center
• Information provided by (Responsible Party): Indiana University

Study Description

Brief Summary:

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. Inserting a specific gene into a person's peripheral stem cells may improve the body's ability to fight cancer or make the cancer more sensitive to chemotherapy.

PURPOSE: Phase I trial to study the effectiveness of combination chemotherapy plus gene therapy in treating patients who have CNS tumors.

Condition or disease	Intervention/treatment	Phase
Bone Marrow Suppression; Brain and Central Nervous System Tumors; Drug/Agent Toxicity by Tissue/Organ	Procedure: filgrastim; Biological: gene therapy; Drug: lomustine; Drug: procarbazine hydrochloride; Drug: vincristine sulfate; Procedure: in vitro-treated peripheral blood stem cell transplantation	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: February 2000
• Actual Primary Completion Date: June 2003
• Actual Study Completion Date: December 2011

Arms and Interventions

Arm

Intervention/treatment

Experimental: Single arm; PCV therapy

Procedure: filgrastim; GCSF is given after chemo administration; Biological: gene therapy; stem cells are collected and given back to the patients after chemotherapy adminstration; Drug: lomustine; chemotherapy is administered every 21 days; Drug: procarbazine hydrochloride; chemotherapy is administered every 21 days.; Drug: vincristine sulfate; chemotherapy is administered every 21 days; Procedure: in vitro-treated peripheral blood stem cell transplantation; stem cells are reinfused after chemotherapy administration

Outcome Measures

Primary Outcome Measures :

1. 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. [ Time Frame: Year 2 ]

Eligibility Criteria

• Ages Eligible for Study: 5 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Indiana

Indiana University Cancer Center

Indianapolis, Indiana, United States, 46202-5265

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Indiana University

Indiana University Melvin and Bren Simon Cancer Center

Investigators

• Study Chair: James Croop, MD, PhD; Riley's Children Cancer Center at Riley Hospital for Children

More Information

• Responsible Party: Indiana University
• ClinicalTrials.gov Identifier: NCT00005796 History of Changes
• Other Study ID Numbers: 9607-22; IUMC-9607-22; NCI-H00-0049
• First Posted: April 28, 2004
• Last Update Posted: March 25, 2015
• Last Verified: March 2015

Keywords provided by Indiana University:

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

Additional relevant MeSH terms:

Nervous System Neoplasms; Central Nervous System Neoplasms; Neoplasms; Neoplasms by Site; Nervous System Diseases; Vincristine; Lomustine; Procarbazine; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Alkylating; Alkylating Agents