A Study of a Retroviral Replicating Vector Administered to Subjects With Recurrent Malignant Glioma

A Study of a Retroviral Replicating Vector Administered to Subjects With Recurrent Malignant Glioma
This study is currently recruiting participants.
Verified May 2012 by Tocagen Inc.

First Received on July 1, 2010.  
Last Updated on June 20, 2012  
History of Changes
Sponsor: Tocagen Inc.
Information provided by (Responsible Party): Tocagen Inc.
ClinicalTrials.gov Identifier: NCT01156584
  Purpose

This is a multicenter, open-label, ascending-dose trial of the safety and tolerability of increasing, single doses of Toca 511, a Retroviral Replicating Vector (RRV), administered transcranially to subjects with recurrent high grade glioma (rHGG) who have undergone surgery, radiation therapy and chemotherapy with temozolomide. Approximately 3-4 weeks following injection of the RRV, 6-day courses of treatment with oral 5-FC will commence and will be repeated monthly for up to 6 cycles.

Condition Intervention Phase
Glioblastoma
Anaplastic Astrocytoma
Anaplastic Oligodendroglioma
Anaplastic Oligoastrocytoma
Biological: Toca 511
Drug: 5-FC
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511 in Patients With Recurrent High Grade Glioma

Resource links provided by NLM:

Further study details as provided by Tocagen Inc.:

Primary Outcome Measures:

  • Determine the Maximum Tolerated Dose of Toca 511 [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

  • Determine Response Rate at MTD [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Determine the PFS-6 at MTD [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: June 2010
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)

Arms

Assigned Interventions
Experimental: Single arm Biological: Toca 511

Single, stereotactic, transcranial, intratumoral injection
Other Names:
  • Retroviral Replicating Vector (RRV)
  • Gene Therapy
  • Gene Transfer

Drug: 5-FC

130 mg/kg/day for 6 days, repeated every month for 6 months
Other Name: flucytosine, 5-FC, 5-FC XR, Toca FC (extended release flucytosine)

Detailed Description:

There is an ongoing, intensive search for novel therapies to improve the prognosis of patients with the most common and aggressive form of primary brain cancer, glioblastoma multiforme (GBM). Gene transfer is one such approach. Early gene-transfer studies with replication incompetent vectors showed this approach to be generally safe, but ineffective due to limited transduction of the tumor. More recently gene transfer has been attempted with oncolytic, replicating viruses. However these viruses are rapidly cleared by the immune system. To overcome these shortcomings of previous gene transfer protocols, Toca 511 has been developed utilizing a Retroviral Replicating Vector (RRV). This platform has the following potential advantages: 1) The vector only infects dividing cells, 2) The virus stably integrates into the genome of the tumor cells allowing for the potential for long-term control of the tumor, 3) The virus is not intrinsically oncolytic and is not cleared from the tumor by the immune system, and 4) The virus has been engineered to express the prodrug-activator, cytosine deaminase (CD), a gene that catalyzes the intracellular conversion of the antifungal drug, 5-FC (flucytosine) to the cytotoxic drug 5-FU. In both xenograft and syngeneic intracranial mouse tumor models the Toca 511/5-FC combination was able to significantly increase the survival of treated animals. The goal of the current trial is to demonstrate the safety and efficacy of Toca 511 administered intratumorally to patients with recurrent GBM followed by cyclic treatment with the prodrug 5-FC.

This is a multicenter, open-label, ascending-dose trial of the safety and tolerability of increasing, single doses of Toca 511 administered transcranially to subjects with rHGG who have undergone surgery, radiation therapy and chemotherapy with temozolomide. The study will be conducted in 2 parts. Part one will study ascending, single doses of Toca 511 delivered via stereotactic, transcranial injection into the tumor. Approximately 3-4 weeks later subjects will undergo a baseline Gd-MRI exam and then begin treatment with oral 5-FC administered for 6 consecutive days. If tolerated, these 6-day courses of 5-FC will be repeated every 4 weeks for 6 cycles. Subjects will undergo Gd-MRI scanning every 8 weeks. In part 2 of the study, 9 additional subjects will be studied at the highest dose of Toca 511 found in part one to be safe and well tolerated. Each subject will receive a single, transcranial injection of Toca 511. Approximately 3-4 weeks later subjects will undergo a baseline Gd-MRI exam and then begin treatment with oral 5-FC administered for 6 consecutive days. If tolerated, these 6-day courses of 5-FC will be repeated every 4 weeks for 6 cycles. Subjects will undergo Gd-MRI scanning every 8 weeks. Tumor response will be assessed using the Macdonald criteria.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • at least 18 years of age
  • single, supratentorial HGG (WHO grade III or IV) less than or equal to 9 cm^2 in its greatest cross sectional area
  • at least one surgical gross-total or subtotal resection
  • postoperative radiation with concurrent temozolomide
  • at least 2 cycles of maintenance temozolomide
  • must have progressive disease and be at least 12 weeks post radiation therapy
  • stable or decreasing dose of corticosteroids for past 7 days
  • KPS:18-75 years of age, at least 60; > 75 years of age, at least 70
  • absolute neutrophil count > 1500/mm^3
  • absolute lymphocyte count > 500/mm^3
  • hemoglobin > 10 g/dL
  • estimated glomerular filtration rate > 50 mL/min
  • ALT/AST < 3 times ULN and bilirubin < 1.5 mg/dL
  • negative serum pregnancy test
  • if being screened for part two of study, must have evaluable disease on Gd-MRI

Exclusion Criteria:

  • cytotoxic therapy within the past 4 weeks (6 weeks for BCNU/CCNU)
  • implanted Gliadel wafer/wafers within past 8 weeks
  • injection of enhancing rim of tumor would require violation of ventricular system
  • clinical evidence of increased intracranial pressure
  • bleeding diathesis
  • use of anticoagulants/antiplatelet agents that cannot be stopped
  • poorly controlled seizures
  • HIV positive
  • Avastin use within 5 weeks of projected vector injection
  • allergy or intolerance to 5-FC
  • g.i. condition that would prevent ingestion or absorption of 5-FC
  • any investigational treatment within the past 30 days
  • pregnant or breast feeding
  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01156584

Contacts
Contact: Dan Pertschuk, MD 858-412-8409 dpertschuk@tocagen.com

Locations
United States, California
UCLA Recruiting
Los Angeles, California, United States, 90095
Contact: Tim Cloughesy, MD     310-825-5321     tcloughesy@mednet.ucla.edu    
Contact: Emy Filka     310-794-3521        
Principal Investigator: Tim Cloughesy, MD            
UCSD Recruiting
San Diego, California, United States, 92093
Contact: Ryan Kim     858-822-6176     rykim@ucsd.edu    
Principal Investigator: Santosh Kesari, MD            
UCSF Recruiting
San Francisco, California, United States, 94143
Contact: Kristen Lawton     415-353-2746     LawtonK@neurosurg.ucsf.edu    
Contact: Manish Aghi, MD         AghiM@neurosurg.ucsf.edu    
Principal Investigator: Manish Aghi, MD            
United States, Michigan
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202
Contact: Nichell Fowlkes, RN, BSN     313-916-7231     nfowlke1@hfhs.org    
Principal Investigator: Tom Mikkelsen, MD            
United States, Ohio
Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Contact: Cathy Brewer, RN     216-444-7937     BrewerC1@ccf.org    
Contact: Michael Vogelbaum, MD         Vogelbm@ccf.org    
Principal Investigator: Michael Vogelbaum, MD            
Sponsors and Collaborators
Tocagen Inc.
  More Information

Additional Information:

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Tocagen Inc.
ClinicalTrials.gov Identifier: NCT01156584    
History of Changes
Other Study ID Numbers: Tg 511-08-01
Study First Received: July 1, 2010
Last Updated: June 20, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Tocagen Inc.:

glioma
glioblastoma
glioblastoma multiforme
Grade IV astrocytoma
brain cancer
recurrent glioblastoma
GBM
AA
AOD
anaplastic astrocytoma
anaplastic oligodendroglioma
anaplastic oligoastrocytoma
malignant glioma
high grade glioma

Additional relevant MeSH terms:

Astrocytoma
Glioblastoma
Glioma
Oligodendroglioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Flucytosine
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 21, 2012

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