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A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511 in Patients With Recurrent High Grade Glioma


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Glioblastoma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma

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Trial Information

A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511 in Patients With Recurrent High Grade Glioma


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.


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Determine the Maximum Tolerated Dose of Toca 511

Outcome Time Frame:

8 weeks

Safety Issue:

Yes

Authority:

United States: Food and Drug Administration

Study ID:

Tg 511-08-01

NCT ID:

NCT01156584

Start Date:

June 2010

Completion Date:

Related Keywords:

  • Glioblastoma
  • Anaplastic Astrocytoma
  • Anaplastic Oligodendroglioma
  • Anaplastic Oligoastrocytoma
  • 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
  • Astrocytoma
  • Glioblastoma
  • Glioma
  • Oligodendroglioma

Name

Location

UCSDSan Diego, California  92103
Cleveland Clinic FoundationCleveland, Ohio  44195
UCSFSan Francisco, California  941430324
Henry Ford HospitalDetroit, Michigan  48202
UCLALos Angeles, California  90095