Study of a Retroviral Replicating Vector to Treat Patients Undergoing Surgery for a Recurrent Malignant Brain Tumor

Study Description

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Brief Summary:

This is a multicenter study evaluating the safety and tolerability of increasing doses of Toca 511, a retroviral replicating vector, injected into the resection cavity of subjects with Grade III or Grade IV Gliomas who have elected to undergo surgical removal of their tumor. Approximately 6 weeks after injection of Toca 511, subjects will take an oral course of 5-FC, an antifungal antibiotic. These one week courses of 5-FC will be repeated during the 31 week study. In some subjects, Toca 511 and Toca FC will also be evaluated with either of the following standard treatments for glioma: lomustine, a drug approved by the FDA to treat brain tumors or bevacizumab, an alternative drug approved by the FDA to treat brain tumors. After completion of this study, all subjects will be eligible for enrollment and encouraged to be in a long-term continuation protocol that enables additional Toca FC treatment cycles to be given, as well as permits the collection of long-term safety and survival data.

Condition or disease	Intervention/treatment	Phase
Glioblastoma Multiforme; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Oligoastrocytoma	Biological: Toca 511	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	58 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A P1 Ascending Dose Trial of Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered to Subjects at the Time of Resection for Recurrent High Grade Glioma & Followed by Treatment With Toca FC, Extended-Release 5-FC
Study Start Date :	January 2012
Estimated Primary Completion Date :	May 2016
Estimated Study Completion Date :	July 2016

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Toca 511 vector; Toca 511 a retroviral replicating vector expressing the cytosine deaminase enzyme

Biological: Toca 511; All subjects will receive Toca 511, a retroviral replicating vector that expresses the cytosine deaminase (CD) gene. CD converts the antibiotic 5-FC to the anti-cancer drug 5-FU in cells that have been infected by the Toca 511 vector. Beginning approximately 6 weeks after administration of Toca 511, subjects will take a course of oral 5-FC. These courses of 5-FC will be repeated cyclically during the 6-month study.; Other Names: Toca 511, RRV, retroviral replicating vector; 5-FC, flucytosine, 5-fluorocytosine, Toca FC

Outcome Measures

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Primary Outcome Measures :

1. Dose Limiting Toxicities [ Time Frame: 2 months ]
   Excluding nausea, vomiting and fatigue, any Grade 3 or higher non-hematologic toxicity or any Grade 4 or higher hematologic toxicity, felt to be related to Toca 511 or the Toca 511/5-FC combination.

Secondary Outcome Measures :

1. Overall Survival of Subjects [ Time Frame: Overall survival, Overall survival at 6 months (OS6), 9 months (OS9), and 12 months (OS12) ]
2. Progression Free Survival (PFS) of Subjects [ Time Frame: PFS of subjects at 6 months (PFS-6) ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria (must all be answered "Yes"):

• Has the subject given written informed consent?
• Is the subject between 18 years old and 80 years old inclusive?
• Has the subject had histologically proven HGG with recurrence or progression following initial definitive therapy(s) such as surgery with or without adjuvant radiation therapy and/or chemotherapy (confirmed by diagnostic biopsy or contrast-enhanced MRI and evaluable by Macdonald criteria)? Note if first recurrence of GBM is documented by MRI, an interval of at least 12 weeks after the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiotherapy treatment field.
• Does the subject have a single, HGG tumor recurrence/progression that is ≤ 5 cm in its greatest dimension?
• Based on the pre-operative evaluation, is the tumor recurrence/progression a candidate for ≥ 80% resection?
• Has the subject elected not to undergo treatment with the Gliadel® wafer?
• Does the subject have a Karnofsky performance status ≥ 70?
• Does the subject have an absolute neutrophil count (ANC) ≥ 1500/mm3?
• Does the subject have an absolute lymphocyte count ≥ 500/mm3?
• Does the subject have a platelet count ≥ 100,000/mm3?
• Does the subject have a Hgb ≥ 10 g/dL?
• Does the subject have a normal PT/PTT? (subnormal PT/PTT acceptable)
• Does the subject have an estimated glomerular filtration rate of at least 50 mL/min (inclusive) by the Cockcroft-Gault formula?
• Does the subject have an ALT < 3 times the upper limit of the laboratory reference range and total bilirubin < 1.5 mg/dL?
• If the subject is a female of childbearing potential, has she had a negative serum pregnancy test within the past 21 days?
• Is the subject willing to use condoms for contraception for 6 months after receiving Toca 511 or until there is no evidence of the virus in his/her blood, whichever is longer. If the subject is a fertile female, is she willing to use contraception for at least 12 months?
• Is the subject willing and able to abide by the protocol?

Exclusion Criteria (must all be answered "No"):

• Has the subject received cytotoxic chemotherapy within the past 3 weeks (6 weeks for nitrosoureas) of the planned surgery date?
• Does the subject have, or has the subject had, within the past 4 weeks any infection requiring antibiotic, antifungal or antiviral therapy?
• Has the subject had a surgical procedure in the last 28 days or a surgical wound that is not healed?
• Does the subject have any bleeding diathesis, or must the subject take any anticoagulants, or antiplatelet agents, including NSAIDs that cannot be stopped for surgery?
• Does the subject have a history of allergy or intolerance to flucytosine?
• Is the subject HIV positive?
• Does the subject have any gastrointestinal disease that would prevent him or her from being able to ingest or absorb flucytosine?
• Has the subject received any investigational treatment within the past 30 days?
• Is the subject breast feeding?
• Has the subject received Avastin® (bevacizumab) for this recurrence/progression, or within the past 5 weeks?
• Does the patient have a history of prior malignancy, excluding basal or squamous cell carcinoma of the skin, with an expected survival of less than five years?

Contacts and Locations

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Locations

United States, California
UCLA
Los Angeles, California, United States, 90095
University of California at San Diego
San Diego, California, United States, 92093
United States, Michigan
Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, New Jersey
JFK Medical Center
Edison, New Jersey, United States, 08820
United States, Ohio
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
Ohio State University
Columbus, Ohio, United States, 43210
United States, Washington
Swedish Neuroscience Institute
Seattle, Washington, United States, 98122

Sponsors and Collaborators

Tocagen Inc.

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Tocagen Inc.
ClinicalTrials.gov Identifier:	NCT01470794 History of Changes
Other Study ID Numbers:	Tg 511-11-01
First Posted:	November 11, 2011
Last Update Posted:	February 25, 2016
Last Verified:	February 2016

Keywords provided by Tocagen Inc.:

GBM; HGG; High grade glioma	Malignant glioma; Grade III glioma; Grad IV glioma

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Oligodendroglioma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors	Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue