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Glioblastoma MultiformePhase 2/3Toca5NCT02414165

The Toca 5 Trial: Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma

A Phase 2/3 study testing Toca 511, Toca FC and Lomustine in people with Glioblastoma Multiforme and Anaplastic Astrocytoma, run by Tocagen Inc. at 67 sites in 4 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial summary

This is a multicenter, randomized, open-label phase 2/3 study of Toca 511 and Toca FC versus standard of care that comprises Investigator's choice of single agent chemotherapy (lomustine or temozolomide) or bevacizumab administered to subjects undergoing resection for first or second recurrence (including this… Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
Toca 511, Toca FC and Lomustine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
403 participants
Where
67 sitesin 4 countries
Study dates
30 Nov 2015to 20 Dec 2019
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Subject has given written informed consent
  • Subject is between 18 years old and 75 years old, inclusive
  • Subjects must have histologically proven GBM or AA and:
  • Must have received first-line multimodal therapy with surgery followed by temozolomide (unless MGMT promoter unmethylated) and radiation (subjects with GBM must have received temozolomide and radiation concurrently)
  • Must be in first or second recurrence (including this recurrence)
  • Recurrence must be confirmed by diagnostic biopsy with local pathology review or contrast-enhanced MRI. 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
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  • Subjects must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as per RANO criteria
  • Subjects must be at least 4 weeks post last dose of temozolomide
  • Prior gamma knife, stereotactic radiosurgery, or other focal high-dose radiotherapy is allowed but the subject must have either histopathologic confirmation of recurrent tumor, or new enhancement on MRI outside of the radiotherapy treatment field
  • Based on the pre-operative evaluation by neurosurgeon, the subject is a candidate for ≥ 80% resection of enhancing region
  • IDH mutation status of the primary tumor must be available or tumor samples must be available for pre randomization testing
  • Laboratory values adequate for patient to undergo surgery, including:
  • Platelet count ≥ 60,000/mm3
  • Hgb ≥ 10 g/dL
  • Absolute neutrophil count (ANC) ≥ 1,500/mm3
  • Absolute lymphocyte count (ALC) ≥ 500/mm3
  • Adequate liver function, including:
  • Total bilirubin ≤ 1.5 x ULN (unless has Gilbert's syndrome)
  • ALT ≤ 2.5 x ULN f. Estimated glomerular filtration rate of at least 50 mL/min by the Cockcroft Gault formula
  • Women of childbearing potential (≥12 months of non-therapy-induced amenorrhea or surgically sterile) must have had a negative serum pregnancy test within the past 21 days and must use a birth control method in addition to barrier methods (condoms).
  • Subject or subject's partner is willing to use condoms for 12 months after receiving Toca 511 or until there is no evidence of the virus in his/her blood, whichever is longer.
  • The subject has a KPS ≥ 70
  • The subject is willing and able to abide by the protocol

Who cannot join

  • History of more than 2 prior recurrences (including this recurrence) of GBM or AA
  • History of other malignancy, unless the patient has been disease free for at least 5 years. Adequately treated basal cell carcinoma or squamous cell skin cancer is acceptable regardless of time, as well as localized prostate carcinoma or cervical carcinoma in situ after curative treatment
  • Histologically confirmed oligodendroglioma or mixed glioma
  • Known 1p/19q co deletion
  • A contrast enhancing brain tumor that is any of the following:
  • Multi focal (defined as 2 separate areas of contrast enhancement measuring at least 1 cm in 2 planes that are not contiguous on either fluid attenuated inversion recovery (FLAIR) or T2 sequences);
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  • Associated with either diffuse subependymal or leptomeningeal dissemination; or
  • > 5 cm in any dimension
  • The subject has or had any active infection requiring systemic antibiotic, antifungal or antiviral therapy within the past 4 weeks
  • The subject has any bleeding diathesis, or must take anticoagulants, or antiplatelet agents, including nonsteroidal anti inflammatory drugs (NSAIDs), at the time of the scheduled resection that cannot be stopped for surgery
  • The subject is human immunodeficiency virus (HIV) positive
  • The subject has a history of allergy or intolerance to flucytosine
  • The subject has a gastrointestinal disease that would prevent him or her from being able to swallow or absorb flucytosine
  • The subject received cytotoxic chemotherapy within the past 4 weeks (6 weeks for nitrosoureas) of the planned surgery date
  • The subject received any investigational treatment within the past 30 days or prior immunotherapy or antibody therapy within the past 45 days.
  • The subject is pregnant or breast feeding
  • The subject intends to undergo treatment with the Gliadel® wafer at the time of this surgery or has received the Gliadel® wafer < 30 days from W1D1 (surgery)
  • The subject has received bevacizumab for their disease unless in the context of primary therapy for newly diagnosed glioma
  • For subjects planned to potentially receive bevacizumab, they have no evidence of uncontrolled hypertension (defined as a blood pressure of ≥ 150 mm Hg systolic and/or ≥ 100 mm Hg diastolic on medication) or active GI perforation
  • The subject has received systemic dexamethasone continuously at a dose > 8 mg/day for 8 weeks prior to the date of the screening assessment
  • Severe pulmonary, cardiac or other systemic disease, specifically:
  • New York Heart Association > Grade 2 congestive heart failure within 6 months prior to study entry, unless asymptomatic and well controlled with medication
  • Uncontrolled or significant cardiovascular disease, clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades des pointes), clinically significant pulmonary disease (such as ≥ Grade 2 dyspnea, according to CTCAE 4.03)
  • Subjects who have any other disease, either metabolic or psychological, which as per Investigator assessment may affect the subject's compliance or place the subject at higher risk of potential treatment complications

Trial locations and contacts

67 sites in 4 countries.

67 sites in 4 countries

United States50 sites

  • University of Michigan

    Ann Arbor, Michigan, 48109

  • University of Colorado Cancer Center

    Aurora, Colorado, 80045

  • Johns Hopkins University School of Medicine

    Baltimore, Maryland, 21287

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • University of Virginia Health System

    Charlottesville, Virginia, 22908

  • Cincinnati's Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • University Hospitals Cleveland Medical Center

    Cleveland, Ohio, 44106

  • Cleveland Clinic

    Cleveland, Ohio, 44195

  • Ohio State University

    Columbus, Ohio, 43210

  • Baylor University Medical Center

    Dallas, Texas, 75246

  • Henry Ford Health System

    Detroit, Michigan, 48202

  • JFK Medical Center Neuroscience Institute

    Edison, New Jersey, 08820

  • Colorado Neurological Institute

    Englewood, Colorado, 80113

  • NorthShore University Health System

    Evanston, Illinois, 60201

  • Inova Dwight and Martha Schar Cancer Institute

    Fairfax, Virginia, 22031

  • Associated Neurologists of Southern Connecticut

    Fairfield, Connecticut, 06824

  • University of Florida McKnight Brain Institute

    Gainesville, Florida, 32611

  • John Theurer Cancer Center at Hackensack University

    Hackensack, New Jersey, 07601

  • Houston Methodist Hospital Outpatient Center

    Houston, Texas, 77030

  • University of Texas Health Science Center at Houston (UTHealth)

    Houston, Texas, 77030

  • University of California, Irvine

    Irvine, California, 92868

  • University of Kansas Medical Center

    Kansas City, Kansas, 66160

  • HCA Midwest / Sarah Cannon

    Kansas City, Missouri, 64132

  • University of California San Diego

    La Jolla, California, 92093

  • North Shore University Hospital

    Lake Success, New York, 11042

  • University of California, Los Angeles

    Los Angeles, California, 90095

  • University of Wisconsin

    Madison, Wisconsin, 53792

  • University of Miami

    Miami, Florida, 33136

  • Abbott Northwestern Hospital / Allina Health

    Minneapolis, Minnesota, 55407

  • University of Minnesota

    Minneapolis, Minnesota, 55455

  • West Virginia University

    Morgantown, West Virginia, 26506

  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37232

  • Yale University/Yale Cancer Center

    New Haven, Connecticut, 06520

  • NYU Langone Medical Center

    New York, New York, 10016

  • Weill Cornell Medical College

    New York, New York, 10021

  • Columbia University

    New York, New York, 10032

  • Sentara Neurosurgery Specialists

    Norfolk, Virginia, 23507

  • University of Nebraska Medical Center

    Omaha, Nebraska, 68198

  • St. Joseph Hospital

    Orange, California, 92868

  • Thomas Jefferson University

    Philadelphia, Pennsylvania, 19101

  • Hospital of the University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • Barrow Neurological Institute at Dignity Health St. Joseph's Hospital and Medical Center

    Phoenix, Arizona, 85013

  • University of Rochester Medical Center

    Rochester, New York, 14642

  • University of California San Francisco

    San Francisco, California, 94143

  • Sanford Research

    Sioux Falls, South Dakota, 57104

  • Washington University St. Louis

    St Louis, Missouri, 63110

  • Stanford University

    Stanford, California, 94305

  • Stony Brook University Hospital

    Stony Brook, New York, 11794

  • Overlook Medical Center

    Summit, New Jersey, 07901

  • Moffitt Cancer Center

    Tampa, Florida, 33612

Other trials in United States

Canada10 sites

  • University of Alberta

    Edmonton, Alberta, T6G 2B7

  • London Regional Cancer Centre

    London, Ontario, N6A 5W9

  • Montreal Neurological Institute

    Montreal, Quebec, H3A 2B4

  • Jewish General Hospital

    Montreal, Quebec, H3T 1E2

  • Ottawa Hospital Regional Cancer Centre

    Ottawa, Ontario, K1H 8L6

  • Sherbrooke Hospital University Centre (CHUS)

    Sherbrooke, Quebec, J1H 5N4

  • Sunnybrook Hospital / Sunnybrook Research Institute

    Toronto, Ontario, M4N 3M5

  • Toronto Western Hospital

    Toronto, Ontario, M5T 2S8

  • University of British Columbia / Vancouver General Hospital

    Vancouver, British Columbia, V5Z 1M9

  • CancerCare Manitoba

    Winnipeg, Manitoba, R3E 0V9

Other trials in Canada

South Korea4 sites

  • Seoul National University Hospital

    Seoul, 03080

  • Severance Hospital

    Seoul, 03722

  • Samsung Medical Center

    Seoul, 06351

  • Seoul St. Mary's Hospital

    Seoul, 06591

Other trials in South Korea

Israel3 sites

  • Rambam Health Care

    Haifa, 3109601

  • Hadassah Medical Center

    Jerusalem, 91120

  • Tel Aviv Sourasky Medical Center

    Tel Aviv, 6423906

Other trials in Israel

About this study

Official title: A Phase 2/3 Randomized, Open-Label Study of Toca 511, a Retroviral Replicating Vector, Combined With Toca FC Versus Standard of Care in Subjects Undergoing Planned Resection for Recurrent Glioblastoma or Anaplastic Astrocytoma

This is a multicenter, randomized, open-label phase 2/3 study of Toca 511 and Toca FC versus standard of care that comprises Investigator's choice of single agent chemotherapy (lomustine or temozolomide) or bevacizumab administered to subjects undergoing resection for first or second recurrence (including this recurrence) of GBM or AA. Subjects meeting all of the inclusion and none of the exclusion criteria will be randomized prior to surgery in a 1:1 ratio to receive either Toca 511 and Toca FC (Experimental arm, Arm T) or control treatment with one option of standard of care (Arm SOC). Stratification will be done by IDH1 mutation status. A second stratification factor is based on the patient's Karnofsky Performance Score (KPS) (70-80 vs 90-100). Further, to account for potential differences in treatment choices for the control arm in regions, the trial will be stratified by geographical region during the randomization process.

Funding Source - FDA OOPD

Being tested
Toca 511, Toca FC, Lomustine, Temozolomide, Bevacizumab
Keywords
Recurrence
Medical subject headings
Glioblastoma, Astrocytoma, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Toca 511Biological

    Also called vocimagene amiretrorepvec, RRV, retroviral replicating vector

    Toca 511 consists of a purified retroviral replicating vector encoding a modified yeast cytosine deaminase (CD) gene. The CD gene converts the antifungal 5-flurocytosine (5FC) to the anticancer drug 5-FU in cells that have been infected by the Toca 511 vector.

  • Toca FCDrug

    Also called flucytosine, 5-FC, 5-fluorocytosine

    Toca FC is an extended-release formulation of flucytosine and is supplied as 500 mg tablets

  • LomustineDrug

    Also called CCNU, CeeNU

  • TemozolomideDrug

    Also called Temodar

  • BevacizumabBiological

    Also called Avastin

Study groups in NCT02414165
Study groupRoleWhat they receive
Toca 511/Toca FCExperimentalResection followed by administration of 4 mL Toca 511 (vocimagene amiretrorepvec). Toca 511 is administered by injection into the wall of the subject's tumor resection cavity on Day 1 (approximately 40 injections of 0.1 mL) Toca FC is an extended-release formulation of flucytosine. Toca FC will be administered at 220 mg/kg/day orally for 7-day courses beginning at least 6 weeks after resection and repeated approximately every 6 weeks.
Receives: Biological: Toca 511; Drug: Toca FC
Lomustine, Temozolomide, or BevacizumabActive comparatorInvestigator selects one of the following: Bevacizumab: Beginning 6 weeks after tumor resection, bevacizumab will be administered by IV infusion at 10 mg/kg and repeated every 2 weeks. Refer to the prescribing information and to institutional guidelines for details on the administration procedure. Lomustine: Beginning 6 weeks after tumor resection, lomustine will be administered as a single oral dose of 110 mg/m2 and repeated every 6 weeks. Refer to the prescribing information and to institutional guidelines for details regarding the administration procedure. Temozolomide: Beginning 6 weeks after tumor resection, temozolomide will be administered per 1 of 2 options: * at a dose of 50 mg/m2 PO once daily continuously, or * at an initial dose of 150 mg/m2 IV or PO once daily for 5 consecutive days per 28-day treatment cycle that may be raised to 200 mg/ m2 once daily for 5 consecutive days in the following 28-day treatment cycles
Receives: Drug: Lomustine; Drug: Temozolomide; Biological: Bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. To compare the overall survival (OS) of subjects treated with Toca 511 combined with Toca FC to subjects treated according to standard of care after tumor resection for recurrence of glioblastoma or anaplastic astrocytoma

    Time from randomization date to death due to any cause

    Measured: 30 December 2019

Secondary outcomes (4)

  1. Durable Response Rate (CR or PR ≥ 24 weeks)

    The proportion of patients whose best response is either CR or PR lasting at least 24 weeks, according to modified RANO criteria

    Measured: 30 December 2019

  2. Durable Clinical Benefit Rate (CR or PR ≥ 24 weeks or SD ≥ 18 months)

    The proportion of subjects whose best overall response is either CR or PR lasting at least 24 weeks, or stable disease (SD) lasting at least 18 months, according to modified RANO criteria

    Measured: 30 December 2019

  3. Duration of Durable Response

    Time from documentation of durable response to disease progression or death due to disease progression

    Measured: 30 December 2019

  4. Overall Survival at 12 months

    Time from randomization date to death due to any cause

    Measured: 30 December 2019

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Apr 2015 (estimated)
  2. Study start30 Nov 2015
  3. Primary completion31 May 2019
  4. Study completion20 Dec 2019

Why it stopped: Sponsor Decision

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
403 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02414165
Sponsor's protocol ID
Tg 511-15-01
Other IDs
FD-R-5732
Acronym
Toca5
Status last verified
Feb 2020
First submitted
3 Apr 2015
Last updated
7 Feb 2020
Results posted
No
Data monitoring committee
Yes

Publications

  • Cloughesy TF, Petrecca K, Walbert T, Butowski N, Salacz M, Perry J, Damek D, Bota D, Bettegowda C, Zhu JJ, Iwamoto F, Placantonakis D, Kim L, Elder B, Kaptain G, Cachia D, Moshel Y, Brem S, Piccioni D, Landolfi J, Chen CC, Gruber H, Rao AR, Hogan D, Accomando W, Ostertag D, Montellano TT, Kheoh T, Kabbinavar F, Vogelbaum MA. Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma: A Randomized Clinical Trial. JAMA Oncol. 2020 Dec 1;6(12):1939-1946. doi: 10.1001/jamaoncol.2020.3161.

    PubMed 33119048

  • Cloughesy TF, Landolfi J, Hogan DJ, Bloomfield S, Carter B, Chen CC, Elder JB, Kalkanis SN, Kesari S, Lai A, Lee IY, Liau LM, Mikkelsen T, Nghiemphu PL, Piccioni D, Walbert T, Chu A, Das A, Diago OR, Gammon D, Gruber HE, Hanna M, Jolly DJ, Kasahara N, McCarthy D, Mitchell L, Ostertag D, Robbins JM, Rodriguez-Aguirre M, Vogelbaum MA. Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci Transl Med. 2016 Jun 1;8(341):341ra75. doi: 10.1126/scitranslmed.aad9784.

    PubMed 27252174

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Toca 511, Toca FC and Lomustine in people with Glioblastoma Multiforme and Anaplastic Astrocytoma, run by Tocagen Inc. at 67 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 7 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 67 sites in United States, Canada, South Korea, Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Sponsor Decision). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

To compare the overall survival (OS) of subjects treated with Toca 511 combined with Toca FC to subjects treated according to standard of care after tumor resection for recurrence of glioblastoma or anaplastic astrocytoma (time frame: 30 December 2019). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02414165, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Feb 2020.

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