The Toca 5 Trial: Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma (Toca5)

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

Study Overview

• Status: Terminated
• Conditions: Glioblastoma Multiforme; Anaplastic Astrocytoma
• Intervention / Treatment: Drug: Temozolomide; Drug: Lomustine; Biological: Bevacizumab; Biological: Toca 511; Drug: Toca FC

• Study Type: Interventional
• Enrollment (Actual): 403
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • University of British Columbia / Vancouver General Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Regional Cancer Centre
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital Regional Cancer Centre
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Hospital / Sunnybrook Research Institute
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Sherbrooke Hospital University Centre (CHUS)
• Israel
  • Haifa, Israel, 3109601
    • Rambam Health Care
  • Jerusalem, Israel, 91120
    • Hadassah Medical Center
  • Tel-Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 06591
    • Seoul St. Mary's Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute at Dignity Health St. Joseph's Hospital and Medical Center
  • California
    • Irvine, California, United States, 92868
      • University of California, Irvine
    • La Jolla, California, United States, 92093
      • University of California San Diego
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Orange, California, United States, 92868
      • St. Joseph Hospital
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center
    • Englewood, Colorado, United States, 80113
      • Colorado Neurological Institute
  • Connecticut
    • Fairfield, Connecticut, United States, 06824
      • Associated Neurologists of Southern Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University/Yale Cancer Center
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida McKnight Brain Institute
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Evanston, Illinois, United States, 60201
      • NorthShore University Health System
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University Of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University School of Medicine
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Abbott Northwestern Hospital / Allina Health
  • Missouri
    • Kansas City, Missouri, United States, 64132
      • HCA Midwest / Sarah Cannon
    • Saint Louis, Missouri, United States, 63110
      • Washington University St. Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • Edison, New Jersey, United States, 08820
      • JFK Medical Center Neuroscience Institute
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University
    • Summit, New Jersey, United States, 07901
      • Overlook Medical Center
  • New York
    • Lake Success, New York, United States, 11042
      • North Shore University Hospital
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati's Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19101
      • Thomas Jefferson University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Research
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital Outpatient Center
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston (UTHealth)
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
    • Fairfax, Virginia, United States, 22031
      • Inova Dwight and Martha Schar Cancer Institute
    • Norfolk, Virginia, United States, 23507
      • Sentara Neurosurgery Specialists
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject has given written informed consent
2. Subject is between 18 years old and 75 years old, inclusive

3. Subjects must have histologically proven GBM or AA and:

   1. 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)
   2. Must be in first or second recurrence (including this recurrence)
   3. 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
4. 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
5. Subjects must be at least 4 weeks post last dose of temozolomide
6. 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
7. Based on the pre-operative evaluation by neurosurgeon, the subject is a candidate for ≥ 80% resection of enhancing region
8. IDH mutation status of the primary tumor must be available or tumor samples must be available for pre randomization testing

9. 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
10. 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).
11. 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.
12. The subject has a KPS ≥ 70
13. The subject is willing and able to abide by the protocol

Exclusion Criteria:

1. History of more than 2 prior recurrences (including this recurrence) of GBM or AA
2. 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
3. Histologically confirmed oligodendroglioma or mixed glioma
4. Known 1p/19q co deletion

5. 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);
   • Associated with either diffuse subependymal or leptomeningeal dissemination; or
   • > 5 cm in any dimension
6. The subject has or had any active infection requiring systemic antibiotic, antifungal or antiviral therapy within the past 4 weeks
7. 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
8. The subject is human immunodeficiency virus (HIV) positive
9. The subject has a history of allergy or intolerance to flucytosine
10. The subject has a gastrointestinal disease that would prevent him or her from being able to swallow or absorb flucytosine
11. The subject received cytotoxic chemotherapy within the past 4 weeks (6 weeks for nitrosoureas) of the planned surgery date
12. The subject received any investigational treatment within the past 30 days or prior immunotherapy or antibody therapy within the past 45 days.
13. The subject is pregnant or breast feeding
14. 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)
15. The subject has received bevacizumab for their disease unless in the context of primary therapy for newly diagnosed glioma
16. 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
17. The subject has received systemic dexamethasone continuously at a dose > 8 mg/day for 8 weeks prior to the date of the screening assessment

18. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Toca 511/Toca FC; Resection 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.	Biological: Toca 511; 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.; Other Names: vocimagene amiretrorepvec; RRV; retroviral replicating vector; Drug: Toca FC; Toca FC is an extended-release formulation of flucytosine and is supplied as 500 mg tablets; Other Names: flucytosine; 5-FC; 5-fluorocytosine
Active Comparator: Lomustine, Temozolomide, or Bevacizumab; Investigator 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	Drug: Temozolomide; Other Names: Temodar; Drug: Lomustine; Other Names: CCNU; CeeNU; Biological: Bevacizumab; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	30 December 2019

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	30 December 2019
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	30 December 2019
Duration of Durable Response	Time from documentation of durable response to disease progression or death due to disease progression	30 December 2019
Overall Survival at 12 months	Time from randomization date to death due to any cause	30 December 2019

Collaborators and Investigators

• Sponsor: Tocagen Inc.
• Investigators: Principal Investigator: Timothy Cloughesy, MD, University of California, Los Angeles

Publications and helpful links

General 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2015
• Primary Completion (Actual): May 31, 2019
• Study Completion (Actual): December 20, 2019

Study Registration Dates

• First Submitted: April 3, 2015
• First Submitted That Met QC Criteria: April 7, 2015
• First Posted (Estimate): April 10, 2015

Study Record Updates

• Last Update Posted (Actual): February 7, 2020
• Last Update Submitted That Met QC Criteria: February 6, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Recurrence
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Astrocytoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antifungal Agents; Temozolomide; Bevacizumab; Flucytosine; Lomustine
• Other Study ID Numbers: Tg 511-15-01; FD-R-5732 (Other Grant/Funding Number: FDA OOPD)