The Toca 5 Trial: Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma
- Conditions
- Glioblastoma MultiformeAnaplastic Astrocytoma
- Interventions
- Registration Number
- NCT02414165
- Lead Sponsor
- Tocagen Inc.
- Brief 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 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
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 403
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Subject has given written informed consent
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Subject is between 18 years old and 75 years old, inclusive
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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
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Subjects must be at least 4 weeks post last dose of temozolomide
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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
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Based on the pre-operative evaluation by neurosurgeon, the subject is a candidate for ≥ 80% resection of enhancing region
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IDH mutation status of the primary tumor must be available or tumor samples must be available for pre randomization testing
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Laboratory values adequate for patient to undergo surgery, including:
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Platelet count ≥ 60,000/mm3
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Hgb ≥ 10 g/dL
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Absolute neutrophil count (ANC) ≥ 1,500/mm3
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Absolute lymphocyte count (ALC) ≥ 500/mm3
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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
-
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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).
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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.
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The subject has a KPS ≥ 70
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The subject is willing and able to abide by the protocol
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History of more than 2 prior recurrences (including this recurrence) of GBM or AA
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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
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Histologically confirmed oligodendroglioma or mixed glioma
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Known 1p/19q co deletion
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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
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The subject has or had any active infection requiring systemic antibiotic, antifungal or antiviral therapy within the past 4 weeks
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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
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The subject is human immunodeficiency virus (HIV) positive
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The subject has a history of allergy or intolerance to flucytosine
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The subject has a gastrointestinal disease that would prevent him or her from being able to swallow or absorb flucytosine
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The subject received cytotoxic chemotherapy within the past 4 weeks (6 weeks for nitrosoureas) of the planned surgery date
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The subject received any investigational treatment within the past 30 days or prior immunotherapy or antibody therapy within the past 45 days.
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The subject is pregnant or breast feeding
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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)
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The subject has received bevacizumab for their disease unless in the context of primary therapy for newly diagnosed glioma
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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
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The subject has received systemic dexamethasone continuously at a dose > 8 mg/day for 8 weeks prior to the date of the screening assessment
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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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Toca 511/Toca FC Toca 511 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. Toca 511/Toca FC 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. Lomustine, Temozolomide, or Bevacizumab 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 Lomustine, Temozolomide, or Bevacizumab Lomustine 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 Lomustine, Temozolomide, or Bevacizumab Temozolomide 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
- Primary Outcome Measures
Name Time Method 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 30 December 2019 Time from randomization date to death due to any cause
- Secondary Outcome Measures
Name Time Method Durable Response Rate (CR or PR ≥ 24 weeks) 30 December 2019 The proportion of patients whose best response is either CR or PR lasting at least 24 weeks, according to modified RANO criteria
Duration of Durable Response 30 December 2019 Time from documentation of durable response to disease progression or death due to disease progression
Durable Clinical Benefit Rate (CR or PR ≥ 24 weeks or SD ≥ 18 months) 30 December 2019 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
Overall Survival at 12 months 30 December 2019 Time from randomization date to death due to any cause
Trial Locations
- Locations (67)
Ohio State University
🇺🇸Columbus, Ohio, United States
Johns Hopkins University School of Medicine
🇺🇸Baltimore, Maryland, United States
University of Miami
🇺🇸Miami, Florida, United States
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
St. Joseph Hospital
🇺🇸Orange, California, United States
Washington University St. Louis
🇺🇸Saint Louis, Missouri, United States
Weill Cornell Medical College
🇺🇸New York, New York, United States
Columbia University
🇺🇸New York, New York, United States
JFK Medical Center Neuroscience Institute
🇺🇸Edison, New Jersey, United States
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
John Theurer Cancer Center at Hackensack University
🇺🇸Hackensack, New Jersey, United States
Tel Aviv Sourasky Medical Center
🇮🇱Tel-Aviv, Israel
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
Houston Methodist Hospital Outpatient Center
🇺🇸Houston, Texas, United States
North Shore University Hospital
🇺🇸Lake Success, New York, United States
University of Wisconsin
🇺🇸Madison, Wisconsin, United States
Overlook Medical Center
🇺🇸Summit, New Jersey, United States
Ottawa Hospital Regional Cancer Centre
🇨🇦Ottawa, Ontario, Canada
University of Alberta
🇨🇦Edmonton, Alberta, Canada
University of British Columbia / Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
Severance Hospital
🇰🇷Seoul, Korea, Republic of
Seoul St. Mary's Hospital
🇰🇷Seoul, Korea, Republic of
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Abbott Northwestern Hospital / Allina Health
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Cincinnati's Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Barrow Neurological Institute at Dignity Health St. Joseph's Hospital and Medical Center
🇺🇸Phoenix, Arizona, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Sunnybrook Hospital / Sunnybrook Research Institute
🇨🇦Toronto, Ontario, Canada
Montreal Neurological Institute
🇨🇦Montreal, Quebec, Canada
Associated Neurologists of Southern Connecticut
🇺🇸Fairfield, Connecticut, United States
NYU Langone Medical Center
🇺🇸New York, New York, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
University of Virginia Health System
🇺🇸Charlottesville, Virginia, United States
Sherbrooke Hospital University Centre (CHUS)
🇨🇦Sherbrooke, Quebec, Canada
University of California San Diego
🇺🇸La Jolla, California, United States
University of California, Irvine
🇺🇸Irvine, California, United States
Colorado Neurological Institute
🇺🇸Englewood, Colorado, United States
NorthShore University Health System
🇺🇸Evanston, Illinois, United States
Sanford Research
🇺🇸Sioux Falls, South Dakota, United States
Stony Brook University Hospital
🇺🇸Stony Brook, New York, United States
Rambam Health Care
🇮🇱Haifa, Israel
Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Baylor University Medical Center
🇺🇸Dallas, Texas, United States
University of Texas Health Science Center at Houston (UTHealth)
🇺🇸Houston, Texas, United States
West Virginia University
🇺🇸Morgantown, West Virginia, United States
Toronto Western Hospital
🇨🇦Toronto, Ontario, Canada
Inova Dwight and Martha Schar Cancer Institute
🇺🇸Fairfax, Virginia, United States
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Stanford University
🇺🇸Stanford, California, United States
University of Colorado Cancer Center
🇺🇸Aurora, Colorado, United States
Yale University/Yale Cancer Center
🇺🇸New Haven, Connecticut, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
HCA Midwest / Sarah Cannon
🇺🇸Kansas City, Missouri, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
University of Florida McKnight Brain Institute
🇺🇸Gainesville, Florida, United States
London Regional Cancer Centre
🇨🇦London, Ontario, Canada
Sentara Neurosurgery Specialists
🇺🇸Norfolk, Virginia, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States