Clinical trial NCT02414165: The Toca 5 Trial: Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Glioblastoma Multiforme
Anaplastic Astrocytoma
Keywords: Recurrence
Lead sponsor: Tocagen Inc.
Sponsor class: INDUSTRY
First posted: 2015-04-10
Enrollment: 403
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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

Primary outcomes:
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
timeFrame: 30 December 2019
Secondary outcomes:
measure: Durable Response Rate (CR or PR ≥ 24 weeks)
timeFrame: 30 December 2019
measure: Durable Clinical Benefit Rate (CR or PR ≥ 24 weeks or SD ≥ 18 months)
timeFrame: 30 December 2019
measure: Duration of Durable Response
timeFrame: 30 December 2019
measure: Overall Survival at 12 months
timeFrame: 30 December 2019
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute at Dignity Health St. Joseph's Hospital and Medical Center
state: Arizona
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Orange
country: United States
facility: St. Joseph Hospital
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Englewood
country: United States
facility: Colorado Neurological Institute
state: Colorado
city: Fairfield
country: United States
facility: Associated Neurologists of Southern Connecticut
state: Connecticut
city: New Haven
country: United States
facility: Yale University/Yale Cancer Center
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida McKnight Brain Institute
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Evanston
country: United States
facility: NorthShore University Health System
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: Abbott Northwestern Hospital / Allina Health
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: HCA Midwest / Sarah Cannon
state: Missouri
city: Saint Louis
country: United States
facility: Washington University St. Louis
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Edison
country: United States
facility: JFK Medical Center Neuroscience Institute
state: New Jersey
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University
state: New Jersey
city: Summit
country: United States
facility: Overlook Medical Center
state: New Jersey
city: Lake Success
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Hospital
state: New York
city: Cincinnati
country: United States
facility: Cincinnati's Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Sioux Falls
country: United States
facility: Sanford Research
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital Outpatient Center
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston (UTHealth)
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Fairfax
country: United States
facility: Inova Dwight and Martha Schar Cancer Institute
state: Virginia
city: Norfolk
country: United States
facility: Sentara Neurosurgery Specialists
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia / Vancouver General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: London
country: Canada
facility: London Regional Cancer Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Regional Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Hospital / Sunnybrook Research Institute
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Montreal
country: Canada
facility: Montreal Neurological Institute
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Sherbrooke
country: Canada
facility: Sherbrooke Hospital University Centre (CHUS)
state: Quebec
city: Haifa
country: Israel
facility: Rambam Health Care
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Tel-Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital
Study officials:
affiliation: University of California, Los Angeles
name: Timothy Cloughesy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.