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

Glioblastoma Multiforme Clinical Trial

— Toca5  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02414165
• Other study ID #: Tg 511-15-01
• Secondary ID: FD-R-5732
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: November 30, 2015
• Est. completion date: December 20, 2019

Study information

• Verified date: February 2020
• Source: Tocagen Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 403
• Est. completion date: December 20, 2019
• Est. primary completion date: May 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Anaplastic Astrocytoma
• Astrocytoma
• Glioblastoma
• Glioblastoma Multiforme

Intervention

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.

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

• Temozolomide

Biological:
• Bevacizumab

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Tocagen Inc.

Countries where clinical trial is conducted

United States,  Canada,  Israel,  Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Duration of Durable Response	Time from documentation of durable response to disease progression or death due to disease progression	30 December 2019
Secondary	Overall Survival at 12 months	Time from randomization date to death due to any cause	30 December 2019