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

Sponsor

Tocagen Inc. (Industry)

Overall Status

Terminated

CT.gov ID

NCT02414165

Collaborator

(none)

403

Enrollment

Locations

Arms

48.7

Actual Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme Anaplastic Astrocytoma	Biological: Toca 511 Drug: Toca FC Drug: Lomustine Drug: Temozolomide Biological: Bevacizumab	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

403 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 30, 2015

Actual Primary Completion Date :

May 31, 2019

Actual Study Completion Date :

Dec 20, 2019

Arms and Interventions

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: Lomustine Other Names: CCNU CeeNU Drug: Temozolomide Other Names: Temodar Biological: Bevacizumab Other Names: Avastin

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: Lomustine

Other Names:

CCNU

CeeNU

Drug: Temozolomide

Other Names:

Temodar

Biological: Bevacizumab

Other Names:

Avastin

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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
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

Exclusion Criteria:

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);
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

Contacts and Locations

Locations

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