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P2/3 Randomized Study of Toca 511 & Toca FC Versus SOC in Subjects Undergoing Surgery for Recurrent GBM/AA (Toca5)

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02414165
First Posted: April 10, 2015
Last Update Posted: February 9, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Tocagen Inc.
  Purpose
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). Due to the prognostic influence of molecular subgroups such as isocitrate dehydrogenase mutation, the trial will be stratified based on this determination from the primary pathology or subsequent biopsy known locally or otherwise determined centrally. 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. The study will be conducted in 2 parts; enrollment in the phase 3 will begin after phase 2 results are available.

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

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Tocagen Inc.:

Primary Outcome Measures:
  • Compare overall survival between two arms (requires 116 events) [ Time Frame: 21 months from first patient randomized ]

Enrollment: 187
Study Start Date: November 2015
Estimated Study Completion Date: September 2019
Estimated Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Toca 511/Toca FC

Resection followed by administration of up to 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 (up to 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 viral
Drug: Toca FC
Toca FC is an extended-release formulation of flucytosine. Toca FC is supplied as 500 mg white, oblong tablets with "TOCA FC" embossed on one side and "500" embossed on the other side
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 Name: Temodar
Biological: Bevacizumab
Other Name: Avastin

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 in first or second recurrence (including this recurrence) or progression following initial definitive multimodal therapy with surgery, temozolomide (unless MGMT promoter unmethylated) and radiation (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, measuring at least 1 cm in 2 planes (axial, coronal, or sagittal)
  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 below:
  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. Histological 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 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 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 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02414165


  Show 67 Study Locations
Sponsors and Collaborators
Tocagen Inc.
Investigators
Principal Investigator: Timothy Cloughesy, MD University of California, Los Angeles
  More Information

Publications:
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Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, Degroot J, Gattamaneni R, Cher L, Rosenthal M, Payer F, Jürgensmeier JM, Jain RK, Sorensen AG, Xu J, Liu Q, van den Bent M. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013 Sep 10;31(26):3212-8. doi: 10.1200/JCO.2012.47.2464. Epub 2013 Aug 12.
Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, Modlich U, Beier R, Göhring G, Steinemann D, Fronza R, Ball CR, Haemmerle R, Naundorf S, Kühlcke K, Rose M, Fraser C, Mathias L, Ferrari R, Abboud MR, Al-Herz W, Kondratenko I, Maródi L, Glimm H, Schlegelberger B, Schambach A, Albert MH, Schmidt M, von Kalle C, Klein C. Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity. Sci Transl Med. 2014 Mar 12;6(227):227ra33. doi: 10.1126/scitranslmed.3007280.
Central Brain Tumor Registry of the United States. 2014 CBTRUS Fact Sheet. Accessed March 30, 2015 at http://www.cbtrus.org/factsheet/factsheet.html.Chamberlain, M. Treatment options for glioblastoma. Neurosurg Focus 20 (4):E19, 2006.
Cornetta K, Moen RC, Culver K, Morgan RA, McLachlin JR, Sturm S, Selegue J, London W, Blaese RM, Anderson WF. Amphotropic murine leukemia retrovirus is not an acute pathogen for primates. Hum Gene Ther. 1990 Spring;1(1):15-30.
Gil-Gil MJ, Mesia C, Rey M, Bruna J. Bevacizumab for the treatment of glioblastoma. Clin Med Insights Oncol. 2013 Jun 6;7:123-35. doi: 10.4137/CMO.S8503. Print 2013.
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003 Oct 17;302(5644):415-9. Erratum in: Science. 2003 Oct 24;302(5645):568.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003.
Hess KR, Wong ET, Jaeckle KA, Kyritsis AP, Levin VA, Prados MD, Yung WK. Response and progression in recurrent malignant glioma. Neuro Oncol. 1999 Oct;1(4):282-8.
Huang RY, Neagu MR, Reardon DA, Wen PY. Pitfalls in the neuroimaging of glioblastoma in the era of antiangiogenic and immuno/targeted therapy - detecting illusive disease, defining response. Front Neurol. 2015 Feb 23;6:33. doi: 10.3389/fneur.2015.00033. eCollection 2015. Review.
Kaufmann JK, Chiocca EA. Glioma virus therapies between bench and bedside. Neuro Oncol. 2014 Mar;16(3):334-51. doi: 10.1093/neuonc/not310. Epub 2014 Jan 26. Review.
Logg CR, Logg A, Tai CK, Cannon PM, Kasahara N. Genomic stability of murine leukemia viruses containing insertions at the Env-3' untranslated region boundary. J Virol. 2001 Aug;75(15):6989-98.
Murphy AM, Rabkin SD. Current status of gene therapy for brain tumors. Transl Res. 2013 Apr;161(4):339-54. doi: 10.1016/j.trsl.2012.11.003. Epub 2012 Dec 11.
Ostertag D, Amundson KK, Lopez Espinoza F, Martin B, Buckley T, Galvão da Silva AP, Lin AH, Valenta DT, Perez OD, Ibañez CE, Chen CI, Pettersson PL, Burnett R, Daublebsky V, Hlavaty J, Gunzburg W, Kasahara N, Gruber HE, Jolly DJ, Robbins JM. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Neuro Oncol. 2012 Feb;14(2):145-59. doi: 10.1093/neuonc/nor199. Epub 2011 Nov 9.
Perez OD, Logg CR, Hiraoka K, Diago O, Burnett R, Inagaki A, Jolson D, Amundson K, Buckley T, Lohse D, Lin A, Burrascano C, Ibanez C, Kasahara N, Gruber HE, Jolly DJ. Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. Mol Ther. 2012 Sep;20(9):1689-98. doi: 10.1038/mt.2012.83. Epub 2012 May 1. Erratum in: Mol Ther. 2013 Feb;21(2):494.
Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther. 2000 Nov 20;11(17):2389-401.
Rans TS, England R. The evolution of gene therapy in X-linked severe combined immunodeficiency. Ann Allergy Asthma Immunol. 2009 May;102(5):357-62; quiz 363-5, 402. doi: 10.1016/S1081-1206(10)60504-2. Review.
Le Rhun E, Taillibert S, Chamberlain MC. The future of high-grade glioma: Where we are and where are we going. Surg Neurol Int. 2015 Feb 13;6(Suppl 1):S9-S44. doi: 10.4103/2152-7806.151331. eCollection 2015. Erratum in: Surg Neurol Int. 2015 Mar 5;6:37. Rhun, Emilie Le [corrected to Le Rhun, Emilie].
Shibahara I, Sonoda Y, Shoji T, Kanamori M, Saito R, Inoue T, Kawaguchi T, Yamashita Y, Watanabe T, Kumabe T, Watanabe M, Suzuki H, Tominaga T. Malignant clinical features of anaplastic gliomas without IDH mutation. Neuro Oncol. 2015 Jan;17(1):136-44. doi: 10.1093/neuonc/nou112. Epub 2014 Jun 23.
Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, Schmidt M, Krämer A, Schwäble J, Glimm H, Koehl U, Preiss C, Ball C, Martin H, Göhring G, Schwarzwaelder K, Hofmann WK, Karakaya K, Tchatchou S, Yang R, Reinecke P, Kühlcke K, Schlegelberger B, Thrasher AJ, Hoelzer D, Seger R, von Kalle C, Grez M. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med. 2010 Feb;16(2):198-204. doi: 10.1038/nm.2088. Epub 2010 Jan 24.
Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014 Aug;15(9):943-53. doi: 10.1016/S1470-2045(14)70314-6. Epub 2014 Jul 15.
Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother. 2000 Aug;46(2):171-9. Review.
Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008 Jul 31;359(5):492-507. doi: 10.1056/NEJMra0708126. Review. Erratum in: N Engl J Med. 2008 Aug 21;359(8):877.
Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. doi: 10.1200/JCO.2009.23.6497. Epub 2009 Nov 9. Erratum in: J Clin Oncol. 2010 Feb 1;28(4):708.
Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010 Mar 1;28(7):1168-74. doi: 10.1200/JCO.2009.23.2595. Epub 2010 Feb 1.
Wogan GN. Tumors of the mouse hematopoietic system: their diagnosis and interpretation in safety evaluation tests. Report of a study group. Crit Rev Toxicol. 1984;13(2):161-81. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Tocagen Inc.
ClinicalTrials.gov Identifier: NCT02414165     History of Changes
Other Study ID Numbers: Tg 511-15-01
First Submitted: April 3, 2015
First Posted: April 10, 2015
Last Update Posted: February 9, 2017
Last Verified: November 2016

Keywords provided by Tocagen Inc.:
Recurrence

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Temozolomide
Dacarbazine
Lomustine
Flucytosine
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Antimetabolites


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