Testing the Addition of an Anti-cancer Viral Gene Therapy, Toca 511/Toca FC, to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed Glioblastoma

NCT04105374 | Withdrawn Phase 2 DMC FDA Drug

• 3 other identifiers: NRG-BN006NCI-2019-04562U10CA180868
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase II/III trial studies how well vocimagene amiretrorepvec (Toca 511) and extended release flucytosine (Toca FC) work when added to the usual treatment (temozolomide and radiation therapy) in treating patients with newly diagnosed glioblastoma. Toca 511 is a live virus that has been built to carry a gene into tumor cells. This gene carries instructions that cause the tumor cells to turn Toca FC, typically used to treat fungal infections, into a drug that may kill the tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving Toca 511 and Toca FC in addition to the usual treatment (temozolomide and radiation therapy) may help shrink or stabilize cancer or extend the life of patients with newly diagnosed glioblastoma.

Conditions

Anaplastic Astrocytoma; Glioblastoma; Oligodendroglioma; Supratentorial Glioblastoma

Keywords

Toca 511; Toca FC

Outcome Measures

Primary Outcomes (2)

• Progression free survival (PFS) (Phase II)

  Analysis of treatment comparison between the experimental and standard-of-care arms will be performed once the required number of centrally-reviewed PFS events is reached . The Kaplan-Meier method will be used to calculate the PFS rates for each of the two arms. Hazard ratio (HR) on the treatment effect will be calculated using the stratified Cox proportional hazard model. A one-sided stratified log-rank test will be used to test the difference in PFS between the two arms.

  Time from randomization to the first documented progressive disease (PD) as determined by central review, or death due to any cause, whichever occurs first, assessed for up to 5 years

• Overall survival (OS) (Phase III)

  Analysis of the treatment comparison between the experimental and standard of care arms will be performed once the required number of deaths is reached. The Kaplan-Meier method will be used to calculate the OS rates for each of the two arms. The primary endpoint will be assessed using a one-sided stratified log-rank test, incorporating only stratification factors, to test the difference in OS between the two arms. Hazard ratio (HR) on the treatment effect will be calculated using the stratified Cox proportional hazard model adjusting for stratification factors. In addition to assessing the effect of treatment arm, IDH mutation status, MGMT status, the interaction between MGMT status and treatment arm, extent of resection, and use of Optune (in only the standard-of-care arm) will be assessed using a log-rank test and Cox proportional hazards models.

  The time from randomization to death due to any cause, assessed up to 5 years

Secondary Outcomes (4)

• Incidence of grade 3 or higher adverse events

  Until death, assessed up to 5 years

• Overall survival (OS) (Phase II)

  The time from randomization to death due to any cause, assessed up to 5 years

• Progression free survival (PFS) (Phase III)

  Time from randomization to the first documented PD as determined by central review, or death due to any cause, whichever occurs first, assessed for up to 5 years

• Objective response rate (ORR)

  Up to 18 months

Other Outcomes (4)

• Duration of response (DOR)

  The duration in which a durable response is observed, spanning from time of initial response until PD, assessed for up to 5 years

• Tumor-microenvironment signature

  Up to 5 years

• Genome-wide deoxyribonucleic acid (DNA) methylation and copy number profiles

  Up to 5 years

Study Arms (2)

Arm I (surgery, radiation therapy, temozolomide)

ACTIVE COMPARATOR

Beginning on week 5 following standard of care surgery, patients undergo radiation therapy over 30 fractions 5 days per week for up to 6 weeks, and receive temozolomide PO QD for up to 49 days. At the discretion of treating physician, patients may also receive novoTTF-100A (Optune) device 0-7 weeks following radiation and temozolomide treatment. One month following completion of radiation therapy, patients continue to receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Device: NovoTTF-100A Device; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Radiation: Radiation Therapy; Drug: Temozolomide; Procedure: Therapeutic Conventional Surgery

Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)

EXPERIMENTAL

Patients receive vocimagene amiretrorepvec via intracranial injection during surgery on day 1. Beginning on week 5 following surgery, patients receive extended release flucytosine PO TID for 7 consecutive days every 7 weeks. Patients also undergo radiation therapy and receive temozolomide as in arm I. After completion of radiation therapy and at the discretion of the treating physician, patients may continue to receive extended release flucytosine PO TID for 7 consecutive days every 8 weeks in the absence of disease progression or unacceptable toxicity.

Drug: Extended Release Flucytosine; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Radiation: Radiation Therapy; Drug: Temozolomide; Procedure: Therapeutic Conventional Surgery; Biological: Vocimagene Amiretrorepvec

Interventions

Extended Release Flucytosine DRUG

Given PO

Also known as: Extended Release 5-FC, Extended Release 5-Fluorocytosine, Extended-Release 5-FC, Extended-Release 5-Fluorocytosine, Extended-Release Flucytosine, Toca FC

Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)

NovoTTF-100A Device DEVICE

Receive Optune device

Also known as: NovoTTF-100A, NovoTTF-100A System, NovoTTFields, NovoTumor Treatment Fields, Optune, Optune Device

Arm I (surgery, radiation therapy, temozolomide)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Arm I (surgery, radiation therapy, temozolomide); Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)

Questionnaire Administration OTHER

Ancillary studies

Arm I (surgery, radiation therapy, temozolomide); Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)

Radiation Therapy RADIATION

Undergo radiation

Also known as: Cancer Radiotherapy, Irradiate, Irradiated, irradiation, Radiation, Radiotherapeutics, RADIOTHERAPY, RT, Therapy, Radiation

Arm I (surgery, radiation therapy, temozolomide); Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)

Temozolomide DRUG

Given PO

Also known as: CCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, Temomedac, TMZ

Arm I (surgery, radiation therapy, temozolomide); Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)

Therapeutic Conventional Surgery PROCEDURE

Undergo standard of care surgery

Arm I (surgery, radiation therapy, temozolomide); Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)

Vocimagene Amiretrorepvec BIOLOGICAL

Given via intracranial injection

Also known as: DNA (Synthetic Toca 511-encoding Retroviral Vector AC3-yCD2(V)), Toca 511

Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Presumptive diagnosis of glioblastoma based on magnetic resonance imaging (MRI) imaging within 14 days prior to registration.
• NOTE: Patients who undergo treatment with Toca 511 whose final pathology shows diagnosis other than glioblastoma (e.g. anaplastic astrocytoma or oligodendroglioma or any other histology) will be treated with Toca FC and chemoradiation; however they will not be analyzed in the primary endpoint. The outcomes of these patients will be reported descriptively. Similarly the patients with anaplastic astrocytoma or oligodendroglioma or any other histology treated on the standard-of-care arm will be reported separately and they are allowed to receive the treatment per choice of the treating physician/ investigator (for e.g. radiation therapy \[RT\] plus temozolomide or RT plus procarbazine-lomustine-vincristine \[PCV\])
• In addition, patients who have undergone biopsy with diagnosis of glioblastoma and who have never received any chemotherapy and/or radiation and are candidates for \>= 80% resection of enhancing region are eligible
• The tumor must be unifocal, confined to the supratentorial compartment and based on the pre-operative evaluation, the patient is a candidate for \>= 80% resection of enhancing region
• Measurable disease preoperatively, defined as at least 1 contrast enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as per Response Assessment in Neuro-Oncology (RANO) criteria
• The hematoxylin and eosin (H\&E) slide and formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be available to be sent for mandatory central pathology review after registration
• Patients must be able to undergo an evaluation by MRI within 96 hours post surgery to assess extent of resection
• Karnofsky performance status \>= 70 within 14 days prior to registration
• History/physical examination within 14 days prior to registration
• Platelet count \>= 100,000/mm\^3 (within 14 days prior to registration)
• Hemoglobin (Hgb) \>= 10 g/dL (within 14 days prior to registration)
• Absolute neutrophil count (ANC) \>= 1,500/mm\^3 (within 14 days prior to registration)
• Absolute lymphocyte count (ALC) \>= 1000/mm\^3 (within 14 days prior to registration)
• Total bilirubin =\< 1.5 x upper limit of normal (ULN) (unless has Gilbert?s syndrome) (within 14 days prior to registration)
• Alanine aminotransferase (ALT) =\< 2.5 x ULN (within 14 days prior to registration)

You may not qualify if:

• History of prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years
• A contrast enhancing brain tumor on MRI that is any of the following:
• Multi focal (defined as 2 separate areas of contrast enhancement measuring at least 10 mm in 2 planes that are not contiguous on either fluid attenuated inversion recovery \[FLAIR\] or T2 hyperintensity);
• Associated with either diffuse subependymal or leptomeningeal dissemination; or
• \> 50 mm in any dimension
• Active infection (excluding skin or toenail infections) requiring systemic antibiotic, antifungal or antiviral therapy within 28 days prior to registration
• 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
• Known human immunodeficiency virus (HIV) positive status
• History of allergy or intolerance to flucytosine
• Swallowing difficulty that would prevent patient from being able to swallow either temozolomide or Toca FC or severe active mal-absorption
• Patients who are breast feeding or lactating
• Intent to undergo treatment with the Gliadel wafer at the time of this surgery or has received the Gliadel
• Prior to registration, steroid treatment beyond a maximum of 8 mg/day of dexamethasone (or equivalent) or a total of 8 weeks (56 days) is excluded
• Severe pulmonary, cardiac or other systemic disease, specifically:
• New York Heart Association \> =Class II congestive heart failure within 6 months (180 days) prior to registration, unless asymptomatic and well controlled with medication

Sponsors & Collaborators

• NRG Oncology: lead
• National Cancer Institute (NCI): collaborator

MeSH Terms

Conditions

Astrocytoma; Glioblastoma; Oligodendroglioma

Interventions

Radiotherapy; Radiation; Temozolomide; vocimagene amiretrorepvec; DNA

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Therapeutics; Physical Phenomena; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Manmeet S Ahluwalia

  NRG Oncology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 20, 2019
• First Posted: September 26, 2019
• Study Start: January 31, 2020
• Primary Completion: November 30, 2025
• Study Completion (Estimated): November 30, 2030
• Last Updated: March 24, 2020

Record last verified: 2020-03