The Toca 5 Trial: Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma
This clinical trial will evaluate the efficacy of Toca511 and TocaFC compared to standard of care (either lomustine, temozolomide, or bevacizumab alone), in treating patients with recurrent glioblastoma or anaplastic astrocytoma (first or second recurrence only).
Together, Toca511 and TocaFC work to specifically expose tumor cells to an anti-cancer drug. Toca511 is a gene therapy agent that is delivered to the tumor cavity after the tumor is surgically removed. Toca511 is a genetically engineered retrovirus that only replicates in cells that divide (at the tumor cavity, only the remaining cancer cells divide), and delivers a gene called cytosine deaminase. This causes the targeted cancer cells to begin producing the cytosine deaminase protein.
TocaFC is an orally administered drug that can cross the blood-brain barrier. Once in the brain, TocaFC can be converted into 5-fluorouracil, a known anti-cancer drug. This conversion requires the protein cytosine deaminase, so the conversion only occurs in cells infected by Toca511, the gene therapy agent. The combination of Toca511 and TocaFC results in the localized exposure of tumor cells to 5-fluorouracil, preserving normal brain cells.
This Phase II/III clinical trial will examine the efficacy of Toca511 and TocaFC, compared to standard of care treatments consisting of lomostine (chemotherapy drug), temozolomide (another chemotherapy drug), or bevacizumab (an anti-angiogenic therapy):
- Experimental Group: Toca511 + TocaFC
- Active Comparator Group: Lomustine, Temozolomide, or Bevacizumab
- 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:
- histopathologic confirmation of recurrent tumor, or
- 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 13. The subject is willing and able to abide by the protocol
For the most up-to-date list of criteria, please visit clinicaltrials.gov.
- 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
- > 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
For the most up-to-date list of criteria, please visit clinicaltrials.gov.