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DB107-RRV Alone at Resection and then in Combination with DB107-FC and Standard of Care for the Treatment of Newly Diagnosed IDH-mutant Astrocytoma and IDH-wildtype Glioblastoma
Trial Status: active
This phase I/IIa trial tests how well retroviral replicating vector containing modified yeast cytosine deaminase transgene (DB107-RRV) given at time of resection and then in combination with flucytosine extended-release tablets, 5-fluorocytosine, 5-FC, 5-FC XR (DB107-FC) and standard of care (SOC) radiation therapy and temozolomide in treating patients with newly diagnosed isocitrate dehydrogenase (IDH)-mutant astrocytoma and IDH-wildtype glioblastoma. DB107-RRV is a live virus that has been built to carry a gene into tumor cells in a process called gene transfer. Genes are made up of deoxyribonucleic acid (DNA) and serve as the instruction book for the cells in the body. The gene inside of DB107-RRV carries instructions that cause the tumor cells to turn a medication called 5-fluorocytosine (5-FC) into a chemotherapy medication called fluorouracil (5-FU). DB107-FC is a drug containing 5-FC. 5-FC is a type of anti-fungal medication. Tumor cells that have the gene from DB107-RRV inside them may turn 5-FC into 5-FU and may kill tumor cells. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells and slow down or stop tumor growth. Giving DB107-RRV at time of resection and then in combination with DB107-FC and SOC radiation therapy and temozolomide may kill more tumor cells in patients with newly diagnosed IDH-mutant astrocytomas and IDH-wildtype glioblastomas.
Inclusion Criteria
Subject has provided written informed consent
Subject is between 18 years of age and 75 years of age, inclusive
Subject must have a Karnofsky performance status (KPS) of ≥ 70
Subjects must have newly diagnosed adult-type diffuse gliomas (World Health Organization Classification 2021) that has not been previously treated with surgery, radiation or chemotherapy (specifically astrocytoma, IDH-mutant or glioblastoma, IDH-wildtype)
Based on the pre-operative evaluation by neurosurgeon, the subject is a candidate for ≥ 80% resection of the enhancing region
The primary tumor must be made available for central testing for IDH1 mutation, MGMT methylation status
Willing to provide a blood sample to determine DGM7 status
Platelet count ≥ 60,000/mm^3
Hemoglobin (Hgb) ≥ 10 g/dL
Absolute neutrophil count (ANC) ≥ 1,500/mm^3
Absolute lymphocyte count ≥ 500/mm^3
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless patient had Gilbert's syndrome)
Alanine aminotransferase (ALT) ≤ 2.5 x ULN
Estimated glomerular filtration rate of at least 50mL/min by Cockcroft Gault formula
Female patients of child-bearing potential and male patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for 30-days prior to the first administration of study drug, for the duration of study participation, and for 90-days following completion of the therapy. Should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. IF a male patient impregnates a woman or suspects he has impregnated a woman while participating in this study, he should inform his treating physician immediately.
* A female of child-bearing potential is any women (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
** Has not undergone a hysterectomy or bilateral oophorectomy; or
** Has not had ≥ 12 months of non-therapy-induced amenorrhea
Women must not be breastfeeding
Subjects must have the ability to understand, and the willingness to comply with the scheduled visits, treatment schedule, laboratory testing and other requirements of the study
Exclusion Criteria
Prior treatment for HGG
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 not exclusionary regardless of time, as well as localized prostate carcinoma or cervical carcinoma in situ after curative treatment
Histological confirmed oligodendroglioma (IDH-mutant and 1p.19q-codeleted) or mixed glioma
A contrast-enhancing brain tumor that is any of the following:
* Multi-focal (defined as 2 separate areas of presumed tumor whether contrast enhancing or not, measuring at least 1cm in 2 planes that are not contiguous
* Associated with either diffuse subependymal or leptomeningeal dissemination
* > 5cm in any dimension
The subject has or had an active infection requiring antibiotic, antifungal or antiviral therapy in the 4 weeks preceding study cycle 1: day 1
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 interrupted for surgery
Subject is HIV positive
The subject has hepatitis B (positive test for hepatitis B surface antigen [HBsAg] or hepatitis B core antibody [HBcAb] and positive test for hepatitis B virus [HBV]-DNA) or hepatitis C (positive tests for hepatitis C virus [HCV] antibody and HCV-ribonucleic acid [RNA]) or hepatitis B and C co-infection (positive test for ABsAg or HBcAb and positive test for HCV antibody)
Subject has a history of allergy or intolerance to flucytosine (DB107-FC)
The subject has a gastrointestinal disease that would, in the opinion of the investigator, prevent him or her from being able to swallow or absorb flucytosine
The subject intends to undergo treatment with the Gliadel, registered trademark, wafer at the time of resection surgery or has received Gliadel wafer < 30 days from cycle 1: day 1
Severe pulmonary, cardiac or other systemic disease, which as per Investigator assessment would prevent surgical resection
Subjects who have any other disease or condition, which as per Investigator assessment may affect the subject’s compliance or place the subject at higher risk of potential treatment complications
Additional locations may be listed on ClinicalTrials.gov for NCT06504381.
I. To evaluate the safety and tolerability of vocimagene amiretrorepvec (DB107-RRV) administered intracranially followed by intravenous (IV) DB107-RRV and extended release flucytosine (DB107-FC). (Phase I)
II. To determine median progression free survival (PFS) (informed by biomarker status, DGM7 and patient subsets to minimally include genomic profile and histology) of newly diagnosed high grade glioma (HGG) patients treated with DB107-RRV combined with DB107-FC delivered with standard of care following tumor resection. (Phase IIa)
SECONDARY OBJECTIVES:
I. To confirm the recommended phase 2 dose (RP2D) of DB107-RRV and DB107-FC when administered to newly diagnosed HGG patients. (Phase I)
II. To evaluate radiographic response by immunotherapy Response Assessment in Neuro-Oncology (iRANO). (Phase I)
III. To assess best overall response rates (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]) and overall response rate (CR and PR) of each arm and subset. (Phase IIa)
IV. To assess the duration of response of each arm and subset. (Phase IIa)
V. To assess the median PFS and PFS at 6 months (PFS-6) of each arm and subset. (Phase IIa)
VI. To assess the median overall survival (OS) of each arm and subset. (Phase IIa)
VII. To evaluate the safety of DB107-RRV administered intracranially followed by IV DB107-RRV and DB107-FC. (Phase IIa)
OUTLINE: Patients receive DB107-RRV intracranially over approximately 10 seconds at time of surgical resection then IV in the operating room immediately following resection. Patients are then assigned to 1 of 2 treatment groups based on MGMT methylation.
GROUP I (NO MGMT METHYLATION):
STUDY TREATMENT: Starting no later than 6 weeks after surgical resection, patients undergo SOC radiation therapy on Monday-Friday for 6 weeks per standard of care and receive DB107-FC orally (PO) on 5 consecutive days (Monday-Friday) during weeks 1-2 and weeks 5-6. After the conclusion of radiation therapy, patients receive DB107-RRV IV on days 7 and 14 during rest period.
ADJUVANT THERAPY: Patients receive DB107-FC PO on days 1-5 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with no disease progression after 6 cycles may continue to receive additional cycles until disease progression or unacceptable toxicity.
Additionally, patients undergo blood sample collection and gadolinium-enhanced magnetic resonance imaging (GdMRI) throughout the study.
GROUP II (LOW MGMT TO HIGH METHYLATION):
STUDY TREATMENT: Starting no later than 6 weeks after surgical resection, patients receive DB107-FC PO over 5 consecutive days (Monday-Friday) during weeks 1-2 and weeks 5-6. Patients receive temozolomide PO while undergoing radiation therapy Monday-Friday for 6 weeks per SOC. After the conclusion of radiation therapy, patients receive DB107-RRV IV on days 7 and 14 during rest period.
ADJUVANT THERAPY: Patients receive DB107-FC PO on days 1-5 of each cycle and SOC temozolomide PO on days 1-5 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with no disease progression after 6 cycles may continue to receive additional cycles of DB107-FC until disease progression or unacceptable toxicity.
Additionally, patients undergo blood sample collection and GdMRI throughout the study.
After completion of study treatment, patients are followed within 15 days, yearly for 5 years then for up to 10 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationUniversity of California San Francisco
