High Grade Glioma, MGMT-Unmethylated Glioblastoma, MGMT-Methylated Glioblastoma
Conditions
Keywords
Gene therapy, Combination therapy
Brief summary
This is a multicenter, open-label study of DB107-RRV (formerly Toca 511) and DB107-FC (formerly Toca FC) when administered following surgical resection in newly diagnosed High Grade Glioma (HGG) patients. The study is designed to evaluate whether treatment with DB107-RRV in combination with DB107-FC when added to standard of care provides clinical benefit to newly diagnosed HGG when compared to historical performance previously determined in well controlled clinical trials published in the peer reviewed literature. This study is going to be conducted in newly diagnosed HGG patients receiving with maximum surgical resection treatment followed by radiation and temozolomide treatment using the established Stupp Protocol for O6-methylguanine-DNA methyl-transferase (MGMT) methylated patients or radiation therapy for MGMT unmethylated patients.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of DB107-RRV administered intracranially followed by intravenous (IV) DB107-RRV and DB107-FC (Phase I). II. To determine the median progression-free survival (PFS) (informed by biomarker status, DGM7 and patient subsets to minimally include genomic profile and histology) of newly diagnosed 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 overall PFS and PFS at month 6 (PFS-6) for each arm and subset (Phase IIa). VI. To assess the median overall survival 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: Participants will initially be enrolled in Phase I and treated with DB107-RRV intracranially, at time of surgical resection, and intravenously within 8 hours following surgery. Pathology will be performed locally as per standard practice to confirm participant's HGG diagnosis and Isocitrate dehydrogenase 1 (IDH1) mutation status. Participants in Phase I will then be assigned to one of 2 cohorts: No MGMT methylation (MGMT unmethylated) which will receive DB107-FC and RT following DB107-RRV or Low-High MGMT methylated which will receive DB107-FC, Temozolomide (TMZ) and RT following DB107-RRV. The safety and tolerability will be examined for the Phase I participants and RP2D dose confirmed. New participants will then be enrolled in Phase IIa under the established RP2D determined in Phase I, with the first 2 participants receiving a safety run-in at the RP2D. Once participant safety and tolerability are confirmed, additional participants will be enrolled in the Phase IIa portion of the study. All participants who receive DB107-RRV and DB107-FC will be followed for up to15 years.
Interventions
GENETICDB107-RRV
Given intracranially (IC) during resection and intravenously (IV) immediately following
DRUGDB107-FC
Given orally (PO)
RADIATIONRadiation Therapy (RT)
Undergo RT
DRUGTemozolomide
Given PO
PROCEDUREMagnetic Resonance Imaging (MRI)
Undergo standard of care MRI
PROCEDURESurgical resection
Undergo non-investigational tumor resection
Sponsors
University of California, San Francisco
California Institute for Regenerative Medicine (CIRM)
Denovo Biopharma LLC
Anova Enterprises, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be eligible for study entry: 1. Participant has provided written informed consent. 2. Participant is between 18 years of age and 75 years of age, inclusive. 3. Participant must have a Karnofsky Performance Scale (KPS) of \>= 70. 4. Participant 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, Isocitrate dehydrogenase (IDH)-mutant or glioblastoma, IDH-wildtype). 5. Based on the pre-operative evaluation by neurosurgeon, participant is a candidate for \>= 80% resection of the enhancing region. 6. The primary tumor must be made available for central testing for IDH1 mutation, O6-methylguanine-DNA methyl-transferase (MGMT) methylation status. 7. Willing to provide a blood sample to determine Denovo Genomic Marker 7 (DGM7) status. 8. Laboratory values adequate for patient to undergo surgery, including: 1. Platelet count \>= 60,000/mm\^3 2. Hemoglobin \>= 10 g/dL 3. Absolute neutrophil count (ANC) \>= 1,500/mm\^3 4. Absolute lymphocyte count \>= 500/mm\^3 5. Total bilirubin \<=1.5 x upper limit of normal (ULN) (unless patient had Gilbert's syndrome) 6. alanine aminotransferase (ALT) \<= 2.5 x ULN 7. Estimated glomerular filtration rate of at least 50 mL/min by Cockcroft Gault Formula 9. Female participants of child-bearing potential and male participants 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 participant become pregnant or suspect a pregnancy while participating in this study, the treating physician must be informed immediately. IF a male participant impregnates or is suspected of impregnating a woman while participating in this study, the treating physician must be informed 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. 10. Participants must not be breastfeeding. 11. Participants 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
Participants may not meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with dose limiting toxicities (Phase I) | Up to 1 year | Tolerability is defined as the proportion of participants receiving at least one dose of DB107-RRV and DB107-FC with a reported dose-limiting toxicity for all participants in Phase I. |
| Proportion of participants with treatment-emergent adverse events (Phase I) | Up to 3 years | Safety is defined as the proportion of participants with treatment-emergent adverse events as classified by the Medical Dictionary for Regulatory Activities (MEDDRA) preferred terms and graded for severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for participants in Phase 1. |
| Median Progression free survival (PFS) by biomarker status (Phase IIa) | Up to 3 years | PFS is defined as time from first receipt of DB107-RRV until progression or death, whichever occurs first for newly diagnosed HGG patients with unmethylated MGMT and methylated MGMT. Participants without an event will be censored at the last disease assessment. PFS (months) = (earlier date of documentation of progression of disease or death/censored - date of first dose of DB107-RRV+1) (365.25/12) using Immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria to determine disease status. The median and the 95% confidence interval will be estimated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose (RP2D) (Phase I) | Up to 1 year | The confirmed RP2D of DB107-RRV and DB107-FC implemented for participants enrolled in Phase IIa will be reported. |
| Overall Response Rate (ORR) (Phase IIa) | Up to 5 years | ORR is defined as the percentage of subjects who obtained either a disease status of CR or PR according to iRANO criteria per investigator. |
| Median Progression-free survival (PFS) at 6 months (Phase IIa) | Up to 6 months | PFS is defined as time from first receipt of DB107-RRV until progression or death, whichever occurs first at the 6-month visit. Participants without an event will be censored at the last disease assessment. PFS (months) = (earlier date of documentation of progression of disease or death/censored - date of first dose of DB107-RRV+1) (365.25/12) using Immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria to determine disease status. The median and the 95% confidence interval will be estimated using the Kaplan-Meier method. |
| Median Progression-free survival (PFS) (Phase IIa) | 6 months | PFS is defined as time from first receipt of DB107-RRV until progression or death, whichever occurs first at the 6-month visit. Participants without an event will be censored at the last disease assessment. PFS (months) = (earlier date of documentation of progression of disease or death/censored - date of first dose of DB107-RRV+1) (365.25/12) using Immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria to determine disease status. The median and the 95% confidence interval will be estimated using the Kaplan-Meier method. |
| Median Overall Survival (OS) at 6 months (Phase IIa) | 6 months | Overall survival at 6 months is defined as the time from the date of first DB107-RRV injection until death. Participants who are alive at 6 months will be censored. The median and the 95% confidence interval will be estimated using the Kaplan-Meier method. |
| Median Overall Survival (OS) (Phase IIa) | Up to 15 years | Overall survival will be analyzed using the date of first DB107-RRV injection as baseline until death, participant withdrawal, or study closure. The median and the 95% confidence interval will be estimated using the Kaplan-Meier method. |
Countries
United States
Contacts
CONTACTStephanie Lewis, RN
CONTACTNeuro-Oncology New Patient Coordinator
PRINCIPAL_INVESTIGATORNicholas Butowski, MD
University of California, San Francisco
PRINCIPAL_INVESTIGATORNoriyuki Kasahara, MD, PhD
University of California, San Francisco
Outcome results
None listed