A Phase I/IIa Study to Evaluate the Efficacy of DB107-RRV (Formerly Toca511), Administered to Subjects at Time of Resection and Intravenously Thereafter, in Combination With DB107-FC (Formerly Toca FC) and Radiation Therapy or DB107-FC, Temozolomide (TMZ) and Radiation Therapy in Patients With Newly Diagnosed High Grade Glioma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 70
- 试验地点
- 7
- 主要终点
- Proportion of participants with dose limiting toxicities (Phase I)
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Each patient must meet all of the following inclusion criteria to be eligible for study entry:
- •Participant has provided written informed consent.
- •Participant is between 18 years of age and 75 years of age, inclusive.
- •Participant must have a Karnofsky Performance Scale (KPS) of >=
- •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).
- •Based on the pre-operative evaluation by neurosurgeon, participant is a candidate for >= 80% resection of the enhancing region.
- •The primary tumor must be made available for central testing for IDH1 mutation, O6-methylguanine-DNA methyl-transferase (MGMT) methylation status.
- •Willing to provide a blood sample to determine Denovo Genomic Marker 7 (DGM7) status.
- •Laboratory values adequate for patient to undergo surgery, including:
- •Platelet count >= 60,000/mm^3
- •Hemoglobin >= 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 50 mL/min by Cockcroft Gault Formula
- •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.
- •Participants must not be breastfeeding.
- •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.
排除标准
- •Participants may not meet any of the following exclusion criteria to be eligible for study entry:
- •Prior treatment for High Grade Glioma (HGG).
- •History of other malignancy unless the participant 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 or
- •> 5cm in any dimension.
- •Participant has or had an active infection requiring antibiotic, antifungal or antiviral therapy in the 4 weeks preceding study Cycle 1: Day
- •Participant 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.
- •Participant is HIV positive.
- •Participant 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-RNA) or Hepatitis B and C co-infection (positive test for HBsAg or HBcAb and positive test for HCV Antibody).
- •Participant has a history of allergy or intolerance to flucytosine (DB107-FC).
- •Participant has a gastrointestinal disease that would, in the opinion of the Investigator, prevent him or her from being able to swallow or absorb flucytosine.
- •Participant intends to undergo treatment with the Gliadel® wafer at the time of resection surgery or has received Gliadel® wafer < 30 days from Cycle 1: Day
- •Severe pulmonary, cardiac or other systemic disease, which as per Investigator assessment would prevent surgical resection.
- •Participant who have any other disease or condition, which as per Investigator assessment may affect the participant's compliance or place the participant at higher risk of potential treatment complications.
研究组 & 干预措施
No MGMT Methylation (DB107-RRV, DB107-FC, Radiation therapy)
Participants receive a 4.0 x 10^8 transduction units per milliliter (TU/mL)) dose of DB107-RRV intracranially (IC) at resection and a 1.4 x 10^9 TU/mL dose IV prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Unmethylated MGMT participants receive 300 mg/kg/day DB107-FC PO during RT over 5 days during weeks 1-2, & 5-6. 2 gray (Gy)/day standard of care (SOC) RT will be given for 5 consecutive days for 6 weeks. After RT, participants receive 1.4 x 10^9 TU/mL of DB107-RRV IV on days 7 and 14 and continue during a 4-week rest period between RT and adjuvant therapy. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle up to 6 cycles or until PD. Participants with no PD during adjuvant treatment may receive additional cycles of DB107-FC until PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: DB107-RRV (Genetic)
No MGMT Methylation (DB107-RRV, DB107-FC, Radiation therapy)
Participants receive a 4.0 x 10^8 transduction units per milliliter (TU/mL)) dose of DB107-RRV intracranially (IC) at resection and a 1.4 x 10^9 TU/mL dose IV prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Unmethylated MGMT participants receive 300 mg/kg/day DB107-FC PO during RT over 5 days during weeks 1-2, & 5-6. 2 gray (Gy)/day standard of care (SOC) RT will be given for 5 consecutive days for 6 weeks. After RT, participants receive 1.4 x 10^9 TU/mL of DB107-RRV IV on days 7 and 14 and continue during a 4-week rest period between RT and adjuvant therapy. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle up to 6 cycles or until PD. Participants with no PD during adjuvant treatment may receive additional cycles of DB107-FC until PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: DB107-FC (Drug)
No MGMT Methylation (DB107-RRV, DB107-FC, Radiation therapy)
Participants receive a 4.0 x 10^8 transduction units per milliliter (TU/mL)) dose of DB107-RRV intracranially (IC) at resection and a 1.4 x 10^9 TU/mL dose IV prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Unmethylated MGMT participants receive 300 mg/kg/day DB107-FC PO during RT over 5 days during weeks 1-2, & 5-6. 2 gray (Gy)/day standard of care (SOC) RT will be given for 5 consecutive days for 6 weeks. After RT, participants receive 1.4 x 10^9 TU/mL of DB107-RRV IV on days 7 and 14 and continue during a 4-week rest period between RT and adjuvant therapy. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle up to 6 cycles or until PD. Participants with no PD during adjuvant treatment may receive additional cycles of DB107-FC until PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: Radiation Therapy (RT) (Radiation)
No MGMT Methylation (DB107-RRV, DB107-FC, Radiation therapy)
Participants receive a 4.0 x 10^8 transduction units per milliliter (TU/mL)) dose of DB107-RRV intracranially (IC) at resection and a 1.4 x 10^9 TU/mL dose IV prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Unmethylated MGMT participants receive 300 mg/kg/day DB107-FC PO during RT over 5 days during weeks 1-2, & 5-6. 2 gray (Gy)/day standard of care (SOC) RT will be given for 5 consecutive days for 6 weeks. After RT, participants receive 1.4 x 10^9 TU/mL of DB107-RRV IV on days 7 and 14 and continue during a 4-week rest period between RT and adjuvant therapy. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle up to 6 cycles or until PD. Participants with no PD during adjuvant treatment may receive additional cycles of DB107-FC until PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: Temozolomide (Drug)
No MGMT Methylation (DB107-RRV, DB107-FC, Radiation therapy)
Participants receive a 4.0 x 10^8 transduction units per milliliter (TU/mL)) dose of DB107-RRV intracranially (IC) at resection and a 1.4 x 10^9 TU/mL dose IV prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Unmethylated MGMT participants receive 300 mg/kg/day DB107-FC PO during RT over 5 days during weeks 1-2, & 5-6. 2 gray (Gy)/day standard of care (SOC) RT will be given for 5 consecutive days for 6 weeks. After RT, participants receive 1.4 x 10^9 TU/mL of DB107-RRV IV on days 7 and 14 and continue during a 4-week rest period between RT and adjuvant therapy. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle up to 6 cycles or until PD. Participants with no PD during adjuvant treatment may receive additional cycles of DB107-FC until PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: Magnetic Resonance Imaging (MRI) (Procedure)
No MGMT Methylation (DB107-RRV, DB107-FC, Radiation therapy)
Participants receive a 4.0 x 10^8 transduction units per milliliter (TU/mL)) dose of DB107-RRV intracranially (IC) at resection and a 1.4 x 10^9 TU/mL dose IV prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Unmethylated MGMT participants receive 300 mg/kg/day DB107-FC PO during RT over 5 days during weeks 1-2, & 5-6. 2 gray (Gy)/day standard of care (SOC) RT will be given for 5 consecutive days for 6 weeks. After RT, participants receive 1.4 x 10^9 TU/mL of DB107-RRV IV on days 7 and 14 and continue during a 4-week rest period between RT and adjuvant therapy. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle up to 6 cycles or until PD. Participants with no PD during adjuvant treatment may receive additional cycles of DB107-FC until PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: Surgical resection (Procedure)
Low to High MGMT Methylation (DB107-RRV, DB107-FC, Temozolomide (TMZ), Radiation therapy)
Participants receive a 4.0 x 10^8 TU/mL dose of DB107-RRV IC at resection and a 1.4 x 10^9 TU/mL dose IV prior to prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Low to high MGMT methylation participants receive 75 mg/m^2 TMZ per SOC and 300mg/kg/day DB107-FC PO concurrent with 2 Gy/day over 5 consecutive days during weeks 1-2, & 5-6. After RT, participants receive 1.4 x 10^9 TU/mL DB107-RRV IV on days 7 and 14. IV DB107-RRV occurs during a 4-week rest period between RT and adjuvant portions of the protocol. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle for up to 6 cycles or until PD with 150-200 mg/m^2 adjuvant TMZ per SOC on days 1-5 of each cycle for up to 6 cycles. Participants with no PD may continue to receive additional cycles of DB107-FC PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: DB107-RRV (Genetic)
Low to High MGMT Methylation (DB107-RRV, DB107-FC, Temozolomide (TMZ), Radiation therapy)
Participants receive a 4.0 x 10^8 TU/mL dose of DB107-RRV IC at resection and a 1.4 x 10^9 TU/mL dose IV prior to prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Low to high MGMT methylation participants receive 75 mg/m^2 TMZ per SOC and 300mg/kg/day DB107-FC PO concurrent with 2 Gy/day over 5 consecutive days during weeks 1-2, & 5-6. After RT, participants receive 1.4 x 10^9 TU/mL DB107-RRV IV on days 7 and 14. IV DB107-RRV occurs during a 4-week rest period between RT and adjuvant portions of the protocol. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle for up to 6 cycles or until PD with 150-200 mg/m^2 adjuvant TMZ per SOC on days 1-5 of each cycle for up to 6 cycles. Participants with no PD may continue to receive additional cycles of DB107-FC PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: DB107-FC (Drug)
Low to High MGMT Methylation (DB107-RRV, DB107-FC, Temozolomide (TMZ), Radiation therapy)
Participants receive a 4.0 x 10^8 TU/mL dose of DB107-RRV IC at resection and a 1.4 x 10^9 TU/mL dose IV prior to prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Low to high MGMT methylation participants receive 75 mg/m^2 TMZ per SOC and 300mg/kg/day DB107-FC PO concurrent with 2 Gy/day over 5 consecutive days during weeks 1-2, & 5-6. After RT, participants receive 1.4 x 10^9 TU/mL DB107-RRV IV on days 7 and 14. IV DB107-RRV occurs during a 4-week rest period between RT and adjuvant portions of the protocol. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle for up to 6 cycles or until PD with 150-200 mg/m^2 adjuvant TMZ per SOC on days 1-5 of each cycle for up to 6 cycles. Participants with no PD may continue to receive additional cycles of DB107-FC PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: Radiation Therapy (RT) (Radiation)
Low to High MGMT Methylation (DB107-RRV, DB107-FC, Temozolomide (TMZ), Radiation therapy)
Participants receive a 4.0 x 10^8 TU/mL dose of DB107-RRV IC at resection and a 1.4 x 10^9 TU/mL dose IV prior to prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Low to high MGMT methylation participants receive 75 mg/m^2 TMZ per SOC and 300mg/kg/day DB107-FC PO concurrent with 2 Gy/day over 5 consecutive days during weeks 1-2, & 5-6. After RT, participants receive 1.4 x 10^9 TU/mL DB107-RRV IV on days 7 and 14. IV DB107-RRV occurs during a 4-week rest period between RT and adjuvant portions of the protocol. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle for up to 6 cycles or until PD with 150-200 mg/m^2 adjuvant TMZ per SOC on days 1-5 of each cycle for up to 6 cycles. Participants with no PD may continue to receive additional cycles of DB107-FC PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: Temozolomide (Drug)
Low to High MGMT Methylation (DB107-RRV, DB107-FC, Temozolomide (TMZ), Radiation therapy)
Participants receive a 4.0 x 10^8 TU/mL dose of DB107-RRV IC at resection and a 1.4 x 10^9 TU/mL dose IV prior to prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Low to high MGMT methylation participants receive 75 mg/m^2 TMZ per SOC and 300mg/kg/day DB107-FC PO concurrent with 2 Gy/day over 5 consecutive days during weeks 1-2, & 5-6. After RT, participants receive 1.4 x 10^9 TU/mL DB107-RRV IV on days 7 and 14. IV DB107-RRV occurs during a 4-week rest period between RT and adjuvant portions of the protocol. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle for up to 6 cycles or until PD with 150-200 mg/m^2 adjuvant TMZ per SOC on days 1-5 of each cycle for up to 6 cycles. Participants with no PD may continue to receive additional cycles of DB107-FC PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: Magnetic Resonance Imaging (MRI) (Procedure)
Low to High MGMT Methylation (DB107-RRV, DB107-FC, Temozolomide (TMZ), Radiation therapy)
Participants receive a 4.0 x 10^8 TU/mL dose of DB107-RRV IC at resection and a 1.4 x 10^9 TU/mL dose IV prior to prior to leaving surgery room. Participants have up to 6 weeks for surgical recovery. Low to high MGMT methylation participants receive 75 mg/m^2 TMZ per SOC and 300mg/kg/day DB107-FC PO concurrent with 2 Gy/day over 5 consecutive days during weeks 1-2, & 5-6. After RT, participants receive 1.4 x 10^9 TU/mL DB107-RRV IV on days 7 and 14. IV DB107-RRV occurs during a 4-week rest period between RT and adjuvant portions of the protocol. Participants who begin adjuvant therapy receive 300 mg/kg/day DB107-FC PO on days 1-5 of a 28-day cycle for up to 6 cycles or until PD with 150-200 mg/m^2 adjuvant TMZ per SOC on days 1-5 of each cycle for up to 6 cycles. Participants with no PD may continue to receive additional cycles of DB107-FC PD, withdrawal, death or study closure. Participants will be followed up for safety and survival status for up to 15 years.
干预措施: Surgical resection (Procedure)
结局指标
主要结局
Proportion of participants with dose limiting toxicities (Phase I)
时间窗: 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)
时间窗: 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)
时间窗: 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.
次要结局
- Recommended Phase 2 Dose (RP2D) (Phase I)(Up to 1 year)
- Overall Response Rate (ORR) (Phase IIa)(Up to 5 years)
- Median Progression-free survival (PFS) at 6 months (Phase IIa)(Up to 6 months)
- Median Progression-free survival (PFS) (Phase IIa)(6 months)
- Median Overall Survival (OS) at 6 months (Phase IIa)(6 months)
- Median Overall Survival (OS) (Phase IIa)(Up to 15 years)
研究者
Nicholas Butowski
Professor in Residence
University of California, San Francisco