A Phase Ib/II, Open-label Study of NBM-BMX as Monotherapy or in Combination With Radiotherapy and Temozolomide in Subjects With Solid Tumors or Newly Diagnosed Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 79
- 试验地点
- 7
- 主要终点
- [Arm B, Phase II] Progression-free survival rate at 6 months (PFS6)
研究概览
简要总结
NBM-BMX is an orally available new chemical entity to inhibit histone deacetylases 8 (HDAC8) activity specifically, being developed as a potential anti-cancer therapeutic by NatureWise. This study aims to evaluate the safety, pharmacokinetics, and preliminary efficacy of NBM-BMX as monotherapy in subjects with advanced solid tumors or combination with the standard of care treatment in subjects with newly diagnosed glioblastoma.
详细描述
This is a multi-center, open-label, 2-arm, phase Ib/II study to evaluate the safety, pharmacokinetics, and preliminary efficacy of NBM-BMX as monotherapy in the treatment of solid tumors (Arm A) or in combination with radiotherapy/temozolomide in the treatment of glioblastoma (Arm B).
Arm A consists of dose escalation cohorts in subjects with advanced solid tumors who will be treated with NBM-BMX monotherapy at different dose levels. Arm B consists of dose escalation cohorts (Phase Ib) and expansion cohorts (Phase II) in subjects with newly diagnosed glioblastoma (GBM). Subjects will be treated with NBM-BMX at different dose levels in combination with the first-line standard of care treatment (i.e., concomitant Radiotherapy (RT)/TMZ followed by adjuvant TMZ) in Phase Ib. After the recommended Phase 2 dose (RP2D) is determined in Phase Ib, additional subjects will be enrolled and treated at the RP2D to evaluate the efficacy of NBM-BMX combination therapy.
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
- •Arm A (advanced solid tumors)
- •Having signed and dated the informed consent form.
- •Females or males > 18 years old.
- •Histologically or cytologically confirmed advanced solid tumors refractory to standard of care therapy, or for which no standard of care therapy is available.
- •Disease that is measurable or evaluable as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Response Assessment in Neuro-Oncology (RANO) criteria (for CNS tumors).
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to
- •Adequate organ function as defined by the following criteria:
- •Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 × upper limits of normal (ULN), unless liver metastases present, then ≤ 5 × ULN
- •Total serum bilirubin ≤ 1.5 × ULN unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin ≤ 3 × ULN
- •Absolute neutrophil count (ANC) ≥ 1,000/μL
- •Platelets ≥ 75,000/μL
- •Hemoglobin ≥ 8.0 g/dL
- •Non-indexed estimated glomerular filtration rate (eGFR) ≥ 50 mL/min/1.73 m2 × BSA (m2)/1.
- •Transfusion is not allowed to meet entry criteria.
- •QTcF ≤ 480 msec
- •Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.
- •Arm B (newly diagnosed GBM)
- •Having signed and dated the informed consent form.
- •Females or males > 18 years old.
- •Newly diagnosed, histologically confirmed glioblastoma, non-resectable, partially resected or resected.
- •Karnofsky performance status (KPS) ≥ 60 at screening and before the initiation (Day 1) of concomitant therapy.
- •Disease that is measurable or evaluable as defined by Response Assessment in Neuro-Oncology (RANO) criteria.
- •Adequate organ function as defined by the following criteria:
- •Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 × upper limit of normal (ULN), unless liver metastases present, then ≤ 5 × ULN
- •Total serum bilirubin ≤ 1.5 × ULN unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin ≤ 3 × ULN
- •Absolute neutrophil count (ANC) ≥ 1,500/μL
- •Platelets ≥ 100,000/μL
- •Hemoglobin ≥ 8.0 g/dL
- •Non-indexed estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 × BSA (m2)/1.
- •Transfusion is not allowed to meet entry criteria.
- •QTcF ≤ 480 msec
- •Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.
排除标准
- •Arm A (advanced solid tumors)
- •Systemic anti-cancer treatment (investigational or approved) within 28 days or 5 half-lives of that drug (whichever is shorter) of the first dose of NBM-BMX.
- •Curative radiation therapy within 28 days or palliative RT within 7 days of the first dose of NBM-BMX.
- •Currently taking strong inhibitors (e.g., gemfibrozil) or inducers of CYP2C
- •Any of the following within 6 months of the first dose of NBM-BMX: pulmonary embolism events, deep vein thrombosis (DVT) events, myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack.
- •A positive test for hepatitis B (HBsAg) and/or hepatitis C (anti-HCV antibody), unless the HBV DNA level and/or HCV RNA level is below the limit of detection.
- •Known history of human immunodeficiency virus (HIV) infection.
- •Men and women of childbearing potential who are unwilling to use highly effective contraceptive methods during the study period.
- •Highly effective contraceptive methods include implants, injectables, combined oral contraceptives, intra-uterine devices (IUDs), sexual abstinence, surgical sterilization or a partner who is sterile.
- •Females who are pregnant or breastfeeding.
- •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would impart, in the judgement of the investigator and/or sponsor, excess risks associated with study participation or study drug administration.
- •Arm B (newly diagnosed GBM)
- •Prior systemic therapy (including Gliadel wafer implant), immunotherapy, investigational agents, or radiotherapy for glioblastoma.
- •Currently taking strong inhibitors (e.g., gemfibrozil) or inducers of CYP2C
- •Corticosteroid use of > 8 mg/day dexamethasone or equivalent within 5 days before the first dose of NBM-BMX.
- •A history of hypersensitivity reaction to temozolomide or dacarbazine.
- •Any of the following within 6 months of the first dose of NBM-BMX: pulmonary embolism events, deep vein thrombosis (DVT) events, myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack.
- •A positive test for hepatitis B (HBsAg) and/or hepatitis C (anti-HCV antibody), unless the HBV DNA level and/or HCV RNA level is below the limit of detection.
- •Known history of human immunodeficiency virus (HIV) infection. Note: HIV testing is not required.
- •Men and women of childbearing potential who are unwilling to use highly effective contraceptive methods during the study period and for at least 6 months after the final dose of temozolomide.
- •Highly effective contraceptive methods include implants, injectables, combined oral contraceptives, intra-uterine devices (IUDs), sexual abstinence, surgical sterilization or a partner who is sterile.
- •Female who are pregnant or breastfeeding.
- •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would impart, in the judgement of the investigator and/or sponsor, excess risks associated with study participation or study drug administration.
研究组 & 干预措施
combination therapy in newly diagnosed glioblastoma
Subjects with newly diagnosed glioblastoma will be treated with NBM-BMX at different dose levels in combination with the standard of care treatment (concomitant RT/TMZ followed by adjuvant TMZ). In the expansion study, Subjects will be treated with NBM-BMX at the recommended Phase 2 dose (RP2D) in combination with RT/TMZ.
干预措施: Temozolomide (Drug)
monotherapy in advanced solid tumors
Subjects with advanced solid tumors will be treated with NBM-BMX monotherapy at different dose levels depending on the order of their enrollment.
干预措施: NBM-BMX Capsule (Drug)
combination therapy in newly diagnosed glioblastoma
Subjects with newly diagnosed glioblastoma will be treated with NBM-BMX at different dose levels in combination with the standard of care treatment (concomitant RT/TMZ followed by adjuvant TMZ). In the expansion study, Subjects will be treated with NBM-BMX at the recommended Phase 2 dose (RP2D) in combination with RT/TMZ.
干预措施: NBM-BMX Capsule (Drug)
combination therapy in newly diagnosed glioblastoma
Subjects with newly diagnosed glioblastoma will be treated with NBM-BMX at different dose levels in combination with the standard of care treatment (concomitant RT/TMZ followed by adjuvant TMZ). In the expansion study, Subjects will be treated with NBM-BMX at the recommended Phase 2 dose (RP2D) in combination with RT/TMZ.
干预措施: Standard radiotherapy (Radiation)
结局指标
主要结局
[Arm B, Phase II] Progression-free survival rate at 6 months (PFS6)
时间窗: up to 6 months
To assess the preliminary efficacy of NBM-BMX in combination with RT and TMZ in subjects with newly diagnosed GBM, the investigators will evaluate anti-tumor activity using RANO criteria.
[Arm B, Phase Ib] Frequency of dose-limiting toxicity (DLT) at each dose level
时间窗: up to 10 weeks
To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for NBM-BMX in combination with RT and TMZ in subjects with newly diagnosed GBM, toxicities will be graded according to the National Cancer Institute Common Terminology.
[Arm A, Phase Ib] Frequency of dose-limiting toxicity (DLT) at each dose level
时间窗: up to 28 days
To determine the maximum tolerated dose (MTD) for NBM-BMX monotherapy in subjects with advanced solid tumors, toxicities will be graded according to the National Cancer Institute Common Terminology.
次要结局
- Time to maximum plasma concentration (Tmax) of NBM-BMX(Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days))
- Peak plasma concentration (Cmax) of NBM-BMX(Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days))
- Terminal elimination half-life (T1/2) of NBM-BMX(Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days))
- Frequency, types, severity, and relationship to NBM-BMX of adverse events (AEs)(up to 28 days)
- Area under the plasma concentration versus time curve (AUC) of NBM-BMX(Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days))
- Preliminary assessment of anti-tumor activity by response evaluation criteria(at least 8 weeks)