Phase I/II Study of the Tolerability, Safety, and Efficacy of Liposomal Curcumin in Combination With Radiation and Temozolomide in Patients With Newly Diagnosed High-Grade Gliomas
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- The number of observed Dose Limiting Toxicity (DLTs)
研究概览
简要总结
The objective of this study is to assess the tolerability, safety, and efficacy of Liposomal Curcumin (LC) in combination with radiotherapy (RT) and Temozolomide (TMZ) in patients with newly diagnosed High-Grade Gliomas (HGG).
详细描述
This study is a Phase Ib-IIa, single-center, single-institution, open-label, dose-escalation study in patients with newly diagnosed high-grade malignant gliomas. Dose finding will be performed using a time-to-event Bayesian optimal interval (TITE-BOIN) rule-based schema.
The primary objectives of the study are to determine the maximum tolerated dose /recommended phase 2 dose of Liposomal Curcumin (LC) in combination with radiotherapy (XRT), and TMZ and adjuvant TMZ in newly diagnosed High-Grade Gliomas.
The secondary objectives are to estimate the safety and tolerability of LC in combination with standard XRT and TMZ and adjuvant TMZ, to determine the feasibility of treatment during first 10 week.
This study is an unblinded, sequential treatment intervention employing 3 dose levels.
Approximately 50 patients will be screened to achieve up to 30 patients assigned to study intervention: up to 24 in Study Part 1 and up to 6 in Study Part 2.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 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
- •≥18 years of age
- •Histologically confirmed HGG (WHO grade III or IV, including GBM, astrocytoma, gliosarcoma, H3K27M mutant diffuse midline glioma). Patients with methylated or unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) promoter are eligible, as are IDH WT and mutant patients as long as the treatment plan is for combined XRT/TMZ. The neuropathologic diagnosis of HGG will be made at the respective institution. If any question arises regarding the accuracy of the neuropathologic diagnosis, slides (and pathological blocks, if necessary) will be centrally reviewed
- •Planning standard therapy with TMZ and XRT for 6 weeks and adjuvant TMZ for six 28-day cycles.
- •Karnofsky Performance Scale (KPS) ≥ 70%
- •Adequate organ and marrow function defined as:
- •Hgb > 9 g/dL
- •ANC ≥ 1500/µL
- •Platelet count ≥ 100,000/µL
- •Total bilirubin ≤ 1.5 * institutional ULN
- •AST and ALT ≤ 3 * institutional ULN OR
- •Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 unless data exist supporting safe use at lower values of renal function, but eGFR must be ≥ 30 mL/min/1.73 m2
- •Patients with human immunodeficiency virus (HIV) who are on effective antiretroviral therapy are eligible if the viral load was assessed as undetectable within 6 months prior to baseline
- •Women: WOCBP must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation
- •Men: must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 4 months after completion of LC administration
排除标准
- •Any concurrent cancer diagnosis that is untreated, actively treated, or has undergone any therapy (XRT, cytotoxic, targeted, immunotherapeutic, etc.) within 2 years of study enrollment, with the exception of squamous or basal cell skin cancer
- •Patient has not recovered from AEs due to prior anticancer therapy (i.e., residual toxicities > Grade 1), with the exception of alopecia
- •Receiving any other investigational agent
- •Active infection requiring systemic antibiotics
- •History of allergic reaction to compounds that are chemically or biologically similar to LC
- •Patient is taking a medication that may potentiate hemolysis
- •Unstable angina or myocardial infarction within the past 6 months
- •Prolonged QTc interval, Fridericia formula (QTcF) (> 450 msec for males or > 460 msec for females)
- •Psychiatric illness or social situation that could limit compliance with study requirements
- •Pregnant or breastfeeding
研究组 & 干预措施
Tolerability, Safety, and Efficacy of LC in Combination with RT and TMZ
Define the MTD/recommended Phase 2 dose (RP2D) of LC, administered IV weekly in combination with standard CRT (60 Gy in 30-33 fractions M-F, and daily oral TMZ 75 mg/m2), in patients with high grade malignant gliomas. This study seeks the MTD/RP2D of LC when added to TMZ during concurrent RT and adjuvant TMZ after RT. The study will evaluate escalating doses of LC delivered by IV infusion weekly as a gravity infusion (without infusion pump). Within each cohort, the dose will remain the same. In the first cohort, dosing will begin at Level 1 (300 mg/m2). The infusion of LC will begin at the start of CRT. Patients will be evaluable for the cohort if they have completed 80% of the planned doses of LC, 80% of RT and 60% of TMZ within the first 10 weeks of treatment. Patients who experience a dose-limiting toxicity (DLT) will be evaluable for the cohort if they have received at least 1 dose of LC.
干预措施: Treatment Period 1 (Drug)
Tolerability, Safety, and Efficacy of LC in Combination with RT and TMZ
Define the MTD/recommended Phase 2 dose (RP2D) of LC, administered IV weekly in combination with standard CRT (60 Gy in 30-33 fractions M-F, and daily oral TMZ 75 mg/m2), in patients with high grade malignant gliomas. This study seeks the MTD/RP2D of LC when added to TMZ during concurrent RT and adjuvant TMZ after RT. The study will evaluate escalating doses of LC delivered by IV infusion weekly as a gravity infusion (without infusion pump). Within each cohort, the dose will remain the same. In the first cohort, dosing will begin at Level 1 (300 mg/m2). The infusion of LC will begin at the start of CRT. Patients will be evaluable for the cohort if they have completed 80% of the planned doses of LC, 80% of RT and 60% of TMZ within the first 10 weeks of treatment. Patients who experience a dose-limiting toxicity (DLT) will be evaluable for the cohort if they have received at least 1 dose of LC.
干预措施: Treatment Period 2 (Drug)
Tolerability, Safety, and Efficacy of LC in Combination with RT and TMZ
Define the MTD/recommended Phase 2 dose (RP2D) of LC, administered IV weekly in combination with standard CRT (60 Gy in 30-33 fractions M-F, and daily oral TMZ 75 mg/m2), in patients with high grade malignant gliomas. This study seeks the MTD/RP2D of LC when added to TMZ during concurrent RT and adjuvant TMZ after RT. The study will evaluate escalating doses of LC delivered by IV infusion weekly as a gravity infusion (without infusion pump). Within each cohort, the dose will remain the same. In the first cohort, dosing will begin at Level 1 (300 mg/m2). The infusion of LC will begin at the start of CRT. Patients will be evaluable for the cohort if they have completed 80% of the planned doses of LC, 80% of RT and 60% of TMZ within the first 10 weeks of treatment. Patients who experience a dose-limiting toxicity (DLT) will be evaluable for the cohort if they have received at least 1 dose of LC.
干预措施: Treatment Period 3 (Drug)
Tolerability, Safety, and Efficacy of LC in Combination with RT and TMZ
Define the MTD/recommended Phase 2 dose (RP2D) of LC, administered IV weekly in combination with standard CRT (60 Gy in 30-33 fractions M-F, and daily oral TMZ 75 mg/m2), in patients with high grade malignant gliomas. This study seeks the MTD/RP2D of LC when added to TMZ during concurrent RT and adjuvant TMZ after RT. The study will evaluate escalating doses of LC delivered by IV infusion weekly as a gravity infusion (without infusion pump). Within each cohort, the dose will remain the same. In the first cohort, dosing will begin at Level 1 (300 mg/m2). The infusion of LC will begin at the start of CRT. Patients will be evaluable for the cohort if they have completed 80% of the planned doses of LC, 80% of RT and 60% of TMZ within the first 10 weeks of treatment. Patients who experience a dose-limiting toxicity (DLT) will be evaluable for the cohort if they have received at least 1 dose of LC.
干预措施: Treatment Period 4a (Drug)
结局指标
主要结局
The number of observed Dose Limiting Toxicity (DLTs)
时间窗: The duration of treatment for each patient, minimum of 34 weeks
The safety and tolerability of LC infused IV over 3 hours will be assessed by recording the number of observed DLTs. DLTs, as defined in this study occur if in the first three patients entered at a dose-level, more than one of these 3 experiences a serious adverse event, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5. If one of the first three patients entered at the level experiences an SAE (as defined by NCI CTCAE Version 5), then three additional patients are entered at that same dose level. If one of the additional three patients experiences an SAE (as defined by NCI CTCAE Version 5), the dose is not advanced beyond that level.
次要结局
- The incidence of Adverse Events(The duration of treatment for each patient, minimum of 34 weeks)
- The proportion of patients at each dose level who receive at least 80% of the planned infusions of LC, 80% of XRT, and 60% of TMZ during the first 10 weeks of treatment(10 weeks)
- Overall Survival (OS)(The duration of treatment for each patient, minimum of 34 weeks; OS is time from beginning of therapy to time of death.)
- Progression free survival (PFS)(The duration of treatment for each patient, minimum of 34 weeks; PFS is time from the start of therapy until the date when tumor progression is documented)