A Phase I/II Study of Zotiraciclib for Recurrent Malignant Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 96
- 试验地点
- 1
- 主要终点
- To determine 12 months PFS in participants w/ recurrent glioma, IDH1/2-mutant, WHO grade 3 treated w/ zotiraciclib in comparison w/ the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors
研究概览
简要总结
Background:
Diffuse gliomas are tumors that affect the brain and spinal cord. Gliomas that develop in people with certain gene mutations (IDH1 or IDH2) are especially aggressive. Better treatments are needed.
Objective:
To see if a study drug (zotiraciclib) is effective in people with recurrent diffuse gliomas who have IDH1 or IDH2 mutations.
Eligibility:
People aged 15 years and older with diffuse gliomas that returned after treatment. They must also have mutations in the IDH1 or IDH2 genes.
Design:
Participants will be screened. They will have a physical exam with blood and urine tests. They will have tests of their heart function. They will have an MRI of their brain. A new biopsy may be needed if previous results are not available.
Zotiraciclib is a capsule taken by mouth with a glass of water. Participants will take the drug at home on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. They may also be given medications to prevent side effects of the study drug. The schedule for taking the study drug may vary for participants who will undergo surgery.
Participants will be given a medication diary for each cycle. They will write down the date and time of each dose of the study drug.
Participants will visit the clinic about once a month. They will have a physical exam, blood tests, and tests to evaluate their heart function. An MRI of the brain will be repeated every 8 weeks.
Participants may remain in the study for up to 18 cycles (1.5 years).
详细描述
Background:
- Zotiraciclib is a multi-kinase inhibitor that has been shown to have anti-glioma effects through transcriptional suppression, mitochondrial dysfunction, and adenosine 5'-triphosphate (ATP) reduction in glioblastoma in our preclinical studies
- Zotiraciclib is orally administered and likely penetrates the blood brain barrier (BBB). There has been a clinical experience in using zotiraciclib as a single agent and in combination with other chemotherapy agents in cancers, including malignant gliomas
- Our phase I study of zotiraciclib and temozolomide (TMZ) in recurrent high-grade astrocytomas determined the maximum tolerated dose (MTD) of zotiraciclib in combination with TMZ and demonstrated the safety of the treatment in recurrent high-grade glioma patients
- Preliminary efficacy analysis of Phase I demonstrated an improved response to zotiraciclib in combination with TMZ in IDH-mutant gliomas compared to the IDH-wildtype counterpart
- A selective vulnerability to zotiraciclib as a single agent was demonstrated in the preclinical models of IDH-mutant gliomas
Objectives:
- Phase I: To estimate recommended phase II dose (RP2D) of zotiraciclib
- Phase II: To determine 12-months progression free survival (PFS) in participants with recurrent glioma, IDH1/2-mutant, World Health Organization (WHO) grade 3 treated with zotiraciclib in comparison with the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors
Eligibility:
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
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Participants must have diffuse glioma, WHO grades 2-4, histologically confirmed by Laboratory of Pathology, NCI.
- •IDH1 or IDH2 mutation status confirmed by TruSight(TM) Oncology 500 performed in LP, NCI or prior documentation of IDH1 or IDH2 mutation status
- •Participants must have received prior treatment (e.g., radiation, conventional chemotherapy, or vorasidenib) prior to disease progression.
- •Participants must have recurrent disease, proven histologically or by imaging studies
- •Participants who have undergone prior surgical resection are eligible for enrollment to cohorts 1-
- •Age >15 years
- •Karnofsky >70%
- •Participants must have adequate organ and marrow function as defined below:
- •leukocytes >=3,000/microliter
- •absolute neutrophil count (ANC) >=1,500/microliter
- •platelets >100,000/microliter
- •total bilirubin <=2x ULN (ULN 1.3 mg/dl) except for participants with Gilbert Syndrome
- •AST < 3x ULN (ULN 34U/L)
- •ALT < 3x ULN (ULN 55U/L)
- •serum creatinine < 1.5 mg/dL
- •calculated creatinine clearance by CKD-EPI equation > 60 cc/min
- •Participants must have recovered from the adverse effects of prior therapy to grade 2 or less (per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0)
- •Individuals of child-bearing potential (IOCBP) and men must agree to use highly effective contraception (hormonal, intrauterine device (IUD), abstinence, tube ligation, partner has had a previous vasectomy) at the study entry, for the duration of study treatment, and up to 3 months after the last dose of zotiraciclib
- •Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 3 months after study treatment discontinuation
- •Participants must be scheduled for brain tumor biopsy or surgical resection at NIH (Cohort 5 only)
- •The ability of a participant, parent or legal guardian of minor participant to understand and the willingness to sign a written informed consent document. No Legally Authorized Representative can provide initial consent.
排除标准
- •More than one disease relapse in those with initial diagnosis of WHO grade 3-4, or more than two disease relapses in those with initial diagnosis of WHO grade 2 for Phase II. For Phase I enrollment, there are no limits on the number of prior recurrences.
- •Prior therapy with:
- •any investigational agent (including IDH mutant inhibitor) and/or standard of care cytotoxic therapy within 28 days prior to treatment initiation
- •vincristine within 14 days prior to treatment initiation
- •nitrosoureas within 42 days prior to treatment initiation
- •procarbazine within 21 days prior to treatment initiation
- •non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, within 7 days prior to treatment initiation
- •surgery within 14 days prior to treatment initiation
- •radiation therapy within 30 days prior to treatment initiation
- •bevacizumab for tumor treatment. Note: participants who received bevacizumab for symptom management, including but not limited to cerebral edema, or pseudo progression can be enrolled
- •Prolonged QTc >470ms as calculated by correction formula on screening electrocardiogram (ECG) (QTCf can be used; QTCb can be used for participants with sinus bradycardia)
- •Prior invasive malignancies within the past 3 years prior to study treatment initiation (with the exception of non-melanoma skin cancers, carcinoma in situ of the cervix, melanoma in situ, or any localized cancer for whom the systemic standard of care therapy is not required)
- •History of allergic reactions attributed to compounds of similar chemical composition to zotiraciclib, such as flavopiridol
- •Pregnancy (confirmed with beta-HCG serum or urine pregnancy test performed at screening)
- •Uncontrolled intercurrent illness or social situations that would limit compliance with study requirements
- •Uncontrolled primary diabetes mellitus
研究组 & 干预措施
3
One RP2D dose of zotiraciclib given on the day prior to brain tumor biopsy or resection, a continuation of treatment with estimated RP2D of zotiraciclib given in 28 days cycles following the recovery of the surgery
干预措施: Zotiraciclib (Drug)
1
Escalation/de-escalation dose levels of zotiraciclib given in 28 day cycles
干预措施: Zotiraciclib (Drug)
2
Estimated RP2D of zotiraciclib given in 28 day cycles
干预措施: Zotiraciclib (Drug)
结局指标
主要结局
To determine 12 months PFS in participants w/ recurrent glioma, IDH1/2-mutant, WHO grade 3 treated w/ zotiraciclib in comparison w/ the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors
时间窗: 12 Months
Proportion of patients that have progressive disease after 12 months
To estimate recommended phase II dose (RP2D) of zotiraciclib
时间窗: 28 days
Number of DLTs within the DLT Period
次要结局
- To determine the efficacy of treatment with zotiraciclib in participants with recurrent glioma, IDH1/2-mutant WHO grade 3 in comparison with the established brain tumor database by 5 years overall survival (OS) rate(5 years)
- To determine the efficacy of treatment with zotiraciclib in participants with recurrent glioma, IDH1/2-mutant WHO grade 3 in comparison with the established brain tumor database by 3 years PFS rate(3 years)
- To determine the safety of zotiraciclib in participants with recurrent glioma, IDH1/2-mutant WHO grades 2-4(Day 1 of Cycle 0 (Cohort 5) or Day 1 of Cycle 1 (Cohorts 1-4) through 30 days after the study agent was last administered will be collected on the days study drug is administered, and at the safety follow up visit.)