An Open-Label, Phase 1/2A Dose Escalation Study of Safety and Efficacy of NEO100 in Recurrent or Progressive Grade III or Grade IV Gliomas With IDH1 Mutation
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 49
- 试验地点
- 15
- 主要终点
- Phase 1 Primary Outcome: Number of Participants with Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
研究概览
简要总结
This multi-site, Phase 1/2a clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO100 (perillyl alcohol) for the treatment of patients with radiographically-confirmed progression of Grade IV glioma or recurrent primary or secondary Grade IV glioma. The study will have two phases, Phase 1 and Phase 2a. Phase 1 is a standard cohort dose escalation 3+3 design used to determine the maximum tolerated dose for Phase 2a. There will be up to 24 patients enrolled in Phase 1. There will be 25 patients enrolled in Phase 2a. For both phases of the study, NEO100 will be self-administered four times daily for a 28-day treatment cycles until disease progression, death or patient withdraw from study for any reason, whichever occurs first.
Version 10 of the protocol changed the inclusion criteria for Phase 2a to limit inclusion to those patients with progressive or recurrent primary or secondary Grade IV gliomas expressing IDH1 mutations. Prior to the protocol amendment, 4 patients were enrolled who were IDH1 wild-type. Therefore, an additional 28 patients will be recruited for a total of 32 patients enrolled into Phase 2a of this study to have 35 evaluable cases.
Version 12 of the protocol expanded the inclusion criteria for Phase 2a to include those patients with progressive or recurrent Grade III Astrocytoma expressing IDH1 mutations.
Review of the literature specific to these patients found the same expected time to progression and death. As a result, the number of patients to enroll remains 32 to have 35 evaluable cases.
详细描述
Malignant glioma, particularly glioblastoma multiforme (GBM, WHO grade IV astrocytic glioma) accounts for over half of all gliomas, which in turn account for 80% of all malignant brain and CNS tumors. In European and North American countries, the incidence rate is approximately four to five new cases per 100,000 people per year.
Most patients with glioblastoma are faced with a dismal prognosis. Advances in neurosurgery, radiation, and chemotherapy during the past decade have provided only small improvements in clinical outcome, with a 5-year survival rate remaining at less than 10%.The first-line treatment of GBM is usually surgery, both to confirm the diagnosis and to remove as much of the tumor as possible. Concurrent temozolomide with radiotherapy followed by adjuvant systemic temozolomide has produced a median survival of 14.6 to 16.6 months, and this regimen is now the standard of care for GBM, as well as grade III anaplastic glioma.
Regardless of the treatment regimen, the aggressive infiltration of glioblastoma throughout the brain typically produces progressive disability, ultimately leading to death in nearly all cases. Innovative treatment is urgently needed.
Molecular profiling is being used to separate patients with GBM into prognostic groups. A mutation affecting codon 132 of the isocitrate dehydrogenase 1 (IDH1) gene was found to occur in up to 12% of glioblastomas. A review of sequencing studies on large glioma patient cohorts have found IDH1 mutations present in 6% (range 3-16%).
IDH1 mutation is considered a definitive diagnostic molecular marker of glioblastomas and is considered more reliable and objective than clinical criteria. Long term outcome for patients with high-grade glioma including glioblastoma directly correlates to IDH1 mutation status. IDH1 mutated tumors have been associated with an improved outcome comparable to IDH1 wild-type tumors. IDH1 mutation has remained an independent favorable prognostic marker even after adjustment for age, grade, MGMT status, genomic profile and treatment in multivariate analysis. Median OS for glioblastoma patients following first recurrence is 9.8 months for IDH1 wildtype tumors versus 19.32 months for IDH1 mutated cancers. No increase in PFS was found.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- •To be eligible to participate in the study, a patient must meet all of the following inclusion criteria:
- •Patient must have radiographically-confirmed progression of, or recurrent, primary or secondary Grade IV glioma, including infratentorial (brainstem, cerebellar) glioma (confirmed by biopsy) and subcortical glioma.
- •Patient must have radiographically-confirmed progression of, recurrent, primary or secondary Grade III astrocytoma.
- •All patients must be on a stable or decreasing dose of steroids for at least five days prior to the date of informed consent.
- •Patient must have failed previous radiation treatment or combined treatment with temozolomide and radiation.
- •If progression of disease occurs within 90 days of conformal radiation, the progression/recurrence must be outside of the radiation field or proven by biopsy/resection.
- •Patient must be ≥ 18 years of age.
- •Patient must have an ECOG performance status of 0-2 or KPS ≥ 60 (the latter for Phase 1 only).
- •Patient must have an expected survival of at least three months.
- •Patient must have a baseline MRI with gadolinium within 14 days of first administration of study drug.
- •Patient must be willing to provide blood samples for pharmacokinetic study.
- •If patient suffers from seizures, (s)he must be controlled on a stable dose of anti- epileptics for 14 days prior to the date of informed consent.
- •Patient must have adequate organ and marrow function as defined below:
- •Absolute neutrophil count ≥ 1,500/mcL
- •Platelets ≥ 100,000/mcL
- •Total bilirubin within normal institutional limits
- •AST (SGOT)/ALT (SPGT)≤ 2.5 × institutional upper limit of normal
- •Creatinine within normal institutional limits
- •Female patients of child-bearing potential and male patients 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 therapy. Should a female patient become pregnant, or suspect she is pregnant, while participating in this study, she should inform her treating physician immediately.
- •A female of child-bearing potential is any woman (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 been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
- •A negative serum pregnancy test will be required of all female patients of child-bearing potential within seven days prior to initiating study drug.
- •A serum pregnancy test will be repeated immediately if pregnancy is suspected.
- •Patient must have the ability to understand, and the willingness to sign, a written informed consent.
- •In addition to meeting Inclusion Criteria for the Phase I portion of the study, patients eligible for participation in the Phase 2a portion of the study must additionally meet the following criteria:
- •Patients must have a confirmed IDH1 mutation by reverse transcription polymerase chain reaction (rtPCR) or immunohistochemistry (unless continuing into the Phase 2a portion of the study from the Phase I portion of the study).
排除标准
- •If the patient meets any of the following criteria, the patient must not be enrolled:
- •The size of the tumor is > 30mm (length x width), as assessed at the baseline (pre- study) MRI evaluation.
- •The tumor is multi-focal, as assessed at the baseline (pre-study) MRI evaluation.
- •Patient has completed chemo-radiation within the last 90 days prior to first administration of study drug, unless new contrast enhancement is outside of radiation field, or there is tissue proven recurrence or progression.
- •Patient has had surgery within seven days prior to the date of informed consent.
- •Patient has had any form of anti-cancer therapy or treatment within 28 days prior to first administration of study drug.
- •Patient has not recovered from adverse events due to chemotherapy, immunotherapy, or radiation therapy administered more than 28 days prior to first administration of study drug.
- •Patient has had prior treatment with bevacizumab, a chemotherapy wafer implant (Gliadel®), or any other FDA-approved anti-cancer therapy or treatment except temozolomide.
- •Patient has had more than one recurrence or progression of his/her tumors.
- •Patient has received any other investigational agents within 28 days prior to the first administration of study drug.
- •Patient has had prior treatment with perillyl alcohol, administered either intravenously or intranasally.
- •Patient has a history of allergic reactions attributed to perillyl alcohol.
- •Patient has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Patient must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
- •Patient has a history of new diagnosis or treatment of cancer other than malignant glioma within five years prior to the date of informed consent, except for basal cell carcinoma or squamous cell carcinoma of the skin.
- •Leptomeningeal involvement of the patient's tumor.
研究组 & 干预措施
NEO100 Phase 1
Intranasal delivery of NEO100 (perillyl alcohol) four times a day, escalation up to four different doses to determine maximum tolerated dose.
干预措施: Perillyl alcohol (Drug)
NEO100 Phase 2A
Intranasal delivery of NEO100 (perillyl alcohol) four times a day. Treatment of total of 25 patients at maximum tolerated dose.
干预措施: Perillyl alcohol (Drug)
结局指标
主要结局
Phase 1 Primary Outcome: Number of Participants with Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
时间窗: Up to 6 months
Phase 2 Primary Outcome: Number of Participants Who Are Alive Each Month For 6 Months
时间窗: Up to 6 months
Phase 2 Primary Outcome: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related To Treatment
时间窗: 6 months
次要结局
未报告次要终点