Phase I/II Trial of PLX038 in Primary Central Nervous System Tumors With and Without MYC or MYCN Amplifications
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 146
- 试验地点
- 1
- 主要终点
- Phase I: To confirm the RP2D of PLX038 in participants with progressive or recurrent primary CNS tumors
研究概览
简要总结
Background:
About 90,000 new cases of brain and spinal cord tumors are diagnosed annually in the United States. Most of these tumors are benign; however, about 30% are malignant, and 35% of people with malignant tumors in the brain and spinal cord will die within 5 years. Many of these people have changes in certain genes (MYC or MYCN) that drive the development of their cancers.
Objective:
To test a study drug (PLX038) in people with tumors of the brain or spinal cord.
Eligibility:
People aged 18 years or older with a tumor of the brain or spinal cord. Some participants must also have tumors with changes in the MYC or MYCN genes.
Design:
Participants will be screened. They will have a physical exam and blood tests. They will have imaging scans and a test of their heart function. They may need to have a biopsy: A sample of tissue will be removed from their tumor.
PLX038 is given through a tube attached to a needle inserted into a vein in the arm. All participants will receive PLX038 on the first day of each 21-day treatment cycle. They will take a second drug 3 days later to help reduce the risk of infection; for this drug, participants will be shown how to inject themselves under the skin at home.
Blood tests, imaging scans, and other tests will be repeated during study visits. Hair samples will also be collected during these visits. Some participants may have an additional biopsy.
Study treatment will continue up to 7 months.
Follow-up visits will continue every few months for up to 5 years.
详细描述
Background:
- The MYC genes encode a family of transcription factors (MYC-C, MYC-N, and MYC-L) that regulate the expression of a wide range of genes involved in cell division in development and adulthood.
- Supraphysiologic levels of MYC are oncogenic and drive aggressive behavior across a range of human malignancies. Amplifications of MYC and MYCN are seen in multiple types of primary central nervous system (CNS) tumors, including high-grade gliomas, medulloblastomas, and ependymomas.
- These CNS tumors are rare and there are limited prospective data to inform treatment choices and few efficacious options. At present, they are typically treated with maximal safe surgical resection followed by external beam radiation therapy, with the variable inclusion of cytotoxic chemotherapy regimens as first-line treatment and/or at recurrence. These "standard" options have shown limited to no antitumor activity, leading to an extremely poor prognosis.
- MYC-driven increase in transcription induces the formation of topoisome complexes (MYC-C/N, Topoisomerase 1 (TOP1), Topoisomerase 2 (TOP2), DNA) that are essential to managing the torsional strain that would otherwise oppose transcription and replication.
- PLX038 is a PEGylated macromolecule that contains 4 molecules of SN-38, the active metabolite of irinotecan, that is currently being investigated in non-CNS solid tumor trials. SN38 binds to and inhibits topoisomerase 1 and the unique formulation of PLX038 lead to a longer half-life, which is thought to increase tumor accumulation and potentially decrease toxicity.
Objectives:
-
Phase I: To confirm the recommended Phase II dose (RP2D) of PLX038 in participants with progressive or recurrent primary CNS tumors.
-
Phase II: To assess the efficacy of PLX038 at RP2D in primary CNS tumors based on MYC or MYCN amplifications as measured by:
-
Progression-free survival (PFS) for Cohort Phase IIA (adjuvant treatment), and
-
Disease control rate (DCR), defined as confirmed complete response (CR) / partial response (PR) or durable stable disease (SD) (NOTE: Durable SD is SD lasting for at least 6 months) for Cohorts Phase IIB and Phase IIC (treatment for recurrence with a MYC or MYCN amplification).
-
Progression free Survival at 6 months (PFS6) for Cohort phase IID (recurrent glioblastoma without a MYC or MYCN amplification)
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Participants must have documented pathologic diagnosis of confirmed primary central nervous system (CNS) tumor with one of the below diagnoses:
- •Cohort Phase I: Any recurrent or progressive primary CNS tumor, regardless of molecular features.
- •Cohort Phase IIA: Newly diagnosed MYCN amplified ependymoma after surgery and radiation.
- •Cohort Phase IIB:
- •Recurrent or progressive MYCN amplified ependymoma, OR
- •Recurrent or progressive medulloblastoma with MYC or MYCN amplifications
- •Cohort Phase IIC: Any other recurrent or progressive primary CNS tumor with MYC or MYCN amplifications.
- •Cohort Phase IID: Any recurrent glioblastoma without MYC or MYCN amplifications.
- •NOTE 1: Recurrence or progression may involve CNS, extra CNS, or both.
- •NOTE 2: The presence of MYCN or MYC amplification must be confirmed by documented history. Participants who do not have documented history will be tested by NSR device (via next-generation sequencing panel TruSight(TM) Oncology 500) and the threshold of MYCN or MYC amplification for eligibility purposes is a fold change (FC) of >=2.5X (5 copies) with a minimum tumor content of 20%.
- •Participants must have archival tumor tissue (either a block or 15 formalin-fixed paraffin-embedded (FFPE) unstained slides) available for NCI LP review of MYC or MYCN amplification status (if necessary) and for correlative studies:
- •Cohorts Phase I, Phase IIB, Phase IIC, and Phase IID: tumor tissue obtained at any point before trial treatment initiation, but preferably from most recent surgical resection before study treatment initiation.
- •Cohort Phase IIA: tumor tissue obtained at original diagnosis.
- •Participants in Cohort Phase IIA must have completed surgery followed by radiation at least 4 weeks and no more than 10 weeks from the last dose of radiation prior to study treatment initiation.
- •Participants in Cohorts Phase I, Phase IIB, Phase IIC, and Phase IID must have completed prior cytotoxic chemotherapy or radiation at least 4 weeks prior to study treatment initiation (at least 6 weeks if the last regimen included lomustine (CCNU) or carmustine (BCNU); at least 3 weeks if the last regimen included bevacizumab; at least 4 weeks if the last regimen included a checkpoint inhibitor or any other type of immunotherapy or cellular therapy; at least 5 half-lives if the last regimen included any investigational agent(s).
- •Age >= 18 years.
- •Karnofsky >= 70%. NOTE: Participants with severe paraparesis/paraplegia who need minimal assistance for self-care due to their motor deficit but are otherwise functionally independent will be eligible.
- •Participants must have adequate organ and marrow function as defined below:
- •leukocytes >=3,000/microliter
- •absolute neutrophil count >1,500/microliter
- •platelets >100,000/microliter
- •hemoglobin >= 9 g/ dL (may be transfused within 2 weeks prior to treatment to achieve this level)
- •total bilirubin within normal institutional limits
- •aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <2.5 X institutional upper limit of normal (ULN)
- •creatinine within normal institutional limits OR
- •estimated glomerular filtrate rate (eGFR) using chronic kidney disease epidemiology collaboration) (CKD-EPI) equation:>= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
- •Women of child-bearing potential (WOCBP) and those who can father children must agree to use effective contraception (barrier, hormonal contraception, intrauterine device (IUD), surgical sterilization, barrier at the study entry, for the duration of study treatment and up to 6 months (WOCBP) and 3 months (those who can father children) after the last dose of study treatment.
- •Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 6 months after the last dose of the study drug.
- •Ability to self-report symptoms and physical function as determined by assessment of the clinical team performed at screening.
- •Participants must be able to understand and willing to sign a written informed consent document.
排除标准
- •History of allergic reactions to compounds of similar chemical composition to PLX
- •Major surgery within 2 weeks prior to study treatment initiation. NOTE: The surgery is considered major if a mesenchymal barrier is opened (pleural cavity, peritoneum, meninges).
- •Participants who require treatment with strong inhibitors or inducers of CYP3A or with UGT1A1 inhibitors during the planned period of investigational treatment with PLX
- •Lists including medications and substances known or with the potential to interact with CYP3A or UGT1A1 are provided in https://drug-interactions.medicine.iu.edu/maintable.
- •History of treatment with pegylated topoisomerase inhibitors.
- •Has unresolved or persistent grade 2 or higher GI toxicity from any type of RT at screening
- •Participants with history of homozygous for the UGT1A1*28 variant allele with severely reduced UGT1A1 activity.
- •Participants positive for Human immunodeficiency virus (HIV), Hepatitis C virus (HCV), and Hepatitis B virus (HBV).
- •Pregnancy (confirmed with beta human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in females of childbearing potential at screening).
- •Participants unable to have MRIs.
- •Prior or concurrent malignancy unless its natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen (https://deainfo.nci.nih.gov/advisory/ctac/1117/4-JournalClinicalOncology.pdf, https://ctep.cancer.gov/protocolDevelopment/docs/CTEP_Broadened_Eligibility_Criteria_Guidance.pdf)
- •Uncontrolled intercurrent illness evaluated by history, weight, and physical exam that would limit compliance with study requirements.
研究组 & 干预措施
Phase II
RP2D of PLX038
干预措施: PLX038 (Drug)
Phase I
Escalating and de-escalating doses of PLX038
干预措施: PLX038 (Drug)
结局指标
主要结局
Phase I: To confirm the RP2D of PLX038 in participants with progressive or recurrent primary CNS tumors
时间窗: Days 1-42 (cycles 1-2)
Number of Dose Limiting Toxicities (DLT).
Phase II: To assess the efficacy of PLX038 at RP2D in primary CNS tumors containing MYC or MYCN amplifications
时间窗: 5 years
Adjuvant cohort: Defined as the time from the PLX038 treatment start date to the date of confirmed progression/death or last follow-up. Kaplan-Meier method will be used to estimate the survival function. The median PFS as well as the 95% CI will be summarized.Recurrent cohorts: Defined as the percentage of participants having CR, PR, or SD \>= 6 months as determined by investigator per RANO and/or RECIST v1.1. The DCR and its 95% exact binomial CI will be summarized.
次要结局
- Determine overall survival (OS)(5 years)
- Determine progression free survival (PFS)(5 years)
- Determine the treatment-related toxicities(Days 1-60)
- Longitudinally evaluate patient reported outcomes (PRO)(5 years)