A Target Validation and Efficacy Study of Metformin in Patients With Recurrent or Progressive Posterior Fossa Group A (PFA) Ependymoma
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 20
- 主要终点
- Proportion of participants with changes in biomarkers between the pre-and post-metformin treated samples (Target Validation Phase)
研究概览
简要总结
This is a multi-site study of the pharmacodynamic effects and efficacy of metformin in children and young adults with recurrent or progressive Posterior Fossa Group A (PFA) ependymoma.
详细描述
PRIMARY OBJECTIVES:
I. To assess pharmacodynamic effect on PFA tumor cells of metformin in participants with recurrent or progressive PFA undergoing surgical resection of the tumor by determining change in H3K27me3 and/or EZHIP expression in tumor nuclei compared to pre-treatment levels (TV Phase)
II. To measure disease stabilization rate by Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria (complete (CR), partial (PR) response; ≥50% reduction in size but <CR), and Stable (SD); < 50% reduction in size but not meeting criteria for progressive disease) in participants with recurrent or progressive PFA ependymoma following metformin treatment (Efficacy Phase).
EXPLORATORY OBJECTIVES:
I. Estimate the 1-year progression-free survival and overall-survival of participants with recurrent or progressive PFA treated with single agent metformin (Efficacy Phase).
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
- 1 Year 至 39 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must have recurrent or progressive posterior fossa A (PFA) ependymoma following surgery AND radiation treatment (RT).
- •Participants must have a diagnosis of PFA ependymoma. Any number of previous recurrences are permissible provided the participant meets other enrollment criteria.
- •Participants must have adequate tumor tissue available from initial diagnosis or from pre- trial enrollment. Formalin-fixed paraffin-embedded (FFPE) material (1 full block) should be provided. If FFPE material is not available, 10 unstained slides with an accompanying hematoxylin and eosin (H&E) report should be provided.
- •Target Validation (TV) Phase:
- •o Participants are candidates to undergo elective surgery for removal of all or a portion of their recurrent/progressive tumor.
- •Efficacy Phase:
- •Participant must have measurable disease; this will be defined as lesions that can be accurately measured in two dimensions (longest diameter to be recorded) The size threshold is met if both in-plane diameters are ≥10 mm or both in-plane diameters are at least two times the MRI slice thickness, plus the interslice gap with a minimum size of no less than double the slice thickness on MRI.
- •Participants with an isolated local progression of the tumor following RT (or stereotactic radiosurgery, SRS) must be > 6 months from completion of RT to the lesion to rule out pseudo progression or must have tissue confirmation of progression prior to enrollment.
- •Previously irradiated lesions are considered non-measurable except in cases of documented progression of the lesion since the completion of radiation therapy as outlined above.
- •Prior Therapy: Participants must not be receiving metformin for other medical indications or previous exposure to metformin following their diagnosis of PFA ependymoma. However, participants treated on the TV phase, but did not continue onto maintenance therapy will be allowed to enroll on the efficacy phase with future recurrences or progression of their disease.
- •Age: 1 -39 years at the time of enrollment.
- •Performance Score: Karnofsky >= 50 for participants > 16 years of age and Lansky >=50 for participants <=16 years of age. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
- •Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.
- •Organ Function Requirements
- •Peripheral absolute neutrophil count (ANC) >= 1000/mm^
- •Platelet count >=100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
- •Serum creatinine < 1.5 Upper Limit normal (ULN) based on age and gender
- •Total bilirubin <= 1.5 x ULN for age; in presence of Gilbert's syndrome, total bilirubin < 3 x ULN or direct bilirubin < 1.5 x ULN
- •alanine aminotransferase (ALT) <= 3 x ULN.
- •aspartate aminotransferase (AST) <=3 x ULN.
- •Participants with seizure disorder may be enrolled if well controlled and are on stable dose of anti-seizure medication for > 72 hours prior to enrollment. Participants who have neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration.
- •Participants must enroll on PNOC COMP if PNOC COMP is open to accrual at the enrolling institution.
- •A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.
排除标准
- •Participants with a history of diabetes mellitus or those meeting criteria for pre-diabetes are excluded. Pre-diabetes is defined per American Diabetes Association criteria as any of the following: fasting plasma glucose (FPG) 100-125 mg/dL (5.6-6.9 mmol/L); 2-hour plasma glucose (OGTT) 140-199 mg/dL (7.8-11.0 mmol/L); or hemoglobin A1c (HbA1c) 5.7%-6.4% (39-47 mmol/mol).
- •Participants without any measurable disease.
- •Participants who have had chemotherapy or have received radiotherapy to the non-target lesion within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
- •Participants must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur. Such participants should also be discussed with study chairs.
- •Participants with rapidly progressive symptoms that require urgent surgery that in the investigators assessment cannot be safely deferred for 6 weeks are excluded from target validation phase of the study
- •Participants who are receiving any other investigational agents.
- •Concurrent radiation therapy in any form is not permitted while on the study drug
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection.
- •Women of childbearing potential must not be pregnant or breast-feeding.
- •Human immunodeficiency virus- (HIV) positive participants will be ineligible if HIV therapy regimen has not been stable for at least 4 weeks or there is intent to change the regimen within 8 weeks following enrollment, or if they are severely immunocompromised.
研究组 & 干预措施
Target Validation (TV) Phase (Metformin)
Participants will each receive daily oral metformin with a weekly schedule starting at 250 mg/m^2 twice a day (BID) for the first week, then increasing to 500 mg/m^2 BID for week 2, 1000 mg/m^2 BID for week 3, and then 1666 mg/m^2 BID for week 4-6 prior to planned surgery. Participants with no measurable disease following surgical intervention may either go off treatment or continue metformin at the physician's discretion. Participants have the option of continuing on the efficacy phase of the study without undergoing planned surgery no demonstrated progressive disease on pre-surgery MRI AND if the family opts to continue treatment with metformin without undergoing surgical resection of the tumor. Participants with measurable tumor by RAPNO criteria following surgery may continue onto efficacy phase and receive maintenance metformin until disease progression or till there are unacceptable adverse event(s).
干预措施: Magnetic Resonance Imaging (MRI) (Procedure)
Target Validation (TV) Phase (Metformin)
Participants will each receive daily oral metformin with a weekly schedule starting at 250 mg/m^2 twice a day (BID) for the first week, then increasing to 500 mg/m^2 BID for week 2, 1000 mg/m^2 BID for week 3, and then 1666 mg/m^2 BID for week 4-6 prior to planned surgery. Participants with no measurable disease following surgical intervention may either go off treatment or continue metformin at the physician's discretion. Participants have the option of continuing on the efficacy phase of the study without undergoing planned surgery no demonstrated progressive disease on pre-surgery MRI AND if the family opts to continue treatment with metformin without undergoing surgical resection of the tumor. Participants with measurable tumor by RAPNO criteria following surgery may continue onto efficacy phase and receive maintenance metformin until disease progression or till there are unacceptable adverse event(s).
干预措施: Specimen Collection (Procedure)
Target Validation (TV) Phase (Metformin)
Participants will each receive daily oral metformin with a weekly schedule starting at 250 mg/m^2 twice a day (BID) for the first week, then increasing to 500 mg/m^2 BID for week 2, 1000 mg/m^2 BID for week 3, and then 1666 mg/m^2 BID for week 4-6 prior to planned surgery. Participants with no measurable disease following surgical intervention may either go off treatment or continue metformin at the physician's discretion. Participants have the option of continuing on the efficacy phase of the study without undergoing planned surgery no demonstrated progressive disease on pre-surgery MRI AND if the family opts to continue treatment with metformin without undergoing surgical resection of the tumor. Participants with measurable tumor by RAPNO criteria following surgery may continue onto efficacy phase and receive maintenance metformin until disease progression or till there are unacceptable adverse event(s).
干预措施: Metformin (Drug)
Efficacy Phase (Metformin)
Participants with recurrent or progressive PFA ependymoma that have failed upfront surgery and radiation will receive daily oral metformin until disease progression or till there are unacceptable adverse event(s). Disease response will be assessed by MRI imaging using RAPNO criteria. Participants already enrolled on the TV phase may enroll in this phase if they have measurable disease post-surgery. Treatment may continue until disease progression or until there are unacceptable adverse event(s).
干预措施: Magnetic Resonance Imaging (MRI) (Procedure)
Efficacy Phase (Metformin)
Participants with recurrent or progressive PFA ependymoma that have failed upfront surgery and radiation will receive daily oral metformin until disease progression or till there are unacceptable adverse event(s). Disease response will be assessed by MRI imaging using RAPNO criteria. Participants already enrolled on the TV phase may enroll in this phase if they have measurable disease post-surgery. Treatment may continue until disease progression or until there are unacceptable adverse event(s).
干预措施: Metformin (Drug)
Efficacy Phase (Metformin)
Participants with recurrent or progressive PFA ependymoma that have failed upfront surgery and radiation will receive daily oral metformin until disease progression or till there are unacceptable adverse event(s). Disease response will be assessed by MRI imaging using RAPNO criteria. Participants already enrolled on the TV phase may enroll in this phase if they have measurable disease post-surgery. Treatment may continue until disease progression or until there are unacceptable adverse event(s).
干预措施: Planned Surgical Resection (Procedure)
Efficacy Phase (Metformin)
Participants with recurrent or progressive PFA ependymoma that have failed upfront surgery and radiation will receive daily oral metformin until disease progression or till there are unacceptable adverse event(s). Disease response will be assessed by MRI imaging using RAPNO criteria. Participants already enrolled on the TV phase may enroll in this phase if they have measurable disease post-surgery. Treatment may continue until disease progression or until there are unacceptable adverse event(s).
干预措施: Specimen Collection (Procedure)
Target Validation (TV) Phase (Metformin)
Participants will each receive daily oral metformin with a weekly schedule starting at 250 mg/m^2 twice a day (BID) for the first week, then increasing to 500 mg/m^2 BID for week 2, 1000 mg/m^2 BID for week 3, and then 1666 mg/m^2 BID for week 4-6 prior to planned surgery. Participants with no measurable disease following surgical intervention may either go off treatment or continue metformin at the physician's discretion. Participants have the option of continuing on the efficacy phase of the study without undergoing planned surgery no demonstrated progressive disease on pre-surgery MRI AND if the family opts to continue treatment with metformin without undergoing surgical resection of the tumor. Participants with measurable tumor by RAPNO criteria following surgery may continue onto efficacy phase and receive maintenance metformin until disease progression or till there are unacceptable adverse event(s).
干预措施: MR spectroscopy (MRS) (Procedure)
Efficacy Phase (Metformin)
Participants with recurrent or progressive PFA ependymoma that have failed upfront surgery and radiation will receive daily oral metformin until disease progression or till there are unacceptable adverse event(s). Disease response will be assessed by MRI imaging using RAPNO criteria. Participants already enrolled on the TV phase may enroll in this phase if they have measurable disease post-surgery. Treatment may continue until disease progression or until there are unacceptable adverse event(s).
干预措施: MR spectroscopy (MRS) (Procedure)
Target Validation (TV) Phase (Metformin)
Participants will each receive daily oral metformin with a weekly schedule starting at 250 mg/m^2 twice a day (BID) for the first week, then increasing to 500 mg/m^2 BID for week 2, 1000 mg/m^2 BID for week 3, and then 1666 mg/m^2 BID for week 4-6 prior to planned surgery. Participants with no measurable disease following surgical intervention may either go off treatment or continue metformin at the physician's discretion. Participants have the option of continuing on the efficacy phase of the study without undergoing planned surgery no demonstrated progressive disease on pre-surgery MRI AND if the family opts to continue treatment with metformin without undergoing surgical resection of the tumor. Participants with measurable tumor by RAPNO criteria following surgery may continue onto efficacy phase and receive maintenance metformin until disease progression or till there are unacceptable adverse event(s).
干预措施: Planned Surgical Resection (Procedure)
结局指标
主要结局
Proportion of participants with changes in biomarkers between the pre-and post-metformin treated samples (Target Validation Phase)
时间窗: From initiation of study treatment until surgical resection of tumor, approximated 6 weeks
Proportion of participants with a 10% reduction in Enhancer of Zeste Inhibitory Protein (EZHIP) and/or a 10% increase in the epigenetic modification to the DNA packaging protein histone H3, with tri-methylation of lysine 27 on histone H3 (H3K27me3) between the pre- and post-metformin treated samples by Immunohistochemistry (IHC).
Disease Stabilization Rate (Efficacy Phase)
时间窗: From initiation of study treatment until discontinuation of treatment, up to 2 years
The primary endpoint of the efficacy phase is the disease stabilization rate by RAPNO criteria (complete (CR), partial (PR); response \>50% reduction in size \< CR, and stable (SD) which is a \< 50% reduction in size and not meeting the definition for progressive disease) tumor responses), CR+PR+SD.
次要结局
未报告次要终点