Next Generation Personalized Neuroblastoma Therapy (The NEPENTHE Trial)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 66
- 试验地点
- 1
- 主要终点
- Incidence of dose limiting toxicities when combining ceritinib with ribociclib
研究概览
简要总结
The purpose of this research study is to match genomic aberrations in tumor cells at time of relapse to rationally designed combinations of molecularly targeted agents. This study will be done in two parts:
Part I: Tumor will be accessed at study entry via a biopsy and subjected to deep sequencing to identify protocol-specified biomarkers for therapy assignment.
Part II: If the tumor contains a genetic change defined by the study as being actionable, and other criteria are met, participants will be assigned to therapy based upon the genetic changes identified in the tumor biopsy.
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
- 1 Year 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged ≥1 years to ≤ 21 years
- •Relapsed or refractory neuroblastoma
- •A sufficient interval between the last dose of prior anti-cancer therapy (including cytotoxic and biological therapies) and enrollment in this study, to allow recovery from the acute toxic effects of all prior anti-cancer therapy. Please contact site for specific details
- •Adequate bone marrow function (bone marrow may be involved with tumor. Contact site for specific details)
- •Adequate renal function, defined as Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2 OR serum creatinine based on age/gender normal (contact site for details)
- •Adequate liver function, defined as total serum bilirubin ≤ 1.5 times the upper limit of normal AND alanine transaminase (ALT) ≤ 110 U/L.
- •Adequate cardiac function, defined as corrected QT interval (QTc) ≤ 480 msec AND shortening fraction > 27%
- •Males and females who are sexually active must agree to use effective contraception during and for 3 months after treatment
排除标准
- •Subjects taking certain drugs or herbal medications that impact drug metabolism and/or cardiac function that cannot be discontinued (contact site for details).
- •Subjects with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (contact site for details)
- •Other concomitant therapies:
- •Corticosteroids initiated for tumor therapy within 7 days prior to study enrollment
- •Other anti-cancer agents
- •Other investigational drugs
- •Hematological growth factors
- •Radiation therapy
- •Subjects < 0.5m2
- •Pregnant or lactating females
- •Sexually active males unless they use a condom during intercourse while taking study drug/s and for 3 months after study drug discontinuation and thus do not attempt to father a child in this period.
研究组 & 干预措施
Molecular Analysis
All participants with relapsed or refractory neuroblastoma will have a tumor biopsy to identify genetic mutations. There is no drug given in this arm of the trial.
干预措施: Biopsy (Procedure)
Molecular Analysis
All participants with relapsed or refractory neuroblastoma will have a tumor biopsy to identify genetic mutations. There is no drug given in this arm of the trial.
干预措施: Next Generation Sequencing (Genetic)
Molecular Analysis
All participants with relapsed or refractory neuroblastoma will have a tumor biopsy to identify genetic mutations. There is no drug given in this arm of the trial.
干预措施: Tumor Scans (Procedure)
Molecular Analysis
All participants with relapsed or refractory neuroblastoma will have a tumor biopsy to identify genetic mutations. There is no drug given in this arm of the trial.
干预措施: Physical Exam (Other)
Molecular Analysis
All participants with relapsed or refractory neuroblastoma will have a tumor biopsy to identify genetic mutations. There is no drug given in this arm of the trial.
干预措施: Labs (Other)
Molecular Analysis
All participants with relapsed or refractory neuroblastoma will have a tumor biopsy to identify genetic mutations. There is no drug given in this arm of the trial.
干预措施: Pregnancy Test (Other)
Molecular Analysis
All participants with relapsed or refractory neuroblastoma will have a tumor biopsy to identify genetic mutations. There is no drug given in this arm of the trial.
干预措施: Interviews (Behavioral)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Tumor Scans (Procedure)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Bone marrow Tests (Procedure)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Physical Exam (Other)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Eye Exam (Other)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Labs (Other)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Pregnancy Test (Other)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Interviews (Behavioral)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: ECG (Other)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Echocardiogram (Other)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Ribociclib (Drug)
Group 1: ALK
Qualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles.
Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level.
It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
干预措施: Ceritinib (Drug)
结局指标
主要结局
Incidence of dose limiting toxicities when combining ceritinib with ribociclib
时间窗: At the end of Cycle 1 (each cycle is 28 days)
The primary variable is the incidence of dose limiting toxicities (DLTs) during the first 28 days of therapy
Area under the curve from time zero to last quantifiable concentration
时间窗: At the end of Cycle 1 (each cycle is 28 days)
Area under the plasma concentration time-curve from zero to the last measured concentration
Percentage of patients with overall objective response
时间窗: 2 years
To describe whether the assigned targeted therapy can mediate anti-tumor effects in subjects with relapsed or refractory high-risk neuroblastoma within the context of a phase 1/phase1b biomarker-driven trial. Percentage of patients with objective response will be according to the International Neuroblastoma Response Criteria.
次要结局
- Cataloguing of genomic alterations identified from biopsies performed at time of relapse in patients with relapsed or refractory neuroblastoma(3 years)
研究者
Yael P Mosse
Principal Investigator
Children's Hospital of Philadelphia