Next Generation Personalized Neuroblastoma Therapy

Study Overview
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Brief Summary
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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.

Official Title
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Next Generation Personalized Neuroblastoma Therapy (The NEPENTHE Trial)

Conditions
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Neuroblastoma, Cancer

Intervention / Treatment
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* Procedure: Biopsy
* Genetic: Next Generation Sequencing
* Procedure: Tumor Scans
* Procedure: Bone marrow Tests
* Other: Physical Exam
* Other: Eye Exam
* Other: Labs
* Other: Pregnancy Test
* Behavioral: Interviews
* Other: ECG
* Other: Echocardiogram
* Drug: Ribociclib
* Drug: Ceritinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Molecular Analysis<br>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. | Procedure: Biopsy<br>* Needle or incisional tumor biopsy<br>* Other names: Genetic Sequencing;Genetic: Next Generation Sequencing<br>* Tumor tissue will be sent to Foundation Medicine laboratory for molecular profiling.<br>* Other names: Genetic Sequencing;Procedure: Tumor Scans<br>* Participants will undergo different types of scans to look at your tumor. These scans include CT (computerized tomography), MIBG (meta-iodobenzylguanidine) PET (positron emission tomography), and MRI (magnetic resonance imaging). Participants may have more than one type of scan.<br>Other: Physical Exam<br>* The exam includes taking participant weight, height, blood pressure, heart rate and respiratory rate and performing a examination of the participants body. The investigators may also check the participants vision with an eye chart.<br>Other: Labs<br>* Standard blood tests will be done to measure different types of blood cells, to measure the amount of certain substances, and tests to check how well liver and kidneys are working. When possible, the investigators will take blood from the participants central line. If this is not possible, the investigators will take blood from a vein in the participants arm. First, the investigators will put some cream on the skin so that drawing blood will not be painful. Then the investigators will put a thin needle into the vein to draw the blood.<br>* Other names: Blood tests;Other: Pregnancy Test<br>* If the participant is 11 years old or older or has already started having periods, the participant will be asked to take a pregnancy test before starting this study. The results will be shared with the participant but not with the participants' parent(s). We strongly encourage the participant to share the results with the parents. If the participant is found to be pregnant, the participant will not be able to continue participation in the study. About 1 teaspoon of blood (or urine if a urine test) will be needed.<br>Behavioral: Interviews<br>* A team member will take the participant's medical history, along with a listing of any medications that are being taken. Throughout the study, participants will be asked to report if they think that anything bad has happened as a result of the study.<br>|
| Experimental: Group 1: ALK<br>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. | Procedure: Tumor Scans<br>* Participants will undergo different types of scans to look at your tumor. These scans include CT (computerized tomography), MIBG (meta-iodobenzylguanidine) PET (positron emission tomography), and MRI (magnetic resonance imaging). Participants may have more than one type of scan.<br>Procedure: Bone marrow Tests<br>* Participants will have needles inserted through their hip bone to remove fluid from inside the bone marrow. This test determines if participants have tumor in the bone marrow.<br>* Other names: Bone marrow aspiration;Other: Physical Exam<br>* The exam includes taking participant weight, height, blood pressure, heart rate and respiratory rate and performing a examination of the participants body. The investigators may also check the participants vision with an eye chart.<br>Other: Eye Exam<br>* Participants will have their eyes will be evaluated using different instruments. Participants will also be asked to read an eye chart. The exams will take about 15 minutes.<br>* Other names: Ophthalmic Exam;Other: Labs<br>* Standard blood tests will be done to measure different types of blood cells, to measure the amount of certain substances, and tests to check how well liver and kidneys are working. When possible, the investigators will take blood from the participants central line. If this is not possible, the investigators will take blood from a vein in the participants arm. First, the investigators will put some cream on the skin so that drawing blood will not be painful. Then the investigators will put a thin needle into the vein to draw the blood.<br>* Other names: Blood tests;Other: Pregnancy Test<br>* If the participant is 11 years old or older or has already started having periods, the participant will be asked to take a pregnancy test before starting this study. The results will be shared with the participant but not with the participants' parent(s). We strongly encourage the participant to share the results with the parents. If the participant is found to be pregnant, the participant will not be able to continue participation in the study. About 1 teaspoon of blood (or urine if a urine test) will be needed.<br>Behavioral: Interviews<br>* A team member will take the participant's medical history, along with a listing of any medications that are being taken. Throughout the study, participants will be asked to report if they think that anything bad has happened as a result of the study.<br>Other: ECG<br>* This is a test of electrical activity of the heart. The investigators will put electrodes (sticky pads attached to wires) on the participant's chest, arms and legs. The electrocardiogram (ECG) will not be uncomfortable, but the participant will have to lie still. It does not hurt and takes about 15 minutes.<br>* Other names: Electrocardiogram;Other: Echocardiogram<br>* The participant will have an ultrasound of the heart taken to assess heart function. The investigators will put some gel on the skin and use a machine to take pictures of the heart.<br>* Other names: ECHO;Drug: Ribociclib<br>* Participants will take ribociclib once per day orally for Days 1-21 of a 28-day cycle.<br>* Other names: LEE011;Drug: Ceritinib<br>* Participants will take ceritinib once per day orally for 28 days of a 28-day cycle.<br>* Other names: LDK378;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities when combining ceritinib with ribociclib | The primary variable is the incidence of dose limiting toxicities (DLTs) during the first 28 days of therapy | At the end of Cycle 1 (each cycle is 28 days) | 
| Area under the curve from time zero to last quantifiable concentration | Area under the plasma concentration time-curve from zero to the last measured concentration | At the end of Cycle 1 (each cycle is 28 days) | 
| Percentage of patients with overall objective response | 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. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cataloguing of genomic alterations identified from biopsies performed at time of relapse in patients with relapsed or refractory neuroblastoma | Neuroblastomas undergo substantial mutational evolution during therapy, and relapsed disease is more likely to be driven by a targetable oncogenic pathway. Genomic alterations measured by next-generation sequencing at time of disease progression will be characterized and reported in a descriptive manner. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neuroblastoma, cancer, genetic profiling, ceritinib, ribociclib, NEPENTHE