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Next Generation Personalized Neuroblastoma Therapy (NEPENTHE)

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ClinicalTrials.gov Identifier: NCT02780128
Recruitment Status : Recruiting
First Posted : May 23, 2016
Last Update Posted : July 19, 2018
Sponsor:
Collaborators:
Novartis Pharmaceuticals
Foundation Medicine
Information provided by (Responsible Party):
Yael P Mosse, Children's Hospital of Philadelphia

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Neuroblastoma Cancer Procedure: Biopsy Drug: Ceritinib Drug: Trametinib Drug: HDM201 Genetic: Next Generation Sequencing Procedure: Tumor Scans Radiation: X-ray Procedure: Bone marrow Tests Other: Physical Exam Other: Eye Exam Other: Labs Other: Pregnancy Test Behavioral: Interviews Other: ECG Other: Echocardiogram Drug: Ribociclib Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 105 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Next Generation Personalized Neuroblastoma Therapy (The NEPENTHE Trial)
Study Start Date : July 2016
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : May 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arm Intervention/treatment
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.
Procedure: Biopsy
Needle or incisional tumor biopsy
Other Name: Genetic Sequencing

Genetic: Next Generation Sequencing
Tumor tissue will be sent to Foundation Medicine laboratory for molecular profiling.
Other Names:
  • Molecular Profiling
  • Genetic Sequencing

Procedure: Tumor Scans
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.

Other: Physical Exam
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.

Other: Labs
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.
Other Name: Blood tests

Other: Pregnancy Test
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.

Behavioral: Interviews
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.

Experimental: 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.

Drug: Ceritinib
Participants will take ceritinib once per day orally for 28 days of a 28-day cycle.
Other Name: LDK378

Procedure: Tumor Scans
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.

Procedure: Bone marrow Tests
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.
Other Name: Bone marrow aspiration

Other: Physical Exam
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.

Other: Labs
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.
Other Name: Blood tests

Other: Pregnancy Test
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.

Behavioral: Interviews
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.

Other: ECG
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.
Other Names:
  • EKG
  • electrocardiogram

Other: Echocardiogram
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.
Other Name: echo

Drug: Ribociclib

Group 1: Participants will take ribociclib once per day orally for Days 1-21 of a 28-day cycle.

Group 2B: Participants will take ribociclib once per day orally for Days 8-21 of a 21-day cycle.

Other Name: LEE011

Experimental: Group 2B: RAS-MAPK or CDK4/6

Qualified participants whose tumors show certain mutations in the rat sarcoma - mitogen activated protein kinase (RAS-MAPK) or CDK4/6 pathway (based on genetic sequencing results) will receive a combination therapy of trametinib and ribociclib, to be administered orally in 21-day cycles.

Two different doses of trametinib 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.

Drug: Trametinib
Participants will take trametinib once per day orally for Days 1-14 of a 21-day cycle.
Other Name: MEKINIST

Procedure: Tumor Scans
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.

Radiation: X-ray
Participants will have x-rays of the wrist and leg.

Procedure: Bone marrow Tests
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.
Other Name: Bone marrow aspiration

Other: Physical Exam
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.

Other: Eye Exam
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.
Other Name: Ophthalmic Exam

Other: Labs
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.
Other Name: Blood tests

Other: Pregnancy Test
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.

Behavioral: Interviews
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.

Other: ECG
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.
Other Names:
  • EKG
  • electrocardiogram

Other: Echocardiogram
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.
Other Name: echo

Drug: Ribociclib

Group 1: Participants will take ribociclib once per day orally for Days 1-21 of a 28-day cycle.

Group 2B: Participants will take ribociclib once per day orally for Days 8-21 of a 21-day cycle.

Other Name: LEE011

Experimental: Group 3: p53

Qualified participants that do not match Groups 1 or 2, and whose tumors show wild-type p53 (based on genetic sequencing results) will receive HDM201 as a single agent, to be administered orally on Day 1 and Day 8 in 28-day cycles.

The investigators will perform a dose-escalation of HDM201. Once the investigators have identified the highest safe dose of HDM201, additional participants will be enrolled in the study at this dose level.

Drug: HDM201
Participants will take HDM201 orally on Day 1 and Day 8 of a 28-day cycle.

Procedure: Tumor Scans
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.

Procedure: Bone marrow Tests
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.
Other Name: Bone marrow aspiration

Other: Physical Exam
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.

Other: Labs
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.
Other Name: Blood tests

Other: Pregnancy Test
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.

Behavioral: Interviews
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.

Other: ECG
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.
Other Names:
  • EKG
  • electrocardiogram

Other: Echocardiogram
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.
Other Name: echo




Primary Outcome Measures :
  1. Incidence of dose limiting toxicities when combining ceritinib combined with ribociclib [ Time Frame: 28-day cycle one of therapy ]
    The primary variable is the incidence of dose limiting toxicities (DLTs) during the first 28 days of therapy.

  2. Incidence of dose limiting toxicities when combining trametinib with ribociclib [ Time Frame: 21-day cycle one of therapy ]
    The primary variable is the incidence of dose limiting toxicities (DLTs) during the first 21 days of therapy.

  3. Incidence of dose limiting toxicities of HDM201 [ Time Frame: 28-day cycle one of therapy ]
    The primary variable is the incidence of dose-limiting toxicities (DLTs) during the first 28 days of therapy. Estimation of the maximum tolerated dose (MTD) of HDM201 will be based upon the estimation of the probability of DLT during the first 21 days of therapy for patients in the dose-escalation portion.

  4. Area under the curve from time zero to last quantifiable concentration [ Time Frame: Pre-dose, 1, 2, 4, 6, and 24 hours post first dose of cycle 1; pre-dose on day 8 of cycle 1 ]
    Area under the plasma concentration time-curve from zero to the last measured concentration

  5. Volume of distribution at steady state [ Time Frame: pre-dose, 1, 2, 4, 6, and 24 hours on day 15 of cycle 1 ]
    The theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug

  6. Percentage of patients with overall objective response [ Time Frame: 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.


Secondary Outcome Measures :
  1. Cataloguing of genomic alterations identified from biopsies performed at time of relapse in patients with relapsed or refractory neuroblastoma [ Time Frame: 3 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02780128


Contacts
Contact: Alana Fitzsimmons, BS 2674252131 fitzsimmoa@email.chop.edu

Locations
United States, Pennsylvania
The Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Alana Fitzsimmons, BS    267-425-2131    fitzsimmoa@email.chop.edu   
Principal Investigator: Yael P Mossé, MD         
Sub-Investigator: John M Maris, MD         
Sub-Investigator: Rochelle Bagatell, MD         
Sponsors and Collaborators
Yael P Mosse
Novartis Pharmaceuticals
Foundation Medicine
Investigators
Principal Investigator: Yael P Mossé, MD Children's Hospital of Philadelphia, The University of Pennsylvania
Principal Investigator: John M Maris, MD Children's Hospital of Philadelphia, The University of Pennsylvania

Publications:

Responsible Party: Yael P Mosse, Principal Investigator, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT02780128     History of Changes
Other Study ID Numbers: 14-011071
First Posted: May 23, 2016    Key Record Dates
Last Update Posted: July 19, 2018
Last Verified: July 2018

Keywords provided by Yael P Mosse, Children's Hospital of Philadelphia:
neuroblastoma
cancer
genetic profiling
ceritinib
ribociclib
trametinib
HDM201

Additional relevant MeSH terms:
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Trametinib
Ceritinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action