Next Generation Personalized Neuroblastoma Therapy (NEPENTHE)

November 27, 2023 updated by: Yael P Mosse

Next Generation Personalized Neuroblastoma Therapy (The NEPENTHE Trial)

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

66

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • The Children's Hospital of Philadelphia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Procedure: Biopsy
Needle or incisional tumor biopsy
Other Names:
  • Genetic Sequencing
Genetic: Next Generation Sequencing
Tumor tissue will be sent to Foundation Medicine laboratory for molecular profiling.
Other Names:
  • Genetic Sequencing
  • Molecular Profiling
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 Names:
  • 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.
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 Names:
  • 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.
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 Names:
  • Bone marrow aspiration
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 Names:
  • Ophthalmic Exam
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 Names:
  • ECHO
Drug: Ribociclib
Participants will take ribociclib once per day orally for Days 1-21 of a 28-day cycle.
Other Names:
  • LEE011
Drug: Ceritinib
Participants will take ceritinib once per day orally for 28 days of a 28-day cycle.
Other Names:
  • LDK378

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of dose limiting toxicities when combining ceritinib with ribociclib
Time Frame: 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
At the end of Cycle 1 (each cycle is 28 days)
Area under the curve from time zero to last quantifiable concentration
Time Frame: 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
At the end of Cycle 1 (each cycle is 28 days)
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.
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
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.
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yael P Mosse

Collaborators

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 and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2016

Primary Completion (Actual)

August 1, 2022

Study Completion (Actual)

August 1, 2022

Study Registration Dates

First Submitted

May 11, 2016

First Submitted That Met QC Criteria

May 19, 2016

First Posted (Estimated)

May 23, 2016

Study Record Updates

Last Update Posted (Actual)

November 29, 2023

Last Update Submitted That Met QC Criteria

November 27, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 14-011071

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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