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Next Generation Personalized Neuroblastoma Therapy (NEPENTHE)

Primary Purpose

Neuroblastoma, Cancer

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Biopsy

Next Generation Sequencing

Tumor Scans

Bone marrow Tests

Physical Exam

Eye Exam

Labs

Pregnancy Test

Interviews

ECG

Echocardiogram

Ribociclib

Ceritinib

About this trial

This is an interventional treatment trial for Neuroblastoma focused on measuring neuroblastoma, cancer, genetic profiling, ceritinib, ribociclib, NEPENTHE

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

The Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Experimental

Arm Label

Molecular Analysis

Group 1: ALK

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

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

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.

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT02780128

First Posted

May 11, 2016

Last Updated

January 31, 2023

Sponsor

Yael P Mosse

Collaborators

Novartis Pharmaceuticals, Foundation Medicine

1. Study Identification

Unique Protocol Identification Number

NCT02780128

Brief Title

Next Generation Personalized Neuroblastoma Therapy

Acronym

NEPENTHE

Official Title

Next Generation Personalized Neuroblastoma Therapy (The NEPENTHE Trial)

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Terminated

Why Stopped

The goals of Part 1 (molecular screening) were met, but lack of therapies to match molecular aberrations made Part 2 (treatment) no longer feasible.

Study Start Date

July 2016 (Actual)

Primary Completion Date

August 2022 (Actual)

Study Completion Date

August 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Yael P Mosse

Collaborators

Novartis Pharmaceuticals, Foundation Medicine

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neuroblastoma, Cancer

Keywords

neuroblastoma, cancer, genetic profiling, ceritinib, ribociclib, NEPENTHE

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

66 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Molecular Analysis

Arm Type

Other

Arm Description

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.

Arm Title

Group 1: ALK

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

Biopsy

Other Intervention Name(s)

Genetic Sequencing

Intervention Description

Needle or incisional tumor biopsy

Intervention Type

Genetic

Intervention Name(s)

Next Generation Sequencing

Other Intervention Name(s)

Molecular Profiling, Genetic Sequencing

Intervention Description

Tumor tissue will be sent to Foundation Medicine laboratory for molecular profiling.

Intervention Type

Procedure

Intervention Name(s)

Tumor Scans

Intervention Description

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.

Intervention Type

Procedure

Intervention Name(s)

Bone marrow Tests

Other Intervention Name(s)

Bone marrow aspiration

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Physical Exam

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Eye Exam

Other Intervention Name(s)

Ophthalmic Exam

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Labs

Other Intervention Name(s)

Blood tests

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Pregnancy Test

Intervention Description

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.

Intervention Type

Behavioral

Intervention Name(s)

Interviews

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

ECG

Other Intervention Name(s)

EKG, Electrocardiogram

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Echocardiogram

Other Intervention Name(s)

ECHO

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Ribociclib

Other Intervention Name(s)

LEE011

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Ceritinib

Other Intervention Name(s)

LDK378

Intervention Description

Participants will take ceritinib once per day orally for 28 days of a 28-day cycle.

Primary Outcome Measure Information:

Title

Incidence of dose limiting toxicities when combining ceritinib with ribociclib

Description

The primary variable is the incidence of dose limiting toxicities (DLTs) during the first 28 days of therapy

Time Frame

At the end of Cycle 1 (each cycle is 28 days)

Title

Area under the curve from time zero to last quantifiable concentration

Description

Area under the plasma concentration time-curve from zero to the last measured concentration

Time Frame

At the end of Cycle 1 (each cycle is 28 days)

Title

Percentage of patients with overall objective response

Description

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Cataloguing of genomic alterations identified from biopsies performed at time of relapse in patients with relapsed or refractory neuroblastoma

Description

Time Frame

3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yael P Mossé, MD

Organizational Affiliation

Children's Hospital of Philadelphia, The University of Pennsylvania

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

John M Maris, MD

Organizational Affiliation

Children's Hospital of Philadelphia, The University of Pennsylvania

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

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24045179

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Next Generation Personalized Neuroblastoma Therapy

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