Next Generation Personalized Neuroblastoma Therapy

NCT02780128 | Terminated Phase 1 DMC

• 1 other identifier: 14-011071
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

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.

Conditions

Neuroblastoma; Cancer

Keywords

neuroblastoma; cancer; genetic profiling; ceritinib; ribociclib; NEPENTHE

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (1)

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

  3 years

Study Arms (2)

Molecular Analysis

OTHER

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; Genetic: Next Generation Sequencing; Procedure: Tumor Scans; Other: Physical Exam; Other: Labs; Other: Pregnancy Test; Behavioral: Interviews

Group 1: ALK

EXPERIMENTAL

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; 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

Interventions

Biopsy PROCEDURE

Needle or incisional tumor biopsy

Also known as: Genetic Sequencing

Molecular Analysis

Next Generation Sequencing GENETIC

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

Also known as: Molecular Profiling, Genetic Sequencing

Molecular Analysis

Tumor Scans PROCEDURE

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.

Group 1: ALK; Molecular Analysis

Bone marrow Tests PROCEDURE

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.

Also known as: Bone marrow aspiration

Group 1: ALK

Physical Exam OTHER

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.

Group 1: ALK; Molecular Analysis

Eye Exam OTHER

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.

Also known as: Ophthalmic Exam

Group 1: ALK

Labs OTHER

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.

Also known as: Blood tests

Group 1: ALK; Molecular Analysis

Pregnancy Test OTHER

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.

Group 1: ALK; Molecular Analysis

Interviews BEHAVIORAL

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.

Group 1: ALK; Molecular Analysis

ECG OTHER

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.

Also known as: EKG, Electrocardiogram

Group 1: ALK

Echocardiogram OTHER

The participant will have an Echocardiogram (ECHO), 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.

Also known as: ECHO

Group 1: ALK

Ribociclib DRUG

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

Also known as: LEE011

Group 1: ALK

Ceritinib DRUG

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

Also known as: LDK378

Group 1: ALK

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Yael P Mosse: lead
• Novartis Pharmaceuticals: collaborator
• Foundation Medicine: collaborator

Study Sites (1)

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (14)

• Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. doi: 10.1158/1078-0432.CCR-13-1675. Epub 2013 Sep 17.

  PMID: 24045179 BACKGROUND

• Bresler SC, Weiser DA, Huwe PJ, Park JH, Krytska K, Ryles H, Laudenslager M, Rappaport EF, Wood AC, McGrady PW, Hogarty MD, London WB, Radhakrishnan R, Lemmon MA, Mosse YP. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell. 2014 Nov 10;26(5):682-94. doi: 10.1016/j.ccell.2014.09.019. Epub 2014 Nov 10.

  PMID: 25517749 BACKGROUND

• Bresler SC, Wood AC, Haglund EA, Courtright J, Belcastro LT, Plegaria JS, Cole K, Toporovskaya Y, Zhao H, Carpenter EL, Christensen JG, Maris JM, Lemmon MA, Mosse YP. Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med. 2011 Nov 9;3(108):108ra114. doi: 10.1126/scitranslmed.3002950.

  PMID: 22072639 BACKGROUND

• Carr-Wilkinson J, O'Toole K, Wood KM, Challen CC, Baker AG, Board JR, Evans L, Cole M, Cheung NK, Boos J, Kohler G, Leuschner I, Pearson AD, Lunec J, Tweddle DA. High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed Neuroblastoma. Clin Cancer Res. 2010 Feb 15;16(4):1108-18. doi: 10.1158/1078-0432.CCR-09-1865. Epub 2010 Feb 9.

  PMID: 20145180 BACKGROUND

• Geoerger B, Bourdeaut F, DuBois SG, Fischer M, Geller JI, Gottardo NG, Marabelle A, Pearson ADJ, Modak S, Cash T, Robinson GW, Motta M, Matano A, Bhansali SG, Dobson JR, Parasuraman S, Chi SN. A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors. Clin Cancer Res. 2017 May 15;23(10):2433-2441. doi: 10.1158/1078-0432.CCR-16-2898. Epub 2017 Apr 21.

  PMID: 28432176 BACKGROUND

• Hart LS, Rader J, Raman P, Batra V, Russell MR, Tsang M, Gagliardi M, Chen L, Martinez D, Li Y, Wood A, Kim S, Parasuraman S, Delach S, Cole KA, Krupa S, Boehm M, Peters M, Caponigro G, Maris JM. Preclinical Therapeutic Synergy of MEK1/2 and CDK4/6 Inhibition in Neuroblastoma. Clin Cancer Res. 2017 Apr 1;23(7):1785-1796. doi: 10.1158/1078-0432.CCR-16-1131. Epub 2016 Oct 11.

  PMID: 27729458 BACKGROUND

• Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008 Oct 16;455(7215):930-5. doi: 10.1038/nature07261. Epub 2008 Aug 24.

  PMID: 18724359 BACKGROUND

• Mosse YP, Lim MS, Voss SD, Wilner K, Ruffner K, Laliberte J, Rolland D, Balis FM, Maris JM, Weigel BJ, Ingle AM, Ahern C, Adamson PC, Blaney SM. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol. 2013 May;14(6):472-80. doi: 10.1016/S1470-2045(13)70095-0. Epub 2013 Apr 16.

  PMID: 23598171 BACKGROUND

• Mosse YP, Voss SD, Lim MS, Rolland D, Minard CG, Fox E, Adamson P, Wilner K, Blaney SM, Weigel BJ. Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children's Oncology Group Study. J Clin Oncol. 2017 Oct 1;35(28):3215-3221. doi: 10.1200/JCO.2017.73.4830. Epub 2017 Aug 8.

  PMID: 28787259 BACKGROUND

• Padovan-Merhar OM, Raman P, Ostrovnaya I, Kalletla K, Rubnitz KR, Sanford EM, Ali SM, Miller VA, Mosse YP, Granger MP, Weiss B, Maris JM, Modak S. Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome. PLoS Genet. 2016 Dec 20;12(12):e1006501. doi: 10.1371/journal.pgen.1006501. eCollection 2016 Dec.

  PMID: 27997549 BACKGROUND

• Rihani A, Vandesompele J, Speleman F, Van Maerken T. Inhibition of CDK4/6 as a novel therapeutic option for neuroblastoma. Cancer Cell Int. 2015 Jul 30;15:76. doi: 10.1186/s12935-015-0224-y. eCollection 2015.

  PMID: 26225123 BACKGROUND

• Van Maerken T, Rihani A, Dreidax D, De Clercq S, Yigit N, Marine JC, Westermann F, De Paepe A, Vandesompele J, Speleman F. Functional analysis of the p53 pathway in neuroblastoma cells using the small-molecule MDM2 antagonist nutlin-3. Mol Cancer Ther. 2011 Jun;10(6):983-93. doi: 10.1158/1535-7163.MCT-10-1090. Epub 2011 Apr 1.

  PMID: 21460101 BACKGROUND

• Van Maerken T, Vandesompele J, Rihani A, De Paepe A, Speleman F. Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis. Cell Death Differ. 2009 Dec;16(12):1563-72. doi: 10.1038/cdd.2009.138. Epub 2009 Sep 25.

  PMID: 19779493 BACKGROUND

• Wood AC, Krytska K, Ryles HT, Infarinato NR, Sano R, Hansel TD, Hart LS, King FJ, Smith TR, Ainscow E, Grandinetti KB, Tuntland T, Kim S, Caponigro G, He YQ, Krupa S, Li N, Harris JL, Mosse YP. Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma. Clin Cancer Res. 2017 Jun 1;23(11):2856-2868. doi: 10.1158/1078-0432.CCR-16-1114. Epub 2016 Dec 16.

  PMID: 27986745 BACKGROUND

MeSH Terms

Conditions

Neuroblastoma; Neoplasms

Interventions

Biopsy; High-Throughput Nucleotide Sequencing; Restraint, Physical; Hematologic Tests; Pregnancy Tests; Interviews as Topic; ribociclib; ceritinib

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Sequence Analysis; Genetic Techniques; Behavior Control; Therapeutics; Immobilization; Diagnostic Techniques, Obstetrical and Gynecological; Data Collection; Epidemiologic Methods; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 11, 2016
• First Posted: May 23, 2016
• Study Start: July 1, 2016
• Primary Completion: August 1, 2022
• Study Completion: August 1, 2022
• Last Updated: March 10, 2026

Record last verified: 2026-03

Locations

US (1)