Molecular-Guided Therapy for Childhood Cancer

Molecular-guided Therapy for the Treatment of Patients With Relapsed and Refractory Childhood Cancers

The purpose of this study is to test the feasibility (ability to be done) of experimental technologies to determine a tumor's molecular makeup. This technology includes a genomic report based on DNA exomes and RNA sequencing that will be used to discover new ways to understand cancers and potentially predict the best treatments for patients with cancer in the future.

Study Overview

• Status: Completed
• Conditions: Glioma; Renal Cell Carcinoma; Osteosarcoma; Ependymoma; Medulloblastoma; Neuroblastoma; Meningioma; Craniopharyngioma; Choroid Plexus Neoplasms; Rhabdomyosarcoma; Wilms Tumor; Ewings Sarcoma; Malignant Rhabdoid Tumor; Liver Tumors; Germ Cell Tumors; Dysembryoplastic Neuroepithelial Tumor; Clear Cell Sarcoma; Non-rhabdomyosarcoma; Primitive Neuroectodermal Tumors (PNETs)
• Intervention / Treatment: Device: Guided Therapy

• Study Type: Interventional
• Enrollment (Actual): 186
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Lebanon
  • Beirut, Lebanon
    • American University of Beirut Medical Center
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Hospital
  • Florida
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hospital for Children
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Kapiolani Medical Center for Women and Children
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospital and Clinics on Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • The Children's Hospital at Montefiore
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Children's Hospital
  • Oregon
    • Portland, Oregon, United States
      • Randall Children's Hospital
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center and Children's Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Monroe Carrell Jr. Children's Hospital at Vanderbilt
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Blood and Cancer Center
    • Houston, Texas, United States, 77030
      • Texas Children's Cancer and Hematology Centers
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects must have proven pediatric cancer with confirmation at diagnosis or at the time of recurrence/progression and clinical determination of disease for which there is no known effective curative therapy or disease that is refractory to established proven therapies fitting into one of the following categories:

   • Neuroblastoma- Patients that have relapsed following standard of care therapy (such as high risk patients, patient presenting after age 15 months or MYCN amplified, and only following (for eligible patients) high-dose chemotherapy followed by hematopoietic stem cell transplantation and maintenance therapy with retinoic acid and antibody therapy) or having progressed during standard of care therapy and non-responsive/progressive to accepted curative chemotherapy.
   • Brain Tumors
   • Medulloblastomas (At relapse after standard of care therapy [surgery, chemotherapy and/or radiation] and/or non-responsive/progressive on accepted curative therapy)
   • Gliomas (At relapse after standard of care therapy [surgery and/or radiation and/or chemotherapy] and/or non-responsive/progressive on accepted curative therapy)
   • Ependymomas (At relapse after standard of care therapy [surgery with or without radiation] and/or non-responsive/progressive on accepted curative therapy)
   • Choroid plexus tumors (At relapse after standard of care therapy [surgery] and/or non-responsive/progressive on accepted curative therapy)
   • Craniopharyngiomas (At relapse after standard of care therapy [surgery or suppressive therapy] and/or non-responsive/progressive on accepted curative therapy)
   • Dysembryoplastic neuroepithelial tumors (DNETs) (At relapse after standard of care therapy [surgery] and/or non-responsive/progressive on accepted curative therapy)
   • Meningiomas (At relapse after standard of care therapy [surgery] and/or non-responsive/progressive on accepted curative therapy)
   • Primitive Neuroectodermal Tumors (PNETs) (At relapse after standard of care therapy [surgery, chemotherapy, and/or radiation] and/or non-responsive/progressive on accepted curative therapy)
   • Germ cell tumors (At relapse after standard of care therapy [surgery, and/or radiation and/or chemotherapy] and/or non-responsive/progressive on accepted curative therapy)
   • Rare Tumors:
   • Soft tissue sarcoma Rhabdomyosarcoma (At relapse after standard of care therapy [surgery, and/or radiation, chemotherapy] and/or non-responsive/progressive to accepted curative chemotherapy) Non-rhabdomyosarcoma (At relapse after standard of care therapy [surgery, and/or radiation, chemotherapy] and/or non-responsive/progressive to accepted curative chemotherapy)
   • Bone Ewings sarcoma (At relapse after standard of care therapy [surgery, and/or radiation, chemotherapy] and/or non- responsive/progressive to accepted curative chemotherapy) Osteosarcoma (At relapse after standard of care therapy [surgery, chemotherapy] and/or non- responsive/progressive to accepted curative chemotherapy)
   • Renal Wilms tumor (At relapse after standard of care therapy [surgery, and/or radiation, chemotherapy] and/or non- responsive/progressive to accepted chemotherapy) Renal cell carcinoma (At relapse after standard of care therapy [surgery, chemotherapy] and/or non- responsive/progressive to accepted curative chemotherapy) Malignant rhabdoid tumor (At diagnosis, as there is no known curative therapy) Clear Cell Sarcoma- (At relapse after standard of care therapy [radiation, chemotherapy] and/or non- responsive/progressive to accepted curative chemotherapy) Germ Cell tumors (At relapse after standard of care therapy [surgery, chemotherapy] and/or non-responsive/progressive to accepted curative chemotherapy)
   • Liver Tumors (At relapse after standard of care therapy [surgery, chemotherapy] and/or non- responsive/progressive to accepted curative chemotherapy)
2. Subjects must be age >12 months at enrollment
3. Subjects must be age ≤ 21 years at initial diagnosis
4. Subjects must have measurable disease as demonstrated by residual abnormal tissue at a primary or metastatic site (measurable on CT or MRI) at the time of biopsy; tumor must be accessible for biopsy. In addition, subjects with bone or bone marrow only disease expected to be >75% tumor are eligible to enroll.
5. Current disease state must be one for which there is currently no known effective therapy
6. Specimens will be obtained only in a non-significant risk manner and not solely for the purpose of investigational testing.
7. Lansky or Karnofsky Score must be ≥ 50
8. Subjects without bone marrow metastases must have an ANC > 750/μl to begin treatment.
9. Subjects with CNS disease must have been on a stable dose of steroids for 2 weeks prior to their biopsy and must not have progressive hydrocephalus at enrollment.

10. Adequate liver function must be demonstrated, defined as:

    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND
    • ALT (SGPT) < 10 x upper limit of normal (ULN) for age
11. A negative serum pregnancy test is required for female participants of child bearing potential (≥13 years of age or after onset of menses)
12. Both male and female post-pubertal study subjects need to agree to use one of the more effective birth control methods during treatment and for six months after treatment is stopped. These methods include total abstinence (no sex), oral contraceptives ("the pill"), an intrauterine device (IUD), levonorgestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive foam with a condom is recommended.
13. Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

1. Subjects who have received any cytotoxic chemotherapy within the last 7 days prior to biopsy
2. Subjects who have received any radiotherapy to the primary sample site within the last 14 days (radiation may be included in treatment decision after biopsy).
3. Subjects receiving any investigational drug concurrently.
4. Subjects with uncontrolled serious infections or a life-threatening illness (unrelated to tumor)
5. Subjects with any other medical condition, including malabsorption syndromes, mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the interpretation of the results or which would interfere with a subject's ability to sign or the legal guardian's ability to sign the informed consent, and subject's ability to cooperate and participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Guided Therapy; A total of 200 neuroblastoma, brain tumor, and rare tumor patients will be treated. Guided therapy will allow the use of any therapeutic combination (up to 4 agents) provided it includes medications contained in the study report. All patients will be followed for survival, disease response, progression and safety. All patients will be treated according to the discretion of the treating oncologist and study committee (minimum 3 oncologists and one pharmacist). Extent of disease will be measured and assessed for changes throughout the course of the study and at 6-8 week intervals (every 2 cycles).

Device: Guided Therapy; A total of 200 neuroblastoma, brain tumor, and rare tumor patients will be treated. Guided therapy will allow the use of any therapeutic combination (up to 4 agents) provided it includes medications contained in the study report. All patients will be followed for survival, disease response, progression and safety. All patients will be treated according to the discretion of the treating oncologist and study committee (minimum 3 oncologists and one pharmacist). Extent of disease will be measured and assessed for changes throughout the course of the study and at 6-8 week intervals (every 2 cycles).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days to Treatment Will be Used in Order to Determine Feasibility of Using Tumor Samples to Assess Genomic Sequencing Using Predictive Modeling to Make Real-time Treatment Decisions for Children With Relapsed/Refractory Cancers.	The definition of feasibility is: Enrollment onto study, genomic profile, analysis and report generation completed, tumor board held with treatment decision, treatment review completed, start of treatment, and completion of 1 cycle of therapy.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With an Unexpected Adverse Events as a Measure of Safety	To determine the safety of allowing a molecular tumor board to determine individualized treatment plans	Adverse Events were collected starting with the date of the first dose of study drug until 30 days after last dose of study drug, ongoing related adverse events were continued to be followed until resolution, on average of 4 years.
Overall Response Rate (ORR) of Participants by the Presence of Radiologically Assessable Disease by Cross-sectional CT or MRI Imaging and/or by MIBG or PET Scans.	To determine the activity of treatments chosen based on Overall response rate (ORR) using RESIST criteria. The assessment of response will include the initial measurable targets and will be performed after cycle 2, then after every other cycle. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI imaging and/or by MIBG or PET scans: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease, At least a 20% increase in the sum of the disease measurements for measurable lesions, Stable Disease, Neither sufficient decrease to qualify for PR or sufficient increase to qualify for PD from study entry. Overall Response (OR) = CR + PR.	Followed until off therapy, generally 4 years
Progression Free Survival (PFS) Interval Will be Measured by Days and Compared to the PFS of Previous Chemotherapy Regimens Since Relapse for Each Patient.	Time to progression (PFS), defined as the period from the start of the treatment until the criteria for progression are met taking as reference the screening measurements. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the disease measurements for measurable lesions, taking as reference the smallest disease measurement recorded since the start of treatment (nadir), and minimum 5 mm increase over the nadir or the appearance of one or more new lesions or appearance of positive bone marrow.	From date of start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years

Collaborators and Investigators

• Sponsor: Giselle Sholler
• Collaborators: Translational Genomics Research Institute; Dell, Inc.
• Investigators: Study Chair: Giselle Sholler, MD, Beat Childhood Cancer at Atrium Health

Publications and helpful links

Helpful Links

• Beat Childhood Cancer

Study record dates

Study Major Dates

• Study Start (Actual): July 8, 2014
• Primary Completion (Actual): January 18, 2024
• Study Completion (Actual): January 18, 2024

Study Registration Dates

• First Submitted: June 11, 2014
• First Submitted That Met QC Criteria: June 12, 2014
• First Posted (Estimated): June 13, 2014

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Neoplasms, Glandular and Epithelial; Genetic Diseases, Inborn; Musculoskeletal Diseases; Glioma; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Kidney Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Bone Diseases; Neoplastic Syndromes, Hereditary; Neoplasms, Complex and Mixed; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Vascular Tissue; Neoplasms, Muscle Tissue; Meningeal Neoplasms; Myosarcoma; Bone Neoplasms; Cerebral Ventricle Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Sarcoma; Sarcoma, Ewing; Ependymoma; Medulloblastoma; Rhabdoid Tumor; Osteosarcoma; Neuroblastoma; Meningioma; Rhabdomyosarcoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Wilms Tumor; Neuroectodermal Tumors, Primitive, Peripheral; Sarcoma, Clear Cell; Neoplasms, Neuroepithelial; Craniopharyngioma; Adamantinoma; Choroid Plexus Neoplasms
• Other Study ID Numbers: NMTRC009