Molecular-Guided Therapy for Relapsed and Refractory Childhood Cancer

Study Overview
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Brief Summary
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The purpose of this study is to test the feasibility (ability to be done) of experimental technologies to determine a tumor's molecular makeup (gene expression profile) and mutations. This technology called the Pediatric Gene Analysis Platform includes a genomic report (gene expression profile) and a DNA Mutation Panel Report that are being used to discover new ways to understand cancers and potentially predict the best treatments for patients with cancer in the future.

Official Title
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A Feasibility Trial Using Molecular-Guided Therapy for the Treatment of Patients With Relapsed and Refractory Childhood Cancer

Conditions
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Neuroblastoma, Medulloblastoma, Brain Tumors, Rare Tumors

Intervention / Treatment
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* Device: Guided Therapy- Pediatric Gene Analysis Platform


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have histologically proven neuroblastoma, brain tumor, or rare tumor and confirmation of refractory or recurrent disease with histologic confirmation at diagnosis or at the time of recurrence/progression Subjects must be age >12 months at enrollment. Subjects must be age ≤ 21 years at initial diagnosis. Subjects must have measurable disease as demonstrated by residual abnormal tissue at a primary or metastatic site measuring more than 1 cm in any dimension by standardized imaging (CT or MRI); tumor must be accessible for biopsy. Patients with bone marrow only disease expected to be >75% tumor are eligible to enroll. Current disease state must be one for which there is currently no known curative therapy Lansky or Karnofsky Score must be more than 50 Subjects without bone marrow metastases must have an ANC > 750/μl Adequate liver function must be demonstrated, defined as: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND SGPT (ALT) < 10 x upper limit of normal (ULN) for age A negative serum pregnancy test is required for female participants of child bearing potential (≥13 years of age or after onset of menses) 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. Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines. Voluntary consent for optional biology studies will be included. Exclusion Criteria: Subjects who have received any cytotoxic chemotherapy within the last 7 days prior to enrollment and 14 days prior to study treatment start date. 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). Subjects receiving anti-tumor therapy for their disease or any investigational drug concurrently Subjects with serious infection or a life-threatening illness (unrelated to tumor) that is > Grade 2 (NCI CTCAE V4.0), or active, serious infections requiring parenteral antibiotic therapy. 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

Ages Eligible for Study
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Minimum Age: 13 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Guided Therapy- Pediatric Gene Analysis Platform<br>A total of 48 neuroblastoma, brain tumor, and rare tumor patients who are refractory or relapsed on conventional therapy 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- Pediatric Gene Analysis Platform<br>* A total of 48 neuroblastoma, brain tumor, and rare tumor patients who are refractory or relapsed on conventional therapy 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).<br>* Other names: Molecular Guided Therapy;|

What is the study measuring?
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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 mRNA expression arrays and DNA Mutation Panels using predictive modeling | The definition of feasibility for this study will include: Enrollment onto study, RNA expression profile completed, DNA Mutation Panel completed, genomic analysis and report generation, tumor board held with treatment decision, treatment review completed and start of treatment by 21 days post biopsy/surgical resection date, and then completion of 1 cycle of therapy. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of Safety | To determine the safety of allowing a molecular tumor board to determine individualized treatment plans | 2 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. | 2 years | 
| Duration of response will be objectively documented | Duration of response, defined as the period of time from when measurement criteria are met for complete response (CR) or partial response (PR), whichever is first recorded, until the first date that recurrent or progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started) | 2 years | 
| Biology studies to include: genomic analysis of cells pre- and post- treatment, correlation of in vitro response to in vivo response, flow cytometry of tumor burden in bone marrow and biomarker development | To explore the relationship between tumor phenotype and response by permitting use of tumor tissue in a correlative biologic study | 2 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 | 2 years |