Clinical trial NCT02559778: Pediatric Precision Laboratory Advanced Neuroblastoma Therapy
Official title: A Study Using Molecular Guided Therapy With Induction Chemotherapy Followed by a Randomized Controlled Trial of Standard Immunotherapy With or Without DFMO Followed by DFMO Maintenance for Subjects With Newly Diagnosed High-Risk Neuroblastoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Neuroblastoma
Lead sponsor: Milton S. Hershey Medical Center
Sponsor class: OTHER
Collaborators: name: Dell, Inc.
name: Beat NB Cancer Foundation
name: K C Pharmaceuticals Inc.
name: Team Parker for Life
First posted: 2015-09-24
Enrollment: 500
Sex: ALL
Maximum age (years): 22
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A prospective open label, multicenter study to evaluate the feasibility and acute toxicity of using molecularly guided therapy in combination with standard therapy followed by a Randomized Controlled Trial of standard immunotherapy with or without DFMO followed by DFMO maintenance for Subjects with Newly Diagnosed High-Risk Neuroblastoma.


Eligibility criteria: Part A- CLOSED:

1. Diagnosis: Subjects must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites. Subjects with the following disease stages at diagnosis are eligible, if they meet the other specified criteria:

   a) Subjects with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following: i. Age \> 18 months (\> 547 days) regardless of biologic features or ii. Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index = 1) or iii. MYCN amplification (\> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.

   b) Subjects with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following: i. MYCN amplification (\> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or ii. Age \> 18 months (\> 547 days) with unfavorable pathology, regardless of MYCN status.

   c) Subjects with newly diagnosed neuroblastoma with INSS Stage 2A/2B with MYCN amplification (\> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.
2. Subjects must be age ≤ 21 years at initial diagnosis
3. Subjects must not have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology.
4. Specimens will be obtained only in a non-significant risk manner and not solely for the purpose of investigational testing.
5. Ability to tolerate PBSC collection: No known contraindication to PBSC collection. Examples of contraindications would include a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure.

   Part A and B both- Part A CLOSED, Part B- OPEN:
6. Adequate Cardiac Function Defined As:

   1. Shortening fraction of ≥ 27% by echocardiogram, or
   2. Ejection fraction of ≥ 50% by radionuclide evaluation or echocardiogram.
7. Adequate liver function must be demonstrated, defined as:

   c. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND d. ALT (SGPT) \< 10 x upper limit of normal (ULN) for age
8. Subjects must have adequate renal function defined as a serum creatinine based on age/gender as follows:

   Age Maximum Serum Creatinine (mg/dL) Male Female 1 month to \< 6 months 0.4 0.4 6 months to \< 1 year 0.5 0.5 1 to \< 2 years 0.6 0.6 2 to \< 6 year 0.8 0.8 6 to \< 10 years 1 1 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.4

   ≥ 16 years 1.7 1.4
9. A negative serum pregnancy test is required for female participants of child bearing potential (≥13 years of age or after onset of menses)
10. 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.
11. Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines.

    Part B- OPEN:
12. All patients must have a pathologically confirmed diagnosis of neuroblastoma, be age ≤ 21 years at initial diagnosis, and classified as high risk by the criteria used by COG or SIOPEN at the time of diagnosis. Exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible.
13. Previous Therapy- subjects must fit into one of the strata categories listed in section 10.5 to be eligible to enroll on Part B of this study.
14. Pre-enrollment tumor survey:

    Prior to enrollment on Part B, a determination of mandatory disease staging must be performed. Tumor imaging studies including CT or MRI, MIBG or PET, and VMA/HVA (PET scan should be done for patients with prior disease that was MIBG non-avid). Bone marrow aspirates and biopsies are required.

    This disease assessment is required for eligibility and should be done preferably within 2 weeks, but must be done within a maximum of 4 weeks before first dose of study drug.
15. Timing- Enrollment to occur prior to Day + 120 post-transplant, preferably when the subject is within 28 days after completing local radiation therapy (if given).

Exclusion Criteria (Part A and B)

1. Subjects who are 12-18 months of age with INSS Stage 4 and all stage 3 subjects with favorable biologic features (ie, nonamplified MYCN, favorable pathology, and DNA index \> 1) are not eligible.
2. Lactating females are not eligible unless they have agreed not to breastfeed their infants.
3. Subjects receiving any investigational drug concurrently.
4. Subjects with any other medical condition, including but not limited to 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

Primary outcomes:
measure: Number of days from start of therapy to date of first relapse
timeFrame: Up to 8 years
measure: Number of subjects that have a targeted agent chosen for treatment.
timeFrame: 2 years
measure: Number of subjects that receive 75% of dosing of medications while on study protocol during cycles 3-6.
timeFrame: 2 years
Secondary outcomes:
measure: Number of days that subjects remain alive
timeFrame: 3 years plus 5 years follow up
measure: 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.
timeFrame: Up to 8 years
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 3 years
measure: Amount of pain medicine required by Arm A versus Arm B
timeFrame: 3 years
measure: Number of subjects required to go off therapy due to treatment-related adverse events as assessed by CTCAE v4.0.
timeFrame: 1 year
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama, Children's of Alabama
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland-
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: Hartford
country: United States
facility: Connecticut Children's Hospital
state: Connecticut
city: Miami
country: United States
facility: Nicklaus Children's Miami
state: Florida
city: Orlando
country: United States
facility: Arnold Palmer Hospital for Children
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Children's Hospital
state: Florida
city: Augusta
country: United States
facility: Augusta University Health
state: Georgia
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Boise
country: United States
facility: St. Lukes
state: Idaho
city: Chicago
country: United States
facility: Advocate Children's Medical Group
state: Illinois
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospital and Clinics of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Medical Center
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Charlotte
country: United States
facility: Levine Children's Hospital
state: North Carolina
city: Portland
country: United States
facility: Randall Children's Hospital
state: Oregon
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center and Children's Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Austin
country: United States
facility: Dell Children's Blood and Cancer Center
state: Texas
city: Dallas
country: United States
facility: Children's Medical Center
state: Texas
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Montréal
country: Canada
facility: UHC Sainte-Justine
state: Quebec
Study officials:
affiliation: Beat Childhood Cancer
name: Giselle Sholler, MD
role: STUDY_CHAIR
References: