Pediatric Precision Laboratory Advanced Neuroblastoma Therapy

Neuroblastoma Clinical Trial

— PEDS-PLAN  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02559778
• Other study ID #: NMTRC012
• Status: Recruiting
• Phase: Phase 2
• Start date: September 2015
• Est. completion date: September 2035

Study information

• Verified date: April 2024
• Source: Milton S. Hershey Medical Center
• Contact: Genevieve Bergendahl, MSN
• Phone: 7175310003
• Email: gbergendahl[@]pennstatehealth.psu.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: September 2035
• Est. primary completion date: September 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 22 Years

Eligibility

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

Related Conditions & MeSH terms

• Neuroblastoma

Intervention

Drug:
• Ceritinib
One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
• dasatinib
One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
• sorafenib
One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
• vorinostat
One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
• DFMO
DFMO will be given to Arm B during immunotherapy and then for 2 years as maintenance to all subjects completing immunotherapy.

Locations

Country	Name	City	State
Canada	UHC Sainte-Justine	Montréal	Quebec
United States	Augusta University Health	Augusta	Georgia
United States	Dell Children's Blood and Cancer Center	Austin	Texas
United States	University of Alabama, Children's of Alabama	Birmingham	Alabama
United States	St. Lukes	Boise	Idaho
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Levine Children's Hospital	Charlotte	North Carolina
United States	Advocate Children's Medical Group	Chicago	Illinois
United States	Children's Medical Center	Dallas	Texas
United States	Helen DeVos Children's Hospital	Grand Rapids	Michigan
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Hospital	Hartford	Connecticut
United States	Penn State Milton S. Hershey Medical Center and Children's Hospital	Hershey	Pennsylvania
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	University of Louisville	Louisville	Kentucky
United States	Nicklaus Children's Miami	Miami	Florida
United States	Children's Hospital and Clinics of Minnesota	Minneapolis	Minnesota
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	UCSF Benioff Children's Hospital Oakland-	Oakland	California
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Randall Children's Hospital	Portland	Oregon
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Rady Children's Hospital	San Diego	California
United States	St. Joseph's Children's Hospital	Tampa	Florida

Sponsors (5)

Lead Sponsor	Collaborator
Giselle Sholler	Beat NB Cancer Foundation, Dell, Inc., K C Pharmaceuticals Inc., Team Parker for Life

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of days from start of therapy to date of first relapse	To measure the response of treatments chosen based on: • Event free survival (EFS)	Up to 8 years
Primary	Number of subjects that have a targeted agent chosen for treatment.	At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as: Subject has a targeted agent identified; Receives 75% of dosing of medications while on study protocol during cycles 3-6; Subject is not removed from study due to targeted agent drug related toxicity.	2 years
Primary	Number of subjects that receive 75% of dosing of medications while on study protocol during cycles 3-6.	At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as: Subject has a targeted agent identified; Receives 75% of dosing of medications while on study protocol during cycles 3-6; Subject is not removed from study due to targeted agent drug related toxicity.	2 years
Secondary	Number of days that subjects remain alive	To measure the response of treatments chosen based on: Overall response rate (ORR) after induction therapy; Overall survival (OS)	3 years plus 5 years follow up
Secondary	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 measure the response of treatments chosen based on: • Overall response rate (ORR) after induction therapy	Up to 8 years
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	To compare toxicity effects of difluoromethylornithine (DFMO) in combination with Dinutuximab/GM-CSF/IL-2 and isotretinoin versus Dinutuximab/GM-CSF/IL-2 and isotretinoin alone.	3 years
Secondary	Amount of pain medicine required by Arm A versus Arm B	To compare level of pain medicine needed during immunotherapy in patients receiving difluoromethylornithine (DFMO) in combination with Dinutuximab/GM-CSF/IL-2 and Isotretinoin versus those receiving Dinutuximab/GM-CSF/IL-2 and isotretinoin alone.	3 years
Secondary	Number of subjects required to go off therapy due to treatment-related adverse events as assessed by CTCAE v4.0.	At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as: Subject has a targeted agent identified; Receives 75% of dosing of medications while on study protocol during cycles 3-6; Subject is not removed from study due to targeted agent drug related toxicity.	1 year

External Links

•   Beat Childhood Cancer Main Website