Preventative Trial of Difluoromethylornithine (DFMO) in High Risk Patients With Neuroblastoma That is in Remission

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02395666
• Collaborator: Beat NB Cancer Foundation (Other), Because of Ezra (Other), K C Pharmaceuticals Inc. (Industry)
• Enrollment: 140
• Locations: 21
• Arm: 1
• Duration (Months): 96
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this research study is to evaluate a new investigational drug to prevent reoccurrence of neuroblastoma that is in remission. This study drug is called DFMO. The objectives of this study will be to monitor for safety and look at efficacy of DFMO.

The safety of the proposed dosing regimen in this trial will be tested by an on-going risk/benefit assessment during the study. A patient benefiting from treatment, not progressing on therapy, and in the absence of any safety issues associated with DFMO may continue on treatment up to 27 cycles with the expectation that there will be an overall clinical benefit.

The procedures involved in this study include Medical history, Physical exam, Vital signs (blood pressure, pulse, temperature), Blood tests, Urine tests, MRI or CT scan of the tumor(s), meta-iodobenzylguanidine (MIBG) scans, and Bone marrow aspirations. All of these tests and procedures are considered standard of care for this population. Drug administration is also part of this protocol, including an investigational new drug called DFMO.

The proposed dosing regimen is an oral dose of DFMO tablets two times a day for each day while on study. There will be 27 cycles. Each cycle will be 28 days in length.

Condition or Disease	Intervention/Treatment	Phase
Neuroblastoma	Drug: DFMO	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase II Preventative Trial of DFMO (Eflornithine HCl) as a Single Agent in Patients With High Risk Neuroblastoma in Remission
• Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Mar 1, 2018
• Anticipated Study Completion Date: Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DFMO twice daily Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.	Drug: DFMO; Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.; Other Names: eflornithine HCl Difluoromethylornithine

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Event Free Survival (EFS) During Study. [2 Years]

   To evaluate the preventative activity of DFMO as a single agent in patients that are in remission based on: Event free survival (EFS)

Secondary Outcome Measures

1. Percentage of Participants With Overall Survival (OS) [2 Years]

   To evaluate the preventative activity of DFMO as a single agent in patients with neuroblastoma who are in remission based on: Overall Survival (OS)

2. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [2 years]

   To continue to determine the safety and tolerability of DFMO as a single agent and in pediatric and young adult patients with high risk neuroblastoma that is in remission.

3. Test the Association of Survival With ODC1 Genotype [2 years]

   Tests (p-value) of the association of survival with ODC1 single nucleotide polymorphism rs2302616 genotype. Blood: microRNA analysis as predictor of DFMO effect, ornithine decarboxylase (ODC) single nucleotide polymorphism (SNP) analysis in DNA isolated from nucleated cells

4. Circulating Tumor Cell Analysis [5 years]

   circulating tumor cell analysis

5. Peak Plasma Concentration (Cmax) [Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days]

   Pharmacokinetic assay Cmax/D Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days.

6. Area Under the Plasma Concentration Versus Time Curve (AUC) [0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose on two different days]

   Pharmacokinetic assay AUC(0-6 hr)/D Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days

7. Time to Reach Peak Plasma Concentration (Tmax) [0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose on two different days]

   Pharmacokinetic assay- tmax, hr Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age: 0-21 years at the time of diagnosis.

• Diagnosis: histologic verification at either the time of original diagnosis or a previous relapse of high risk neuroblastoma.

• Disease Status: Neuroblastoma that is in remission

• First dose of study medication must be greater than 30 days from completion of cytotoxic and antibody therapy and less than 120 days from previous therapy

• A negative serum or urine pregnancy test is required for female subjects of child bearing potential (onset of menses or ≥13 years of age).

• 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), levonorgestrel implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive foam with a condom is recommended.

• Absolute Neutrophil Count (ANC) > 500/μl and platelet count >50,000/μl

• Organ Function Requirements: Subjects must have adequate liver function as defined by:

• Aspartate Aminotransferase (AST) and Alanine transaminase (ALT) <10x upper limit of normal

• Serum bilirubin must be ≤ 2.0 mg/dl

• Serum creatinine based on age/gender

• 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:

• Lansky score < 60%

• Body Surface Area (BSA) (m2) of <0.25

• Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.

• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the effects of prior chemotherapy (hematological and bone marrow suppression effects).

• Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.

• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
2	Rady Children's Hospital	San Diego	California	United States	92123
3	Connecticut Children's Hospital	Hartford	Connecticut	United States	06106
4	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
5	All Children's Hospital Johns Hopkins Medicine	Saint Petersburg	Florida	United States	33701
6	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96813
7	Tufts Medical Center	Boston	Massachusetts	United States	02111
8	Helen DeVos Children's Hospital	Grand Rapids	Michigan	United States	49503
9	Children's Hospital and Clinics on Minnesota	Minneapolis	Minnesota	United States	55404
10	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
11	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
12	The Children's Hospital at Montefiore	Bronx	New York	United States	10467
13	Levine Children's Hospital	Charlotte	North Carolina	United States	28204
14	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
15	Penn State Milton S. Hershey Medical Center and Children's Hospital	Hershey	Pennsylvania	United States	17033
16	Medical University of South Carolina	Charleston	South Carolina	United States	29425
17	Monroe Carrell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee	United States	37232
18	Dell Children's Blood and Cancer Center	Austin	Texas	United States	78723
19	Children's Medical Center	Dallas	Texas	United States	75235
20	Texas Children's Cancer and Hematology Centers	Houston	Texas	United States	77030
21	Primary Children's Hospital	Salt Lake City	Utah	United States	84113

Sponsors and Collaborators

• Wake Forest University Health Sciences
• Beat NB Cancer Foundation
• Because of Ezra
• K C Pharmaceuticals Inc.

Investigators

• Study Chair: Giselle Saulnier-Sholler, MD, Beat Childhood Cancer at Atrium Health

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 18, 2020

More Information

Additional Information:

• Beat Childhood Cancer Consortium website

Publications

None provided.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT02395666
• Other Study ID Numbers: NMTRC003B; NCT01586260
• First Posted: Mar 23, 2015
• Last Update Posted: Apr 22, 2022
• Last Verified: Dec 1, 2021

• Keywords provided by Wake Forest University Health Sciences: Neuroblastoma in remission; Relapsed Neuroblastoma; Refractory Neuroblastoma
• Additional relevant MeSH terms: Neuroblastoma; Eflornithine

Study Results

Participant Flow

Arm/Group Title	Stratum 1	Stratum 2
Arm/Group Description	Subjects that are in remission at the end of upfront therapy defined as chemotherapy (5-7 cycles), surgery as indicated, consolidation therapy as indicated, radiation therapy as indicated, anti-GD2 antibody therapy with retinoic acid up to 6 cycles. Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.	Subjects that are in remission after any previous relapse or refractory therapy. Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.
Period Title: Overall Study
STARTED	101	39
COMPLETED	95	38
NOT COMPLETED	6	1

Baseline Characteristics

Arm/Group Title	Stratum 1	Stratum 2	Total
Arm/Group Description	Subjects that are in remission at the end of upfront therapy defined as chemotherapy (5-7 cycles), surgery as indicated, consolidation therapy as indicated, radiation therapy as indicated, anti-GD2 antibody therapy with retinoic acid up to 6 cycles. Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.	Subjects that are in remission after any previous relapse or refractory therapy. Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.	Total of all reporting groups
Overall Participants	101	39	140
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	4.4	6.8	5.1
Sex: Female, Male (Count of Participants)
Female	44 43.6%	11 28.2%	55 39.3%
Male	57 56.4%	28 71.8%	85 60.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 2%	1 2.6%	3 2.1%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	7 6.9%	3 7.7%	10 7.1%
White	82 81.2%	32 82.1%	114 81.4%
More than one race	3 3%	0 0%	3 2.1%
Unknown or Not Reported	7 6.9%	3 7.7%	10 7.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Event Free Survival (EFS) During Study.
Description	To evaluate the preventative activity of DFMO as a single agent in patients that are in remission based on: Event free survival (EFS)
Time Frame	2 Years

Outcome Measure Data

Analysis Population Description

One subject removed from Stratum 1 due to not fitting study criteria upon review

Arm/Group Title	Stratum 1	Stratum 2
Arm/Group Description	Subjects that are in remission at the end of upfront therapy defined as chemotherapy (5-7 cycles), surgery as indicated, consolidation therapy as indicated, radiation therapy as indicated, anti-GD2 antibody therapy with retinoic acid up to 6 cycles. Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.	Subjects that are in remission after any previous relapse or refractory therapy. Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.
Measure Participants	100	39
Mean (95% Confidence Interval) [percentage of subjects without an event]	84	51

2. Secondary Outcome

Title	Percentage of Participants With Overall Survival (OS)
Description	To evaluate the preventative activity of DFMO as a single agent in patients with neuroblastoma who are in remission based on: Overall Survival (OS)
Time Frame	2 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stratum 1	Stratum 2
Arm/Group Description	Subjects that are in remission at the end of upfront therapy defined as chemotherapy (5-7 cycles), surgery as indicated, consolidation therapy as indicated, radiation therapy as indicated, anti-GD2 antibody therapy with retinoic acid up to 6 cycles. Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.	Subjects that are in remission after any previous relapse or refractory therapy. Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.
Measure Participants	100	39
Mean (95% Confidence Interval) [percentage of subjects without an event]	97	84

3. Secondary Outcome

Title	Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Description	To continue to determine the safety and tolerability of DFMO as a single agent and in pediatric and young adult patients with high risk neuroblastoma that is in remission.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Stratum 1 and 2 were analyzed together as one safety group as per statistical analysis plan.

Arm/Group Title	DFMO Twice Daily
Arm/Group Description	Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle. DFMO: Subjects will receive twenty-seven (27) cycles of oral DFMO at a dose of 500 to 1000 mg/m2 BID on each day of a 28 day cycle.
Measure Participants	140
Count of Participants [Participants]	57 56.4%

4. Secondary Outcome

Title	Test the Association of Survival With ODC1 Genotype
Description	Tests (p-value) of the association of survival with ODC1 single nucleotide polymorphism rs2302616 genotype. Blood: microRNA analysis as predictor of DFMO effect, ornithine decarboxylase (ODC) single nucleotide polymorphism (SNP) analysis in DNA isolated from nucleated cells
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Stratum 1 and 2 were analyzed together as one group as per statistical analysis plan.

Arm/Group Title	GG, GT, TT	GG or GT, TT	GG, GT or TT
Arm/Group Description	Tests of the association of survival with ODC1 single nucleotide polymorphism rs2302616 genotype.	Tests of the association of survival with ODC1 single nucleotide polymorphism rs2302616 genotype.	Tests of the association of survival with ODC1 single nucleotide polymorphism rs2302616 genotype.
Measure Participants	140	140	140
Number [p-value]	0.96	0.58	0.67

5. Secondary Outcome

Title	Circulating Tumor Cell Analysis
Description	circulating tumor cell analysis
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Peak Plasma Concentration (Cmax)
Description	Pharmacokinetic assay Cmax/D Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days.
Time Frame	Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days

Outcome Measure Data

Analysis Population Description

12 subjects from both Stratum 1 and 2 were analyzed together as one group as per statistical analysis plan.

Arm/Group Title	Study Subjects Consented to PK Collection
Arm/Group Description	Includes study subjects from either stratum that signed an optional consent to have PK's collected
Measure Participants	12
Mean (90% Confidence Interval) [ng/mL]	11958

7. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve (AUC)
Description	Pharmacokinetic assay AUC(0-6 hr)/D Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days
Time Frame	0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose on two different days

Outcome Measure Data

Analysis Population Description

12 subjects from both Stratum 1 and 2 were analyzed together as one group as per statistical analysis plan.

Arm/Group Title	Study Subjects Consented to PK Collection
Arm/Group Description	Includes study subjects from either stratum that signed an optional consent to have PK's collected
Measure Participants	12
Mean (90% Confidence Interval) [hr*ng/mL]	47024

8. Secondary Outcome

Title	Time to Reach Peak Plasma Concentration (Tmax)
Description	Pharmacokinetic assay- tmax, hr Samples drawn at 5 timepoints: (0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose) on two different days
Time Frame	0 (pre dose), 30min, 1 hour, 3 hours, and 6 hours post-dose on two different days

Outcome Measure Data

Analysis Population Description

12 subjects from both Stratum 1 and 2 were analyzed together as one group as per statistical analysis plan.

Arm/Group Title	Study Subjects Consented to PK Collection
Arm/Group Description	Includes study subjects from either stratum that signed an optional consent to have PK's collected
Measure Participants	12
Mean (90% Confidence Interval) [hours]	3.3

Adverse Events

Time Frame	Through study completion plus 30 days, an average of 2 years.
Adverse Event Reporting Description	All subjects that received at least one dose of DFMO. Since both arms received the same exact treatment, they were combined into one reporting group.
Arm/Group Title	All Study Subjects
Arm/Group Description	All subjects that received at least one dose of DFMO. Since both arms received the same exact treatment, they were combined into one reporting group.
All Cause Mortality
	All Study Subjects
	Affected / at Risk (%)	# Events
Total	0/140 (0%)
Serious Adverse Events
	All Study Subjects
	Affected / at Risk (%)	# Events
Total	23/140 (16.4%)
Cardiac disorders
Hypotension	1/140 (0.7%)	1
Ear and labyrinth disorders
hearing loss	1/140 (0.7%)	1
Eye disorders
Swelling of Eye	1/140 (0.7%)	1
Gastrointestinal disorders
Vomiting	3/140 (2.1%)	3
Diarrhea	3/140 (2.1%)	3
Constipation	1/140 (0.7%)	1
Obstruction	1/140 (0.7%)	1
General disorders
Pain	1/140 (0.7%)	1
Fever	1/140 (0.7%)	1
Infections and infestations
Infection	8/140 (5.7%)	8
Influenza	1/140 (0.7%)	1
Bacteremia	1/140 (0.7%)	1
Investigations
Hyponatremia	1/140 (0.7%)	1
Metabolism and nutrition disorders
Hypoglycemia	1/140 (0.7%)	1
Musculoskeletal and connective tissue disorders
Fracture	1/140 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory Disorder	1/140 (0.7%)	1
Skin and subcutaneous tissue disorders
Urticaria	1/140 (0.7%)	1
Vascular disorders
Benign vascular lesion	1/140 (0.7%)	1
Other (Not Including Serious) Adverse Events
	All Study Subjects
	Affected / at Risk (%)	# Events
Total	41/140 (29.3%)
Blood and lymphatic system disorders
Neutrophil count decrease	11/140 (7.9%)	11
Anemia	6/140 (4.3%)	6
Ear and labyrinth disorders
Hearing Loss	9/140 (6.4%)	9
Gastrointestinal disorders
Diarrhea	9/140 (6.4%)	9
Hepatobiliary disorders
ALT elevation	14/140 (10%)	14
AST elevation	10/140 (7.1%)	10
Infections and infestations
Otitis Media	6/140 (4.3%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.