Safety Study for Refractory or Relapsed Neuroblastoma With DFMO Alone and in Combination With Etoposide

• ClinicalTrials.gov Identifier: NCT01059071
• Recruitment Status: Completed
• First Posted: January 29, 2010
• Results First Posted: June 20, 2016
• Last Update Posted: April 22, 2022
• Sponsor: Wake Forest University Health Sciences
• Collaborators: Cancer Prevention Pharmaceuticals, Inc.; University of Arizona; University of Hawaii
• Information provided by (Responsible Party): Wake Forest University Health Sciences

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neuroblastoma
• Interventions: Drug: DFMO; Drug: Etoposide
• Enrollment: 21

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Dose Level 1: 500 mg/m2 PO BID	Dose Level 2: 750 mg/m2 PO BID	Dose Level 3:1000 mg/m2 PO BID	Dose Level 4:1500 mg/m2 PO BID
Arm/Group Description	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 1: 500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 2: 750 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 3:1000 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 4:1500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.
Period Title: Overall Study
Started	4	5	3	9
Completed	2	1	1	3
Not Completed	2	4	2	6
Reason Not Completed
Lack of Efficacy	1	4	2	3
Withdrawal by Subject	1	0	0	2
Physician Decision	0	0	0	1

Baseline Characteristics

Arm/Group Title		DFMO and Etoposide
Arm/Group Description		DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 1: 500 mg/m2 PO BID Dose level 2: 750 mg/m2 PO BID Dose level 3:1000 mg/m2 PO BID Dose level 4:1500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.
Overall Number of Baseline Participants		21
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Full Range); Unit of measure: Years
	Number Analyzed	21 participants
		8.75; (1 to 17)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	21 participants
	Female	7 33.3%
	Male	14 66.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	21 participants
	Hispanic or Latino	3 14.3%
	Not Hispanic or Latino	16 76.2%
	Unknown or Not Reported	2 9.5%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	21 participants
	American Indian or Alaska Native	0 0.0%
	Asian	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	2 9.5%
	White	17 81.0%
	More than one race	0 0.0%
	Unknown or Not Reported	2 9.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Description	To determine the safety, tolerability and maximum tolerated dose (MTD) of DFMO as a single agent and in combination with etoposide in pediatric and young adult patients with refractory or recurrent neuroblastoma
Time Frame	length of study plus 30 days

Outcome Measure Data

Analysis Population Description

Received at least one dose of DFMO

Arm/Group Title	Dose Level 1: 500 mg/m2 PO BID	Dose Level 2: 750 mg/m2 PO BID	Dose Level 3:1000 mg/m2 PO BID	Dose Level 4:1500 mg/m2 PO BID
Arm/Group Description:	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 1: 500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 2: 750 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 3:1000 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 4:1500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.
Overall Number of Participants Analyzed	4	5	3	9
Measure Type: Number; Unit of Measure: participants
	2	4	0	5

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

18 subjects out of the 21 enrolled were evaluable. 3 subjects did not make it to an evaluable time point.

Arm/Group Title	DFMO and Etoposide
Arm/Group Description:	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 1: 500 mg/m2 PO BID Dose level 2: 750 mg/m2 PO BID Dose level 3:1000 mg/m2 PO BID Dose level 4:1500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.
Overall Number of Participants Analyzed	18
Median (95% Confidence Interval); Unit of Measure: Days
	85; (62 to 418)

3. Secondary Outcome

Title	Number of Patients With an Overall Response Rate (ORR) of PR or CR
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

18 subjects out of the 21 enrolled were evaluable. 3 subjects did not make it to an evaluable time point.

Arm/Group Title	DFMO and Etoposide
Arm/Group Description:	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 1: 500 mg/m2 PO BID Dose level 2: 750 mg/m2 PO BID Dose level 3:1000 mg/m2 PO BID Dose level 4:1500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.
Overall Number of Participants Analyzed	18
Measure Type: Number; Unit of Measure: participants
	4

4. Secondary Outcome

Title	Tmax of DFMO in Pediatrics Using Pharmacokinetic (PK) Testing.
Description	[Not Specified]
Time Frame	Cycle 1 Day 8 at hour 0 (pre-dose), 30 minutes, 1 hour, 3 hours, and 6 hours

Outcome Measure Data

Analysis Population Description

Cohort at max dose of 1500mg/m2 BID

Arm/Group Title	DFMO and Etoposide
Arm/Group Description:	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 1: 500 mg/m2 PO BID Dose level 2: 750 mg/m2 PO BID Dose level 3:1000 mg/m2 PO BID Dose level 4:1500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.
Overall Number of Participants Analyzed	9
Mean (Standard Deviation); Unit of Measure: hours
	2.88 (1.45)

5. Secondary Outcome

Title	Cmax of DFMO in Pediatrics Using Pharmacokinetic (PK) Testing.
Description	[Not Specified]
Time Frame	Cycle 1 Day 8 at hour 0 (pre-dose), 30 minutes, 1 hour, 3 hours, and 6 hours

Outcome Measure Data

Analysis Population Description

Cohort at max dose of 1500mg/m2 BID

Arm/Group Title	DFMO and Etoposide
Arm/Group Description:	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 1: 500 mg/m2 PO BID Dose level 2: 750 mg/m2 PO BID Dose level 3:1000 mg/m2 PO BID Dose level 4:1500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.
Overall Number of Participants Analyzed	9
Mean (Standard Deviation); Unit of Measure: mcg/ml
	28.89 (14.96)

6. Secondary Outcome

Title	AUC of DFMO in Pediatrics Using Pharmacokinetic (PK) Testing.
Description	[Not Specified]
Time Frame	Cycle 1 Day 8 at hour 0 (pre-dose), 30 minutes, 1 hour, 3 hours, and 6 hours

Outcome Measure Data

Analysis Population Description

Cohort at max dose of 1500mg/m2 BID

Arm/Group Title	DFMO and Etoposide
Arm/Group Description:	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 1: 500 mg/m2 PO BID Dose level 2: 750 mg/m2 PO BID Dose level 3:1000 mg/m2 PO BID Dose level 4:1500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.
Overall Number of Participants Analyzed	9
Mean (Standard Deviation); Unit of Measure: (mcg/ml) * hr
	108.38 (53.23)

Adverse Events

Time Frame	New adverse events collected from first dose of study drug to 30 days past last dose of study drug. Related adverse events followed until resolution.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	DFMO and Etoposide
Arm/Group Description	DFMO: Escalating doses of DFMO in a 3 +3 cohort design. DFMO at current cohort Dose Level orally each day for 21 day cycles Dose level 1: 500 mg/m2 PO BID Dose level 2: 750 mg/m2 PO BID Dose level 3:1000 mg/m2 PO BID Dose level 4:1500 mg/m2 PO BID Etoposide: Starting with Cycle 2, etoposide will be given at 50mg/m2/dose PO daily for the first 14 days of each 21 day cycle. Capsules will be rounded to closest 50 mg.
All-Cause Mortality
	DFMO and Etoposide
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	DFMO and Etoposide
	Affected / at Risk (%)	# Events
Total	3/21 (14.29%)
Musculoskeletal and connective tissue disorders
Pain * 1 [1]	1/21 (4.76%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Progression of Disease resulting in death * 1	2/21 (9.52%)	2
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, CTCAE (3.0); [1] Back Pain unrelated to study drug.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	DFMO and Etoposide
	Affected / at Risk (%)	# Events
Total	11/21 (52.38%)
Blood and lymphatic system disorders
Anemia * 1	4/21 (19.05%)	8
Neutorpenia * 1	5/21 (23.81%)	9
Thrombocytopenia * 1	1/21 (4.76%)	5
Leukopenia * 1	1/21 (4.76%)	1
GGT elevation * 1	1/21 (4.76%)	1
Hypoalbuminemia * 1	1/21 (4.76%)	1
Hypophosphatemia * 1	1/21 (4.76%)	1
Eye disorders
Conjunctivitis * 1	1/21 (4.76%)	1
Gastrointestinal disorders
Constipation * 1	2/21 (9.52%)	2
Diarrhea * 1	1/21 (4.76%)	1
Mouth pain * 1	1/21 (4.76%)	1
Nausea * 1	1/21 (4.76%)	1
vomiting * 1	1/21 (4.76%)	1
General disorders
Anorexia * 1	1/21 (4.76%)	1
Pain * 1	1/21 (4.76%)	1
Sleep disturbance * 1	1/21 (4.76%)	1
Hepatobiliary disorders
ALT elevation * 1	2/21 (9.52%)	2
AST elevation * 1	3/21 (14.29%)	3
Nervous system disorders
Neuropathy * 1	1/21 (4.76%)	1
Renal and urinary disorders
urinary retention * 1	1/21 (4.76%)	1
Respiratory, thoracic and mediastinal disorders
Infection, sinus * 1	1/21 (4.76%)	1
Skin and subcutaneous tissue disorders
Rash * 1	1/21 (4.76%)	1
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, CTCAE (3.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Giselle Sholler, MD
• Organization: NMTRC
• Phone: 6162670335
• EMail: giselle.sholler@helendevoschildrens.org

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Saulnier Sholler GL, Gerner EW, Bergendahl G, MacArthur RB, VanderWerff A, Ashikaga T, Bond JP, Ferguson W, Roberts W, Wada RK, Eslin D, Kraveka JM, Kaplan J, Mitchell D, Parikh NS, Neville K, Sender L, Higgins T, Kawakita M, Hiramatsu K, Moriya SS, Bachmann AS. A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma. PLoS One. 2015 May 27;10(5):e0127246. doi: 10.1371/journal.pone.0127246. eCollection 2015.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT01059071
• Other Study ID Numbers: NMTRC 002
• First Submitted: January 26, 2010
• First Posted: January 29, 2010
• Results First Submitted: May 11, 2016
• Results First Posted: June 20, 2016
• Last Update Posted: April 22, 2022