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

Tracking Information

• First Submitted Date: January 26, 2010
• First Posted Date: January 29, 2010
• Results First Submitted Date: May 11, 2016
• Results First Posted Date: June 20, 2016
• Last Update Posted Date: April 22, 2022
• Study Start Date: February 2010
• Actual Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 11, 2016)

Number of Participants With Adverse Events as a Measure of Safety and Tolerability [ Time Frame: length of study plus 30 days ]

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

• Original Primary Outcome Measures (submitted: January 28, 2010): 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: 2 years ]

Current Secondary Outcome Measures (submitted: September 8, 2016)

• Progression Free Survival (PFS) [ Time Frame: 2 years ]
  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
• Number of Patients With an Overall Response Rate (ORR) of PR or CR [ Time Frame: 1 year ]
  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.
• Tmax of DFMO in Pediatrics Using Pharmacokinetic (PK) Testing. [ Time Frame: Cycle 1 Day 8 at hour 0 (pre-dose), 30 minutes, 1 hour, 3 hours, and 6 hours ]
• Cmax of DFMO in Pediatrics Using Pharmacokinetic (PK) Testing. [ Time Frame: Cycle 1 Day 8 at hour 0 (pre-dose), 30 minutes, 1 hour, 3 hours, and 6 hours ]
• AUC of DFMO in Pediatrics Using Pharmacokinetic (PK) Testing. [ Time Frame: Cycle 1 Day 8 at hour 0 (pre-dose), 30 minutes, 1 hour, 3 hours, and 6 hours ]

Original Secondary Outcome Measures (submitted: January 28, 2010)

• To evaluate the activity of DFMO as a single agent and in combination with etoposide in these tumor types based on: Progression free survival (PFS) [ Time Frame: 2 years ]
• To evaluate the activity of DFMO as a single agent and in combination with etoposide in these tumor types based on: Overall response rate (ORR) [ Time Frame: 1 year ]
• To evaluate the pharmacokinetics (PK) of DFMO as single agent [ Time Frame: Cycle 1 Day 1 and 8 ]
• Biology studies to include: effect on polyamine depletion, ODC activity, 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 [ Time Frame: 1 year ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety Study for Refractory or Relapsed Neuroblastoma With DFMO Alone and in Combination With Etoposide
• Official Title: A Phase I Trial for Refractory or Relapsed Neuroblastoma With DFMO Alone and in Combination With Etoposide

Brief Summary

The purpose of this research study is to evaluate a new investigational drug to treat neuroblastoma. This study drug is called DFMO. The objectives of this study will be to monitor for safety and to find a maximum tolerated dose in this population. A secondary objective will be to 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 and/or etoposide may continue on treatment 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), 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, and later combined with an already approved drug, etoposide.

The proposed dosing regimen is an oral dose of DFMO two times a day for each day while on study. There will be 5 cycles. Each cycle will be 21 days in length. The first cycle will be DFMO alone. In the second cycle etoposide will be added in and will be given orally once a day for the first 14 days of each cycle (cycles 2-5).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neuroblastoma

Intervention

• Drug: 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

  Other Name: Difluoromethylornithine
• Drug: 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.
  Other Names:

  • Eposin
  • Etopophos
  • Vepesid
  • VP-16

Study Arms

Experimental: DFMO and Etoposide

Interventions:

• Drug: DFMO
• Drug: Etoposide

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 10, 2016): 21
• Original Estimated Enrollment (submitted: January 28, 2010): 24
• Actual Study Completion Date: May 2015
• Actual Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age: 0-21 years at the time of diagnosis.
• Diagnosis: Histologic verification at either the time of original diagnosis or relapse of neuroblastoma.
• Disease Status: Refractory or relapsed neuroblastoma
• Measurable disease, including at least one of the following:

Measurable tumor >10mm by CT or MRI A positive MIBG and abnormal urinary catecholamine levels Positive bone marrow biopsy/aspirate.

• Current disease state must be one for which there is currently no known curative therapy.
• A negative urine pregnancy test is required for female subjects of child bearing potential (onset of menses or ≥13 years of age).
• Patients without bone marrow metastases must have an ANC > 500/μl and platelet count >50,000/μl
• Organ Function Requirements Subjects must have adequate liver function as defined by AST or ALT <10x normal Serum bilirubin must be ≤ 2.0 mg/dl Serum creatinine must be ≥ 1.5 mg/dl
• 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:

• Life expectancy <2 months or Lansky score <30%
• 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01059071
• Other Study ID Numbers: NMTRC 002
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Wake Forest University Health Sciences
• Original Responsible Party: Giselle Sholler, MD, University of Vermont
• Current Study Sponsor: Wake Forest University Health Sciences
• Original Study Sponsor: University of Vermont

Collaborators

• Cancer Prevention Pharmaceuticals, Inc.
• University of Arizona
• University of Hawaii

Investigators

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

• PRS Account: Wake Forest University Health Sciences
• Verification Date: November 2020