N2012-01: Phase 1 Study of Difluoromethylornithine (DFMO) and Celecoxib With Cyclophosphamide/Topotecan

Sponsor

New Approaches to Neuroblastoma Therapy Consortium (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02030964

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

114

Duration (Months)

2.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will combine an oral drug called DFMO with celecoxib (also oral) and two IV chemotherapy medicines called cyclophosphamide and topotecan.

To find the highest dose of DFMO that can be given with celecoxib, cyclophosphamide and topotecan without causing severe side effects.
To find out the side effects seen by giving DFMO at different dose levels with celecoxib, cyclophosphamide and topotecan.
To measure the levels of DFMO in the blood at different dose levels.
To determine if your tumor gets smaller after treatment with DFMO, celecoxib, cyclophosphamide and topotecan.
To determine if specific gene changes in you or your tumor makes you more prone to side effects or affects your tumor's response to the combination of DFMO, celecoxib, cyclophosphamide and topotecan.
To determine if the amount of normal chemicals in your body called polyamines go down in response to DFMO, celecoxib, cyclophosphamide and topotecan, and whether you are more likely to have a good response to the treatment if they do.

Condition or Disease	Intervention/Treatment	Phase
Neuroblastoma	Drug: DFMO Drug: Celecoxib Drug: Cyclophosphamide Drug: Topotecan	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

N2012-01: Phase 1 Study of Difluoromethylornithine (DFMO) and Celecoxib With Cyclophosphamide/Topotecan for Patients With Relapsed or Refractory Neuroblastoma

Study Start Date :

Dec 1, 2013

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DFMO, Celecoxib, Cyclophosphamide & Topotecan Reconstituted DFMO powder by mouth for 14 days and celecoxib capsule by mouth daily in each cycle. Cyclophosphamide and Topotecan IV on days 8-12 in cycle 1 and days 1-5 of cycles 2-17. Patients may continue for up to 17 cycles as long as therapy is tolerated (no DLT) and disease progression does not occur (SD or better). *Cycle 1 will include a 7 day lead-in with DFMO and celecoxib to deplete tumor polyamines.	Drug: DFMO Other Names: Difluoromethylornithine Drug: Celecoxib Other Names: Celebrex Drug: Cyclophosphamide Other Names: Cytoxan Drug: Topotecan Other Names: Hycamtin

Arm

Intervention/Treatment

Experimental: DFMO, Celecoxib, Cyclophosphamide & Topotecan

Reconstituted DFMO powder by mouth for 14 days and celecoxib capsule by mouth daily in each cycle. Cyclophosphamide and Topotecan IV on days 8-12 in cycle 1 and days 1-5 of cycles 2-17. Patients may continue for up to 17 cycles as long as therapy is tolerated (no DLT) and disease progression does not occur (SD or better). *Cycle 1 will include a 7 day lead-in with DFMO and celecoxib to deplete tumor polyamines.

Drug: DFMO

Other Names:

Difluoromethylornithine

Drug: Celecoxib

Other Names:

Celebrex

Drug: Cyclophosphamide

Other Names:

Cytoxan

Drug: Topotecan

Other Names:

Hycamtin

Outcome Measures

Primary Outcome Measures

Number of participants with adverse events as a measure of safety and tolerability. [Approximately 1 year]
The standard 3+3 design for dose escalation will be utilized. 3-6 patients will enroll at each of 4 dose levels, but enrollment to a dosing cohort will cease after observation of DLTs in 2 or more patients. A minimum of 2 to a maximum of 24 patients will be enrolled assuming all 4 dose levels require 6 patients before an MTD is determined. A total of 12 patients may be enrolled at the study defined MTD (including those used to define the MTD) to provide additional adverse event data for safety evaluation.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must be > 2 years and < 30 years of age when registered on study.
Patients must have recurrent/progressive high-risk neuroblastoma, refractory high-risk neuroblastoma that had less than a partial response to standard treatment or persistent high-risk neuroblastoma that had at least a partial response to standard treatment.
All patients must have at least ONE site of evaluable disease.
Patients must have adequate heart, kidney, liver and bone marrow function.
Patients who have bone marrow disease must still have adequate bone marrow function to enter the study.
Patients with other ongoing serious medical issues must be approved by the study chair prior to registration.

Exclusion Criteria:

Females of childbearing potential that do not have a negative pregnancy test.
Patients that are pregnant, breast feeding, or unwilling to use effective contraception during the study
Patients status post allogeneic stem cell transplant.
Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
Patients with disease of any major organ system that would compromise their ability to withstand therapy.
Patients who are on hemodialysis.
Patients with an active or uncontrolled infection. Patients on prolonged antifungal therapy are still eligible if they are culture and biopsy negative in suspected radiographic lesions and meet other organ function criteria.
Patients with active bleeding of the GI tract or patients who have symptoms associated with stomach irritation (known as gastritis).
Patients who have had a seizure within 12 months prior to enrollment and patients receiving anti-convulsant therapy for a seizure disorder.
Patients with known Aspirin-Hypersensitivity triad (asthma, allergic rhinitis, ASA hypersensitivity).
Patients with known hypersensitivity to celecoxib or other NSAIDs, aspirin or sulfonamides.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles	Los Angeles	California	United States	90027-0700
2	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
3	Children Hospital of Colorado	Aurora	Colorado	United States	80045
4	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus	Atlanta	Georgia	United States	30322
5	University of Chicago Comer Children's Hospital	Chicago	Illinois	United States	60637
6	Childrens Hospital Boston, Dana-Farber Cancer Institute.	Boston	Massachusetts	United States	02115
7	C.S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
8	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
9	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104-4318
10	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas	United States	76104
11	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington	United States	98105
12	Sydney Childrens Hospital KCC	Randwick		Australia	2031
13	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8