Clinical trial NCT04301843: Eflornithine (DFMO) and Etoposide for Relapsed/Refractory Neuroblastoma
Official title: Phase II Trial of Eflornithine (DFMO) and Etoposide for Relapsed/Refractory Neuroblastoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Neuroblastoma
Lead sponsor: Milton S. Hershey Medical Center
Sponsor class: OTHER
Collaborators: name: K C Pharmaceuticals Inc.
name: Beat NB Cancer Foundation
name: Team Parker for Life
First posted: 2020-03-10
Enrollment: 131
Sex: ALL
Maximum age (years): 31
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

Detailed description: Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in combination with etoposide for subjects with relapsed/refractory neuroblastoma.

In this study subjects will receive six 21-day cycles of Etoposide and DFMO followed by an additional 630 days of DFMO alone.

Subjects will be evaluated in 3 arms:

• Arm 1: Subjects who show no active disease after receiving any additional therapy for neuroblastoma that was refractory to standard induction/consolidation therapy.

Refractory: Subjects with progressive disease on upfront therapy OR did not have at least PR on induction OR required additional second line therapy to achieve remission who are now in first remission.

* Arm 2: Subjects who have previously relapsed and currently show no active disease (in CR2 or greater).
* Arm 3: Subjects who are relapsed or refractory with active disease.

Eligibility criteria: Inclusion Criteria:

* All patients must have a pathologically confirmed diagnosis of neuroblastoma, ≤ 30.99 years of age with history of relapsed/refractory neuroblastoma.
* All patients must have completed upfront therapy with at least 4 cycles of aggressive multi-drug chemotherapy.
* Specific Criteria by Arm:

Arms 1 and 2:

Subjects with no active disease:

i. No evidence of residual disease by CT/MRI and MIBG scan (or PET for patients who have a history of MIBG non-avid disease).

o Note: Patients with residual masses detected by CT/MRI may be considered in CR if their MIBG is negative or if MIBG positive and evaluated by PET and found to have negative PET scans; biopsy confirmation may be considered if there is still reasonable concern for persistent disease but is not required.

ii. No evidence of disease metastatic to bone marrow.

Arm 3:

Measurable or evaluable disease, including at least one of the following:

Measurable tumor by CT or MRI; or a positive MIBG and PET; or positive bone marrow biopsy/aspirate in at least one site.

* Timing from prior therapy: Enrollment (first dose of DFMO) no later than 60 days from last dose of the most recent therapy.
* Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines:

  1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
  2. Hematopoietic growth factors: At least 5 days since the completion of therapy with a growth factor.
  3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the Study Chair.
  4. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells.
  5. Anti-GD2 Monoclonal antibodies: At least 2 weeks must have elapsed since prior treatment with a monoclonal antibody.
  6. XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.
  7. Stem Cell Transplant:

     1. Allogeneic: No evidence of active graft vs. host disease
     2. Allo/Auto: ≥ 2 months must have elapsed since transplant.
  8. MIBG Therapy: At least 8 weeks since treatment with MIBG therapy
* Subjects must have a Lansky or Karnofsky Performance Scale score of 60% or higher.
* Life expectancy \> 2 months
* All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to first dose of study drug unless otherwise indicated below.
* Subjects must have adequate organ functions at the time of registration:

  * Hematological: Total absolute neutrophil count ANC ≥750/μL
  * Liver: Subjects must have adequate liver function as defined by AST and ALT \<5x upper limit of normal (Normal=45), Bilirubin \<1.5x upper limit normal (Normal=1.0). Normal PT, PTT, fibrinogen.
  * Renal: Adequate renal function defined as (perform one of the following): Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or greater or a serum creatinine based on age/gender
* Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
* Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or patients' legal representative).

Exclusion Criteria:

* BSA of \<0.25 m2.
* Subjects that received DFMO at a dose higher than 1000mg/m2 BID prior to this study are not eligible.
* Subjects that received a dose of DFMO in combination with etoposide are not eligible.
* 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 hematological and bone marrow suppression effects of prior chemotherapy.
* 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.

Primary outcomes:
measure: Number of participants with event free survival (EFS) during study
timeFrame: 2 years plus 5 years follow up
Secondary outcomes:
measure: Length of time that participants experience Overall Survival (OS)
timeFrame: 7 years
measure: Determine the Overall Response Rate (ORR) of Participants using INSS Response Evaluation Criteria.
timeFrame: 2 years
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: 2 years plus 30 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama, Children's Alabama
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland-
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: Hartford
country: United States
facility: Connecticut Children's Hospital
state: Connecticut
city: Orlando
country: United States
facility: Arnold Palmer Hospital for Children
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Children's Hospital
state: Florida
city: Augusta
country: United States
facility: Augusta University Health
state: Georgia
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospital and Clinics of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Charlotte
country: United States
facility: Levine Children's Hospital
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Children's
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center and Children's Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Hasbro Children's Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Austin
country: United States
facility: Dell Children's Blood and Cancer Center
state: Texas
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Montréal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Montréal
country: Canada
facility: UHC Sainte-Justine
state: Quebec
city: Quebec City
country: Canada
facility: CHUQ
state: Quebec
Study officials:
affiliation: Beat Childhood Cancer
name: Giselle Sholler, MD
role: STUDY_CHAIR
References: