Clinical trial NCT02139397: Study of Difluoromethylornithine (DFMO) in Combination With Bortezomib for Relapsed or Refractory Neuroblastoma
Official title: A Phase I/II Trial of DFMO in Combination With Bortezomib in Patients With Relapsed or Refractory Neuroblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Neuroblastoma Recurrent
Lead sponsor: Milton S. Hershey Medical Center
Sponsor class: OTHER
Collaborators: name: Beat NB Cancer Foundation
name: Because of Ezra
name: K C Pharmaceuticals Inc.
First posted: 2014-05-15
Enrollment: 16
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this research study is to evaluate an investigational drug (DFMO) in combination with bortezomib, for relapsed and refractory neuroblastoma. DFMO is an investigational drug because it has not been approved by the U.S. Food and Drug Administration (FDA). This study will look at the safety and tolerability of DFMO in combination with bortezomib as well as the tumors response to this study drug.


Eligibility criteria: Inclusion Criteria:

* Age: ≤ 21 years at the time of diagnosis.
* Diagnosis: Histologic verification at either the time of original diagnosis or relapse of neuroblastoma.
* Disease Status: For the purposes of this study, aggressive multidrug chemotherapy is defined as chemotherapy including 2 or more agents that must include an alkylating agent and a platinum-containing compound. Patients must have one of the following:
* First episode of recurrent disease following completion of aggressive multi-drug frontline therapy.
* First episode of progressive disease during aggressive multi-drug frontline therapy.
* Primary resistant/refractory disease detected at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (examples include Children's Oncology Group trials: A3973, ANBL0532, ANBL09P1, etc.).
* Measurable or evaluable disease, including at least one of the following: Measureable tumor by CT or MRI; or A positive meta-iodobenzylguanidine (MIBG) or positron emission computed tomography (PET) scan; or Positive bone marrow biopsy/aspirate.
* Current disease state must be one for which there is currently no known curative therapy or no additional therapies proven to prolong survival with an acceptable quality of life.
* A negative urine pregnancy test is required for female subjects of child bearing potential (onset of menses or ≥13 years of age).
* Organ Function Requirements:

  1. Subjects must have adequate liver function as defined by:

     * AST (aspartate aminotransferase) and alanine aminotransferase (ALT) \<5x upper limit of normal
     * Serum bilirubin must be ≤ 2.0 mg/dl
  2. Subjects must have adequate Bone Marrow function defined as:

For patients without bone marrow involvement:

* Peripheral absolute neutrophil count (ANC) ≤ 750/uL
* Platelet count 50,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment. Exception: Patients that are platelet dependent due to previous extensive treatment- e.g. - MIBG therapy).
* Hemoglobin ≥ 8.0 g/dL (may receive red blood cell transfusions) Patients known to have bone marrow involvement with neuroblastoma are eligible provided that minimum ANC and platelet count criteria are met but are not evaluable for hematological toxicity.

  * Subjects must have adequate renal function defined as: 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 \<50%
* BSA (body surface area) body surface body surface m2 of \<0.25
* Prior Therapy- Patients 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.
  5. Monoclonal antibodies: At least 7 days or 3 half-lives, whichever is longer, must have elapsed since prior treatment with a monoclonal antibody.
  6. Radiotherapy: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.
  7. Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and ≥ 2 months must have elapsed since transplant.
* Investigational Drugs: Subjects who have received another investigational drug within the last 14 days are excluded from participation.
* 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 Adverse Events as a Measure of Safety and Tolerability
timeFrame: Adverse Events were collected starting with the date of the first dose of study drug until 30 days after last dose of study drug, ongoing related adverse events were continued to be followed until resolution, on average 6 months.
Secondary outcomes:
measure: Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria
timeFrame: Followed until off therapy, generally 1 year
measure: Determine the Progression Free Survival (PFS) of Participants Using Days Until Progression
timeFrame: From date of start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Hartford
country: United States
facility: Connecticut Children's Hospital
state: Connecticut
city: Orlando
country: United States
facility: Arnold Palmer Hospital for Children- MD Anderson
state: Florida
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
Study officials:
affiliation: Children's Mercy Hospital Kansas City
name: Kathleen Neville, MD
role: STUDY_CHAIR
References: