Study of DFMO in Combination With Bortezomib for Relapsed or Refractory Neuroblastoma

Study Overview
=================
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.

Official Title
-----------------
A Phase I/II Trial of DFMO in Combination With Bortezomib in Patients With Relapsed or Refractory Neuroblastoma

Conditions
-----------------
Neuroblastoma Recurrent

Intervention / Treatment
-----------------
* Drug: DFMO
* Drug: Bortezomib


Participation Criteria
=================
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 MIBG or 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: Subjects must have adequate liver function as defined by: AST and ALT <5x upper limit of normal Serum bilirubin must be ≤ 2.0 mg/dl 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 RBC 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 (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: Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea). Hematopoietic growth factors: At least 5 days since the completion of therapy with a growth factor. 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. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines. Monoclonal antibodies: At least 7 days or 3 half-lives, whichever is longer, must have elapsed since prior treatment with a monoclonal antibody. XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site. 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.

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DFMO and Bortezomib<br>Subjects will take DFMO by mouth 2 times a day for each day of a 21 day cycle and Bortezomib will be given by IV push on days 1, 4, and 8 of each 21 day cycle. | Drug: DFMO<br> <br> * Other names: Eflornithine;Drug: Bortezomib<br> <br> * Other names: Velcade;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Phase I- To determine the safety and tolerability of DFMO in combination with bortezomib at 3 dose levels of DFMO: 1500mg/m2 twice daily, 2000mg/m2 twice daily, and 2500mg/m2 twice daily in subjects with relapsed or refractory neuroblastoma who receive one full cycle of this dose. | 6 months | 
| Determine the Overall Response Rate (ORR) of Participants using RECIST criteria | To determine the overall response rate (ORR) by the presence of radiologically assessable disease by cross-sectional imaging and in MIBG or PET scans. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Phase II- To continue to determine the safety and tolerability of DFMO in combination with bortezomib in subjects with relapsed or refractory neuroblastoma. | 3 years | 
| Determine the Progression Free Survival (PFS) of Participants using days until progression | To evaluate the activity of DFMO in combination with bortezomib based on: - Progression free survival (PFS) | 3 years | 
| Correlate PET scan changes with Progression Free Survival | For subjects followed with PET scan: comparison of changes in PET activity and correlation with PFS | 3 years | 
| Biology studies | Urine, blood, bone marrow and tumor biological Correlates will be explored. Dose effect of DFMO on biological correlates will also be explored. | 3 years | 
| Correlate urinary polyamine levels with response and progression of disease in neuroblastoma. | Correlation of urinary polyamine levels with response and progression of disease in neuroblastoma. | 3 years |