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

Phase 1

Completed

• Conditions: Neuroblastoma Recurrent
• Interventions: Drug: DFMO; Drug: Bortezomib

• Registration Number: NCT02139397
• Lead Sponsor: Giselle Sholler

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-05-13
• Study First Submitted QC: 2014-05-14
• Study First Posted: 2014-05-15
• Study Start: 2014-06-06
• Primary Completion: 2024-01-19
• Study Completion: 2024-01-19
• Results First Submitted: 2024-03-04
• Results First Submitted QC: 2024-04-01
• Results First Posted: 2024-04-25
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-02
• Last Update Posted: 2024-08-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
DFMO and Bortezomib	DFMO	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.
DFMO and Bortezomib	Bortezomib	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events as a Measure of Safety and Tolerability	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.	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.; Phase II- Study did not enroll to Phase II. Study completed at end of Phase I.

Secondary Outcome Measures

Name	Time	Method
Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria	Followed until off therapy, generally 1 year	To determine the overall response rate (ORR) by the presence of radiologically assessable disease by cross-sectional imaging and in MIBG (meta-iodobenzylguanidine) or PET (positron emission computed tomography) scans. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI imaging and/or by MIBG or PET scans: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the disease measurements for measurable lesions, Stable Disease, Neither sufficient decrease to qualify for PR or sufficient increase to qualify for PD from study entry. Overall Response (OR) = CR + PR.
Determine the Progression Free Survival (PFS) of Participants Using Days Until Progression	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	Time to progression (PFS), defined as the period from the start of the treatment until the criteria for progression are met taking as reference the screening measurements. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the disease measurements for measurable lesions, taking as reference the smallest disease measurement recorded since the start of treatment (nadir), and minimum 5 mm increase over the nadir or the appearance of one or more new lesions or appearance of positive bone marrow.

Trial Locations

Locations (6)

Connecticut Children's Hospital; 🇺🇸 Hartford, Connecticut, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

Helen DeVos Children's Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Children's Mercy Hospitals and Clinics; 🇺🇸 Kansas City, Missouri, United States

Arnold Palmer Hospital for Children- MD Anderson; 🇺🇸 Orlando, Florida, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States