NMTT- Neuroblastoma Maintenance Therapy Trial Using Difluoromethylornithine (DFMO)
Clinical Trial Information
Trial Contact: El-Shami, Jessica; Francois, Laetitia Claire; Leffin, Melissa; Spinelli, Jennifer
IRB No: 16.031.02
Protocol Abbrev: NMTRC-014
Principal Investigator: Don E. Eslin, MD
Sub Investigators: AguilarBonilla, Ana MD; Smith, Amy MD; Giusti, Vincent MD; Levy, Alejandro MD; Sutphin, Robert MD; Pope, Michele ARNP; Story, Allison ARNP; Sullivan Darden, Kelly ARNP
Phase: Drug: Phase II
Age Group: Pediatric
Secondary Protocol No: NMTRC014
Applicable Disease Sites: Neuroblastoma
Therapies Involved: DFMO
ClinicalTrials.gov ID: NCT02679144
The purpose of this research study is to evaluate an investigational drug, called DFMO, for neuroblastoma that is in remission. An investigational drug is one that has not been approved by the U.S. Food and Drug Administration (FDA). This study will look at the ability of this study drug to keep your tumor in remission and will also look at the safety and tolerability of DFMO.
DFMO was shown to be effective in inhibiting tumor growth in adult colon cancers. DFMO has been tested in multiple adult and pediatric clinical trials. Previous studies and laboratory testing in neuroblastoma suggests that this drug may be effective in preventing relapse of this disease.
1. All patients must have a pathologically confirmed diagnosis of neuroblastoma, ≤ 30.99 years of age and classified as high risk by the criteria used by COG or SIOPEN at the time of diagnosis. Exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible.
2. All patients must be in complete remission (CR):
i. No evidence of residual disease by CT/MRI and MIBG scan
o Note: Patients with residual masses detected by CT/MRI who have negative PET scans can be considered to be in CR; 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.
3. Specific Criteria by Stratum:
All patients must have completed standard upfront therapy that replicates treatment which patients who were enrolled on ANBL0032 received, including:
i. intensive induction chemotherapy and (if feasible) resection of primary tumor, followed by:
ii. consolidation with high-dose chemotherapy with ASCT and radiotherapy (see note below), followed by:
iii. immunotherapy with Ch14.18/IL-2/GM-CSF (dinutuximab) and retinoic acid;.
Examples of such therapies include:
• Treatment as per A3973 protocol;
• Treatment as per POG 9341/9342 protocol;
• Treatment as per CCG3891;
• Enrollment on or following treatment as per ANBL02P1;
• Enrollment on or following treatment as per ANBL07P1.
Tandem transplant patients are eligible if treated:
• On or as per ANBL0532;
• On or as per POG 9640;
• On or as per COG ANBL00P1; or,
• On or as CHP 594/DFCI 34-DAT.
All subjects on Stratum 1 must have also met the following criteria:
• A pre-ASCT disease status evaluation that met International Neuroblastoma Response Criteria (INRC) for CR, VGPR, or PR for primary site, soft tissue metastases and bone metastases. Patients who meet those criteria must also meet the protocol-specified criteria for bone marrow response prior to ASCT as outlined below:
o No more than 10% tumor involvement (based on total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy.
o Because of potential sampling variation, patients who had a negative marrow at or following diagnosis, and then subsequently have a positive marrow—but with ≤ 10% tumor involvement—on any of the bilateral marrow aspirate/biopsy specimens done at or prior to pre-ASCT evaluation (which would be considered Progressive Disease by INRC), will still be considered eligible as long as the bone marrow is negative at the time of enrollment and there was no other evidence of progressive disease during upfront therapy.
Note: Radiotherapy may be waived for patients who either have small adrenal masses which are completely resected at the time of diagnosis, or who never have an identifiable primary tumor. In this case please consult with Study Chairs to confirm eligibility.
Neuroblastoma that is in first complete remission following standard upfront therapy different from that described for Stratum 1.
Neuroblastoma that failed to have a response of at least PR following induction chemotherapy and surgical resection of the primary tumor, but that has achieved CR following additional therapy.
Patients who have achieved a second or subsequent CR following relapse(s).
4. Pre-enrollment tumor survey:
Prior to enrollment on this study, a determination of mandatory disease staging must be performed:
• Tumor imaging studies including: CT or MRI, and MIBG scan (or PET if tumor is not MIBG avid)
• Bilateral bone marrow aspirates and biopsy
• This disease assessment is required for eligibility and preferably should be done within 2 weeks prior to enrollment, but must be done within a maximum of 4 weeks before enrollment.
5. Patients who had residual disease prior to post-ASCT radiotherapy must have had re-evaluation of irradiated residual tumors performed no earlier than 5 days after completing radiotherapy. As outlined above, patients with residual disease are eligible if PET negative; confirmation by biopsy is not required.
6. Timing from prior therapy:
Stratum 1: Enrollment no later than 60 days after completion of upfront therapy, (last dose of cis-retinoic acid) with a maximum of 6 cycles of cis-retinoic acid maintenance therapy.
Stratum 2, 3 and 4: Enrollment no later than 60 days from last dose of the most recent therapy.
7. Patients must have a Lansky or Karnofsky Performance Scale score of ≥ 50% (see Appendix II) and patients must have a life expectancy of ≥ 2 months.
8. All clinical and laboratory studies for organ functions to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated below.
9. Patients must have adequate organ functions at the time of registration:
• Hematological: Total absolute phagocyte count ≥1000/μL (APC = (% neutrophils + % bands + % monocytes) x total WBC x 100)
• Liver: Subjects must have adequate liver function as defined by AST and ALT <10x upper limit of normal
• Renal: Adequate renal function defined as: Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or
-A serum creatinine based on age/gender
10. 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.
11. Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or patients’ legal representative).