High-Dose 131I-MIBG Therapy Combined With Vincristine and Five Days of Irinotecan for Resistant/Relapsed Neuroblastoma
Condition: Neuroblastoma
MeSH terms: Neuroblastoma
Intervention: Metaiodobenzylguanidine (MIBG)
Intervention description: Chemotherapy will be given over 5 days for each course, with a single dose of 131I-MIBG on the second day of irinotecan. A total course will be defined as 42 days, or longer if hematopoietic recovery to eligibility criteria occurs after day 42.
Intervention MeSH terms: 3-Iodobenzylguanidine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 1 Year
Maximum age: 30 Years
Healthy volunteers: No
Keywords: Neuroblastoma; MIBG; 131I-MIBG; Irinotecan; Vincristine; Resistant; Relapsed; Treatment; UCSF; Pediatric; Oncology

Summary:

      This is a pilot study to determine whether doses of 15 mCi/kg and 18 mCi/kg of 131I-MIBG are
      tolerable when given with irinotecan/vincristine on a one week schedule to children and young
      adults with high-risk refractory/relapsed neuroblastoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age: Patients must be >1 year and < 30 years of age when registered on study.

          -  Diagnosis: Patients must have a diagnosis of neuroblastoma either by histologic
             verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow
             with increased urinary catecholamines.

          -  Disease status: Patients must have high-risk neuroblastoma with at least ONE of the
             following:

               1. Recurrent/progressive disease at any time. Biopsy not required, even if partial
                  response to intervening therapy except in patients with only one site of
                  MIBG-avid disease that has been radiated within the preceding two months. Such
                  patients require biopsy confirmation of residual active disease, with positive
                  bone marrow biopsy being adequate confirmation of residual active disease.

               2. Refractory disease (i.e. less than a partial response to frontline therapy,
                  including a minimum of 4 cycles of induction chemotherapy). No biopsy is required
                  for eligibility for this study.

               3. Persistent disease after at least a partial response to frontline therapy (i.e.
                  patient has had at least a partial response to frontline therapy but still has
                  residual disease by MIBG scan, CT/MRI, or bone marrow). Patients in this category
                  are REQUIRED to have a biopsy (bone marrow biopsy included) of at least one
                  residual site demonstrating viable neuroblastoma.

          -  131I-MIBG Uptake: Patients must have evidence of MIBG uptake into tumor at ≥ one site
             within 4 weeks prior to entry on study and subsequent to any intervening therapy.

          -  Hematopoietic stem cells: Patients must have an adequate unpurged peripheral blood
             hematopoietic stem cell product, with a minimum of 2 X 106 CD34+ cells/kg available.
             Having a back-up of 2.0 x 106 viable CD34+ cells/kg unpurged PBSC is recommended but
             not required. The use of purged stem cells or autologous bone marrow as donor source
             is not allowed. The use of PBSC from an identical twin is allowed.

          -  Performance and life expectancy: Must have a life expectancy of at least 6 weeks and a
             Lansky or Karnofsky score of at least 60.

          -  Prior therapy: Patients must have fully recovered from the acute toxic effects of all
             prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

               1. Myelosuppressive chemotherapy and/or biologics: Patients are not required to
                  complete re-induction chemotherapy prior to study entry following relapse. Last
                  dose of any myelosuppressive or biologic therapy was given at least 2 weeks
                  before the start date for irinotecan on this protocol.

               2. Radiation: Patients must not have received radiation for a minimum of two weeks
                  prior to study entry. Patients who received radiation to the only site of
                  MIBG-avid disease within two months of study entry require biopsy confirmation of
                  residual active disease, with positive bone marrow biopsy being adequate
                  confirmation of residual active disease. A minimum of 3 months is required
                  following prior large field radiation therapy (i.e. craniospinal therapy, total
                  lung, > 50% marrow space). Patients are excluded if they have received whole
                  abdominal radiation or TBI (total body irradiation).

               3. Stem Cell Transplant (SCT): Patients are eligible three months after autologous
                  stem cell transplant. Patients status post-allogeneic stem cell transplant are
                  excluded. Must meet adequate bone marrow function definition (see organ function
                  requirements, below) post-myeloablative therapy.

               4. Prior 131I-MIBG therapy: Patients may have received prior MIBG therapy, though
                  cumulative lifetime dose should not exceed 18 mCi/kg prior to study entry.
                  Patients must not have received MIBG in combination with irinotecan. For patients
                  previously treated with MIBG, at least 6 months must have elapsed since last MIBG
                  therapy.

               5. Growth factor(s): All cytokines or hematopoietic growth factors must be
                  discontinued a minimum of 7 days prior to the start date for irinotecan on this
                  protocol.

               6. Prior irinotecan and vincristine therapy: are allowed, subject to recovery of
                  adequate bone marrow function as specified in the protocol.

          -  Concomitant Therapy Restrictions: Patients must not be receiving any other anti-cancer
             agents or radiotherapy at the time of study entry or while on study. Enzyme-inducing
             anticonvulsants (phenobarbital, phenytoin, carbamazepine) must not be used as these
             may interfere with irinotecan metabolism. Non-enzyme inducing anticonvulsants (Keppra,
             etc.) can be used after discussion with study chair. The use of high dose
             dexamethasone and the use of aprepitant as antiemetics is not recommended due to
             effects on irinotecan metabolism.

          -  Hematologic function: a. ANC: > 750/uL (no hematopoietic growth factors within 7 days
             of the start date for irinotecan on this protocol) b. Platelet count: > 50,000/µl,
             transfusion independent (defined as no platelet transfusion for one week).

             c. These criteria must be met by all patients, regardless of bone marrow involvement
             with tumor.

          -  Renal function: a. Glomerular Filtration Rate (GFR) or 12-24hr Creatinine Clearance >=
             60 ml/min/1.73 m², OR b. Age-adjusted serum creatinine < 1.5 x normal for age (see
             below):

        Age Maximum Serum Creatinine (mg/dL) < 5 years 0.8 > 5 and < 10 years 1.0 > 10 and < 15
        years 1.2 > 15 years 1.5

          -  Liver function:a. Total bilirubin <= 1.5 x normal for age, and b. SGPT (ALT) and SGOT
             (AST) < 3 x upper limit of normal

          -  Cardiac function: Normal ejection fraction (>=55%) documented by either echocardiogram
             or radionuclide MUGA evaluation OR normal fractional shortening (>= 27%) documented by
             echocardiogram.

          -  Lung function: Normal lung function with no dyspnea at rest, exercise intolerance,
             pleural effusion or oxygen requirement.

          -  Reproductive function: All post-menarchal females must have a negative urine or serum
             beta-HCG. Males and females of reproductive age and childbearing potential must use
             effective contraception for the duration of their participation.

          -  Coexisting medical conditions: Patients with other ongoing serious medical issues must
             be approved by the study chair prior to registration.

        Exclusion Criteria:

          -  Pregnant or lactating.

          -  Patients status post-ALLOGENEIC stem cell transplant are NOT eligible.

          -  Patients who, in the opinion of the investigator, may not be able to comply with the
             safety monitoring requirements of the study.

          -  Patients with disease of any major organ system that would compromise their ability to
             withstand therapy.

          -  Patients who are on hemodialysis.

          -  Patients with a documented allergy to 3rd generation cephalosporins.

          -  Patients must not have active diarrhea (defined as > Grade 2 per CTCAE v4 [ Grade 2 =
             increase of 4-6 stools/day over baseline] ).

          -  Patients with an active or uncontrolled infection, including C. difficile, of > grade
             3 per CTCAE v4. Patients on prolonged antifungal therapy are eligible if they are
             culture and biopsy negative in suspected radiographic lesions and meet other organ
             function criteria.

          -  Patients and/or families who are physically and psychologically unable to cooperate
             with the radiation safety isolation.

          -  Patients who have received prior total body or whole abdominal radiation.

          -  Patients who have received prior 131I-MIBG therapy in combination with irinotecan.