ANBL1221,A Phase II Randomized Trial of Irinotecan/Temozolomide with Temsirolimus (NSC# 683864, IND# 61010) or Chimeric 14.18 Antibody (ch14.18) (NSC# 623408, IND# 4308) in Children with Refractory, Relapsed or Progressive Neuroblastoma


Patients will be randomized 1:1 to Regimen a (irinotecan/temozolomide/temsirolimus) or Regimen B (irinotecan/temozolomide/ch14.18). Patients on Regimen B will also receive GM-CSF following irinotecan/temozolomide/ch14.18.
Treatment cycles will be repeated every 21 days (3 weeks). Tumor response will be assessed after Cycles 2, 4, 6 and every 4 cycles thereafter until the end of protocol therapy. Patients with CR, PR or SD may continue to receive the assigned therapy for a maximum of 17 cycles (approximately 1 year).

Participant Eligibility

1. Age: Patients of all ages are eligible for this study.

2. Disease Status
a. Histologic Diagnosis:
Patients must have had histologic verification of neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (ie, > 2 x ULN), at the time of initial diagnosis.
b. Active Disease:
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 A3973, ANBL0532, ANBL09P1, etc.).
c. Documentation of Disease:
Patients must have at least ONE of the following:
- Measurable tumor on MRI, CT scan obtained within 3 weeks prior to study entry. Measurable is defined as >= 10 mm in at least one dimension on spiral/helical CT that is MIBG avid or demonstrates increased FDG uptake on PET scan.
- MIBG scan obtained within 3 weeks prior to study entry with positive uptake at a minimum of one site. This site must represent disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction.
- Patients with resistant/refractory soft tissue disease that is not MIBG avid or does not demonstrate increased FDG uptake on PET scan must undergo biopsy to document the presence of viable neuroblastoma. Biopsy is not required for patients who have new site of soft tissue disease (radiographic evidence of disease progression) regardless of whether progression occurs while receiving therapy or after completion of therapy.
Note: Patients with elevated catecholamines (ie, > 2 x ULN) only or bone marrow disease only are NOT eligible for this study.

3.Performance Level
Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients <= 16 years of age.

4 Prior Therapy
a. Patients must have received frontline therapy (including surgery, chemotherapy, autologous SCT +/- MIBG, immunotherapy, radiotherapy, and retinoids) but may NOT have received second line chemotherapy for resistant/refractory, relapsed disease or progressive disease.
b. Myelosuppressive chemotherapy: At least 14 days must have elapsed since completion of myelosuppressive therapy.
c. Biologic (anti-neoplastic agent): At least 7 days must have elapsed since the completion of therapy with a non-myelosuppressive biologic agent or retinoid.
d. XRT: No interim time prior to study entry is required following prior RT for non-target lesions. However, patients must not have received radiation for a minimum of 4 weeks prior to study entry at the site of any lesion that will be identified as a target lesion to measure tumor response. Lesions that have been previously radiated cannot be used as target lesions unless there is radiographic evidence of progression at the site following radiation or a biopsy done following radiation shows viable neuroblastoma. Palliative radiation is allowed to sites that will not be used to measure response during this study.
e. Stem Cell Transplants (SCT): Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell infusions as long as hematologic and other eligibility criteria have been met.
f. 131I-MIBG therapy: Patients are eligible >= 6 weeks after therapeutic 131I-MIBG provided that all other eligibility criteria are met.
g. Study specific limitations on prior therapy: Subjects who have previously received anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging are eligible unless they have had progressive disease while receiving prior anti-GD2 therapy. Subjects who have received autologous marrow infusions or autologous stem cell infusions that were purged using monoclonal antibody linked to beads, but no other form of anti-GD2 monoclonal antibody, are eligible.

5.Concomitant Medications Restrictions: Patients must not have received long-acting myeloid growth factors (eg, Neulasta) within 14 days of entry on this study. Seven days must have elapsed since administration of a short-acting myeloid growth factor.

6. Organ Function Requirements
a. Adequate bone marrow function defined as:
- Peripheral absolute neutrophil count (ANC) >= 750/[MICRO-SYMBOL]L
- Platelet count >= 75,000/[MICRO-SYMBOL]L (transfusion independent)
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.
b. Adequate renal function defined as:
- Creatinine clearance or estimated radioisotope GFR >=70 mL/min/1.73 m2 or
- A serum creatinine <= upper limit of normal (ULN) based on age/gender.
c. Adequate liver function defined as:
- Total bilirubin <= 1.5 x ULN for age AND
- SGPT (ALT) <= 5.0 x ULN for age (<= 225 U/L). For the purpose of this study, the ULN for SGPT is 45 U/L.
d. Adequate central nervous system function defined as:
- Patients with a history of CNS disease must have no clinical or radiological evidence of CNS disease at the time of study enrollment
- Patients with seizure disorders may be enrolled if seizures are well controlled on anti-convulsants
- CNS toxicity <= Grade 2
e. Adequate cardiac function defined as:
- Shortening fraction of >= 27% by ECHO or
- Ejection fraction >= 50% by ECHO or gated radionuclide study
f. Adequate coagulation defined as:
- PT <= 1.2 x upper limit of normal.
g. Serum lipids within acceptable range:
- Serum triglyceride level <= 300 mg/dL and serum cholesterol level <= 300 mg/dL.
If non-fasting values exceed these levels, lipid testing should be repeated in the fasting state.
h. Adequate pulmonary function defined as:
- No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and room air pulse oximetry >94% if there is a clinical indication for pulse oximetry. Normal pulmonary function tests in patients who are capable of cooperating with testing (including DLCO) are required if there is a clinical indication for determination. For patients who do not have respiratory symptoms, full PFTs are NOT required.