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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

Phase 2
Not Enrolling

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Trial Information

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

Long-term survival rates for children with high-risk neuroblastoma remain poor. In addition,
survivors experience significant immediate and late toxicities limiting further dose
intensification with conventional chemotherapy agents. Novel biological therapies are
therefore needed. This "Pick the Winner" Phase II study is designed to compare the response
rates (RR) and progression free survival (PFS) for patients with refractory, relapsed or
progressive neuroblastoma receiving temsirolimus or ch14.18 in combination with irinotecan
and temozolomide. The irinotecan and temozolomide combination has shown activity against
relapsed/refractory neuroblastoma. Furthermore, its favorable toxicity profile makes it an
attractive backbone chemotherapy regimen for assessment of the contribution of novel
molecularly targeted agents. Neuroblastoma cells have shown sensitivity to mTOR inhibitors
both in vitro and in vivo. mTOR inhibitors have also been shown to have synergistic or
additive effects when combined with several conventional chemotherapeutic drugs, including
those frequently used in the treatment of neuroblastoma. The combination of irinotecan and
temozolomide with the mTOR inhibitor temsirolimus is well tolerated in children, and this
3-drug regimen will comprise one arm of this study. The second arm will include irinotecan
and temozolomide in combination with the chimeric anti-GD2 antibody ch14.18. The
disialoganglioside GD2 is expressed on neuroblastoma cells, but its expression in normal
human tissues is limited. A randomized Phase III study (COG ANBL0032) compared the event
free survival of patients with high risk neuroblastoma treated with ch14.18 combined with
GM-CSF, interleukin 2 and isotretinoin to that of patients treated with isotretinoin alone
as post-consolidation therapy. Randomization was stopped early because of superior survival
associated with the antibody-containing regimen. Preclinical studies of anti-GD2 antibodies
combined with cytotoxic chemotherapy have shown synergistic or additive effects on
neuroblastoma cells. These data support evaluation of the addition of ch14.18 to
chemotherapy for children with refractory, relapsed or progressive neuroblastoma. The agent
selected for further study as a result of this trial will be integrated into frontline
induction therapy for future patients with high-risk neuroblastoma.

Inclusion Criteria:

- all ages

- 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.

- 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.).

- 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.

- 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.
See under
Standard Sections for Protocols.

- 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.

- At least 14 days must have elapsed since completion of myelosuppressive therapy.

- At least 7 days must have elapsed since the completion of therapy with a
non-myelosuppressive biologic agent or retinoid.

- 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.

- 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.

- Patients are eligible ≥ 6 weeks after therapeutic 131I-MIBG provided that all other
eligibility criteria are met.

- 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

- concomitant therapy restrictions for patients during treatment

- 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.

- Peripheral absolute neutrophil count (ANC) ≥ 750/μL

- Platelet count ≥ 75,000/μL (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.

- Creatinine clearance or estimated radioisotope GFR ≥ 70 mL/min/1.73 m2 or a serum
creatinine ≤ upper limit of normal

- 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.

- 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

- CNS toxicity ≤ Grade 2

- Shortening fraction of ≥ 27% by ECHO OR

- Ejection fraction ≥ 50% by ECHO or gated radionuclide study

- PT ≤ 1.2 x upper limit of normal.

- 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.

- 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.

Exclusion Criteria:

- Men and women of childbearing potential and their partners must agree to use adequate
contraception while enrolled on this study. Based on the established teratogenic
potential of alkylating agents and temsirolimus, pregnant women will be excluded from
this study. Because of potential risks to breastfed infants due to drug metabolites
that could be excreted in breast milk, female patients who are lactating must agree
to stop breastfeeding or will otherwise be excluded from this study. Females of
childbearing potential must have a negative pregnancy test to be eligible for this

- Patients with elevated catecholamines (ie, > 2 x ULN) only or bone marrow disease
only are NOT eligible for this study.

- Patients must have been off pharmacologic doses of systemic steroids for at least 7
days prior to enrollment. Patients who require or are likely to require pharmacologic
doses of systemic corticosteroids while receiving treatment on this study are
ineligible. The only exception is for patients known to require 2 mg/kg or less of
hydrocortisone (or an equivalent dose of an alternative corticosteroid) as
premedication for blood product administration in order to avoid allergic transfusion
reactions. The use of conventional doses of inhaled steroids for the treatment of
asthma is permitted, as is the use of physiologic doses of steroids for patients with
known adrenal insufficiency.

- Patients must not have received enzyme-inducing anticonvulsants including phenytoin,
phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study
enrollment. Patients receiving non-enzyme inducing anticonvulsants such as gabapentin
or levetiracetam will be eligible.

- Patients must not have been diagnosed with myelodysplastic syndrome or with any
malignancy other than neuroblastoma.

- Patients with symptoms of congestive heart failure are not eligible.

- Patients must not have ≥ Grade 2 diarrhea

- Patients must not have uncontrolled infection.

- Patients who have received prior therapy with an mTOR inhibitor in combination with
cytotoxic chemotherapy are not eligible.

- Patients with a history of significant allergic reactions attributed to compounds of
similar chemical or biologic composition to temsirolimus are not eligible.

- Patients with a history of Grade 4 allergic reactions to anti-GD2 antibodies or
reactions that required discontinuation of the anti-GD2 therapy are not eligible.

- Patients with a significant intercurrent illness (any ongoing serious medical problem
unrelated to cancer or its treatment) that is not covered by the detailed exclusion
criteria and that is expected to interfere with the action of study agents or to
significantly increase the severity of the toxicities experienced from study
treatment are not eligible.

- Patients with elevated catecholamines (ie, > 2 x ULN) only or bone marrow disease
only are NOT eligible for this study.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of Patients who are Responders

Outcome Description:

Criteria (toxicity, feasibility, Progression Free Survival) will be used to answer the primary study objective. Patient's response is to be assessed for determination of the best overall response is after the completion of the first 6 cycles.

Outcome Time Frame:

Four months

Safety Issue:


Principal Investigator

Rajen Mody, MD, MS

Investigator Role:

Study Chair

Investigator Affiliation:

C.S. Mott Children's Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

March 2013

Completion Date:

Related Keywords:

  • Neuroblastoma
  • Refractory Relapsed or Progressive Neuroblastoma
  • Neuroblastoma