High-Risk Neuroblastoma Chemotherapy Without G-CSF

Study Overview
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Brief Summary
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Patients will be asked to participate in this study because patients have been diagnosed with high-risk neuroblastoma, a common childhood cancer which has aggressive features. If left untreated, high-risk neuroblastoma is fatal. Children with high-risk neuroblastoma often respond to current available treatments, but there is a high risk that the cancer will return. This study will test the safety of giving standard induction treatment for high-risk neuroblastoma without one of the drugs commonly used to prevent side effects. Current treatment for high-risk neuroblastoma includes anti-cancer drugs (chemotherapy), surgery, radiation therapy and high-dose chemotherapy with hematopoietic stem cell rescue. Treatment takes about one year to complete and occurs in 3 phases: induction, consolidation, and maintenance. This study is limited to the induction phase of treatment. Induction therapy includes six chemotherapy drugs given in different combinations every 3 weeks for a total of 6 courses. For the past decade, induction chemotherapy has been followed by a drug called granulocyte colony stimulating factor (G-CSF, filgrastim, peg-filgrastim, Neupogen, or Neulasta) to prevent side effects from the chemotherapy. G-CSF is routinely given to patients with high risk neuroblastoma after chemotherapy to stimulate white blood cell production and shorten the time period when the absolute neutrophil count (ANC), a type of white blood cell, is low after chemotherapy. G-CSF is known to shorten the period of low ANC by approximately 3 days. When the ANC is lowest, a patient is most at risk of getting a bacterial infection. Recent lab experiments in mice have shown that neuroblastoma tumor cells may respond to G-CSF by growing faster and metastasizing (spreading to other parts of the body). There have been no clinical trials comparing the survival of children with high risk neuroblastoma with or without G-CSF. This clinical trial is the first step towards giving induction chemotherapy with less G-CSF. The goal of this study is to determine if it is safe to give induction chemotherapy to children with neuroblastoma without giving G-CSF routinely.

Detailed Description
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Chemotherapy: CYCLE 1+2: Topotecan and cyclophosphamide Cycle 3+5: Cisplatin and Etoposide Cycle 4+6: Vincristine, Cyclophosphamide and Doxorubicin Stem cell collection: After the third cycle of chemotherapy, stem cells will be collected for possible stem cell transplantation at a later date using apheresis. In order to have enough stem cells present in the blood, the patient will need to receive daily G-CSF injections before this collection. Surgery: After the 5th cycle of chemotherapy, most patients will have surgery to remove as much remaining tumor as possible. Growth factor support: Growth factors to increase the number of white blood cells, G-CSF and GM-CSF(granulocyte-macrophage colony stimulating factor) will not be given routinely in this study. GM-CSF will be given for patients who have serious bacterial infections or delays in administering chemotherapy because of low neutrophil counts. All people enrolled on the study will receive GM-CSF prior to having surgical removal of the main tumor. All people enrolled on the study will also receive G-CSF prior to having patients stem cells collected. Optional survey: This research study includes an optional survey regarding quality of life while on the study. This survey will be filled out after cycles 1 and 4 of chemotherapy. Drug Shortages: In the event of a drug shortage of a medication that is not a G-CSF or GM-CSF product, the provider may use best clinical judgment regarding omission of the agent or substitution with a different agent. The medical and research records of study patients should reflect that the patient was informed of any delays and/or modifications in protocol therapy related to the shortage of the agent and the associated risks.

Official Title
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A Safety Pilot Study of High Risk Induction Chemotherapy for Neuroblastoma Without Prophylactic Administration of Myeloid Growth Factors

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: Topotecan
* Drug: Cyclophosphamide
* Drug: Cisplatin
* Drug: Etoposide
* Drug: Vincristine
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Sargramostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than 12 months and less than 18 years old at diagnosis Newly diagnosed neuroblastoma or ganglioneuroblastoma as verified by histology and/or demonstration of tumor cells in bone marrow with elevated urinary catecholamine metabolites Must meet criteria for High Risk disease Patients with International Neuroblastoma Staging System (INSS) stage 4 disease are eligible with the following: MYCN gene amplification (greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features, Age greater than 18 months ( greater than 547 days) regardless of biologic features, Age 12 -18 months (365 - 547 days) with any of the following unfavorable biologic features (unfavorable pathology and/or DNA index = 1) or any biologic feature that is indeterminate/unsatisfactory/unknown Patients with INSS stage 3 disease are eligible with the following: MYCN amplification, regardless of age or additional biologic features, Age greater than 18 months ( greater than 547 days) with unfavorable pathology, regardless of MYCN status Patients with INSS stage 2a/2b with MYCN amplification regardless of age or additional biologic features Patients greater than or equal to 365 days initially diagnosed with INSS stage 1 or 2 who progressed to a stage 4 without interval chemotherapy Patients may have had no prior systemic therapy except: Localized emergency radiation to sites of life threatening or functioning disease, No more than 1 cycle of chemotherapy according to low or intermediate risk regimens prior to determination of MYCN amplification and histology, as long as the patient DID NOT receive any type of granulocyte colony stimulating factor (G-CSF) as part of that therapy. Patients must have adequate hematopoietic function defined as: Absolute neutrophil count (ANC) greater than or equal to 750/μL, Platelet count greater than or equal to 75,000/μL, The above criteria do not have to be met if the patient has bone marrow involvement of tumor. Patients must have adequate liver function defined as: Direct bilirubin less than or equal to 1.5 mg/dL or total bilirubin ≤ 1.5 mg/dL, aspartate aminotrasnferase (AST) and alanine aminotransferase (ALT) less than or equal to10 x upper limit of normal for age Patients must have adequate renal function as defined as: Creatinine clearance (CrCl) or radioisotope glomerular filtration rate (GFR) greater than or equal to 70 mL/min/.73 m2 OR A serum creatinine based on age/gender. Patients must have adequate cardiac function as defined as: Shortening fraction of greater than or equal to 27 % by echocardiogram, or Ejection fraction of greater than or equal to 50 % by radionuclide angiogram Exclusion Criteria: Patients who do not meet inclusion criteria Patients who are pregnant or lactating Patients who have received G-CSF since the time of diagnosis of the current disease

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neuroblastoma treatment without G-CSF<br>Induction chemotherapy only, including 6 cycles of chemotherapy, tumor resection, and stem cell collection | Drug: Topotecan<br>* CYCLE 1+2 (given by intravenous catheter daily for 5 days)<br>* Other names: hycamtin;Drug: Cyclophosphamide<br>* CYCLE 1+2 (given by intravenous catheter daily for 5 days)<br>* Other names: Cytoxan;Drug: Cisplatin<br>* Cycle 3+5 (given daily x 4 days)<br>* Other names: Platinol;Drug: Etoposide<br>* Cycle 3+5 (given daily for 3 days)<br>Drug: Vincristine<br>* Cycle 4+6 (given daily for 3 days)<br>* Other names: Oncovin;Drug: Cyclophosphamide<br>* Cycle 4+6 (given daily for 2 days)<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Cycle 4+6 (given daily for 3 days)<br>* Other names: Adriamycin;Drug: Sargramostim<br>* Granulocyte macrophage colony stimulating factor (rhu GM-CSF, rGM-CSF, GM-CSF)<br>* Other names: GM-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Infection | Incidence of infections in chemotherapy cycles NOT followed by hematopoietic growth factors | through study completion, approximately 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delay in Chemotherapy Administration Due to Prolonged Neutrophil Recovery | incidence of delay in chemotherapy administration due to prolonged neutrophil recovery | through study completion, approximately 5 months | 
| the Response Rate Following Induction Chemotherapy Without Prophylactic Granulocyte Colony Stimulating Factor (G-CSF) | Response rate in the participants that completed all 6 cycles of induction chemotherapy on study. Response rate as categorize by International neuroblastoma response criteria. Complete response (CR): No evidence of primary tumor; no evidence of metastases (chest, abdomen, liver, bone, bone marrow, nodes, etc.), and urine catecholamines homovanillic acid (HVA)/ vanillylmandelic acid (VMA) normal. MIBG scan must be negative to qualify for CR. Very good partial response (VGPR): Greater than 90% reduction in primary tumor; no metastatic tumor (as above except bone); no new bone lesions, all pre-existing lesions improved, HVA/VMA normal Partial Response (PR): 50-90% reduction of primary tumor; 50% or greater reduction in measurable sites of metastases; 0-1 bone marrow samples with tumor; number of positive bone sites decreased by 50% | through study completion, approximately 5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sargramostim, Cyclophosphamide, Topotecan, Cisplatin, Dexrazoxane, Doxorubicin, Etoposide, Filgrastim, Vincristine, Mesna