Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Neuroblastoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: This randomized phase III trial is studying peripheral stem cell transplantation with treated peripheral stem cells following combination chemotherapy to see how well it works compared to peripheral stem cell transplantation with untreated peripheral stem cells following combination chemotherapy in treating patients with neuroblastoma.

Detailed Description
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OBJECTIVES: Primary Compare the event-free survival in patients with newly diagnosed high risk neuroblastoma or ganglioneuroblastoma treated with myeloablative consolidation chemotherapy and autologous purged versus unpurged peripheral blood stem cells (PBSC). Compare the time to engraftment and CD34 content and tumor content by reverse transcriptase polymerase chain reaction (RT-PCR) of purged versus unpurged PBSC in patients treated with these regimens. Determine event-free survival of patients treated with dose intensive induction chemotherapy comprising cyclophosphamide, doxorubicin, and vincristine alternating with cisplatin and etoposide. Determine the toxicity of this dose-intensive induction chemotherapy regimen in these patients. Evaluate tumor resectability at second look or delayed surgery, response (complete response and very good partial response) at completion of induction therapy, tumor content of peripheral blood and bone marrow, and the comparison of historical data from CCG-3891 induction therapy in these patients. Secondary Compare the toxicity of this myeloablative consolidation regimen using purged vs unpurged PBSC in these patients. Determine if event-free survival is predictable by RT-PCR positivity of the stem cell, minimal residual disease in bone marrow and peripheral blood after transplantation by immunocytology, and extent of disease as measured by MIBG after transplantation in patients treated with these regimens. Evaluate the prognostic impact of tumor biology on event free survival in patients treated with these regimens. Determine the incidence of relapse in the primary site after radiotherapy and in irradiated versus unirradiated metastatic sites in these patients. Assess the toxicity and tolerability of maintenance therapy with topotecan and cyclophosphamide after intensive induction therapy in patients who decline or are unable to receive myeloablative therapy. Determine the health-related quality of life of patients treated with these regimens. Compare late effects of these regimens on the growth, endocrine, pulmonary, and cardiac function of these patients vs general population standards. Determine the incidence of second malignant neoplasms in patients treated with these regimens. Determine the variability of isotretinoin pharmacokinetics and relationship to pharmacogenomic parameters in these patients. Correlate the isotretinoin pharmacokinetics and pharmacogenomic parameters and/or genetic variations in isotretinoin metabolic enzymes with event-free survival or systemic toxicity in these patients. OUTLINE: This is a randomized study. Patients are randomized to one of two treatment arms for peripheral blood stem cell (PBSC) collection. All patients receive induction chemotherapy comprising cyclophosphamide IV over 6 hours on days 0 and 1, doxorubicin IV and vincristine IV continuously over 72 hours on days 0-2, and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 3 and continuing until blood counts recover for courses 1, 2, 4, and 6. Treatment alternates with courses 3 and 5 comprising etoposide IV over 2 hours on days 0-2, cisplatin IV over 1 hour on days 0-3, and G-CSF SC or IV beginning on day 4 and continuing until blood counts recover. Induction chemotherapy repeats every 3 weeks or when blood counts recover in the absence of disease progression or unacceptable toxicity. After course 2 or 3 of induction chemotherapy, patients undergo PBSC collection, either purged or unpurged, depending on randomization. Patients continue on daily G-CSF until cell collection is complete. Arm I: Patients undergo unpurged PBSC collection until the target cell count is reached. Arm II: Patients undergo purged PBSC collection until the target cell count is reached. Patients with immunocytology positive PBSC undergo purged autologous bone marrow collection or repeat purged or unpurged PBSC collection depending on individual patient characteristics. All patients undergo delayed surgical resection of the residual tumor after course 5 of induction chemotherapy. After induction therapy, patients achieving complete response, very good partial response, or partial response receive consolidation therapy comprising melphalan IV on days -7 to -5 followed by carboplatin IV and etoposide IV continuously over days -7 to -4. Patients receive purged or unpurged PBSC infusion or purged autologous bone marrow transplantation on day 0 followed by G-CSF SC or IV beginning 4 hours after completion of transplantation and continuing until blood counts recover. Beginning on day 66, patients receive oral isotretinoin twice daily for 14 days. Isotretinoin therapy repeats every 4 weeks for 6 courses. After completion of consolidation (at least 28 days from stem cell infusion), all patients receive local radiotherapy daily over 7 days. Patients not undergoing transplantation or who are ineligible for consolidation therapy receive maintenance therapy comprising cyclophosphamide IV over 30 minutes followed by topotecan IV over 30 minutes on days 0-4. Patients receive G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. Maintenance therapy repeats every 3 weeks for 3 courses. After completion of maintenance therapy, patients receive radiotherapy as outlined above. Patients then receive oral isotretinoin twice daily for 14 days. Isotretinoin therapy repeats every 4 weeks for 6 courses. Quality of life is assessed at 1* and 5 years. Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter or until disease progression. NOTE: * Patients under 5 years of age at 1 year are not assessed until 5 years. PROJECTED ACCRUAL: A total of 486 patients will be accrued for this study within 4 years.

Official Title
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A Randomized Study of Purged Versus Unpurged Peripheral Blood Stem Cell Transplant Following Dose Intensive Induction Therapy for High Risk Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Biological: filgrastim
* Drug: carboplatin
* Drug: cisplatin
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: etoposide
* Drug: isotretinoin
* Drug: melphalan
* Drug: topotecan hydrochloride
* Drug: vincristine sulfate
* Procedure: autologous bone marrow transplantation
* Procedure: bone marrow ablation with stem cell support
* Procedure: conventional surgery
* Procedure: peripheral blood stem cell transplantation
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed newly diagnosed neuroblastoma OR ganglioneuroblastoma, and/or evidence of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites, meeting 1 of the following criteria: Age greater than 18 months with stage IV disease, regardless of biologic factors Age 12-18 months with stage IV disease meeting one of the following criteria: Any unfavorable biologic feature (e.g., MYCN amplification, unfavorable pathology, and/or DNA index = 1) Any biologic feature that is indeterminate, unsatisfactory, or unknown At least 1 year old with the following: Stage IIa/IIb with MYCN amplification (> 10) AND unfavorable pathology Stage III with MYCN amplification (> 10) OR unfavorable pathology Stage I, II, or IVS with disease progression to stage IV without interval chemotherapy No more than 3 weeks since progression Must have been enrolled on protocol CCG-B973, COG-ANBL00B1, or POG-9047 Less than 1 year old with the following: Stage III, IV, or IVS disease with MYCN amplification (> 10) Registration on protocol COG-ANBL00B1 required within 14 days of diagnosis PATIENT CHARACTERISTICS: Age: See Disease Characteristics 30 and under at time of diagnosis Performance status: Not specified Life expectancy: Not specified Hematopoietic: Absolute neutrophil count ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 Inadequate hematopoiesis secondary to bone marrow involvement with > 10% tumor infiltration allowed Hepatic: Bilirubin ≤ 1.5 mg/dL ALT ≤ 300 units/L Renal: Creatinine ≤ 1.5 mg/dL Creatinine clearance or glomerular filtration rate ≥ 60 mL/min Cardiovascular: ECG normal Ejection fraction ≥ 55% by echocardiogram or MUGA OR Fractional shortening ≥ 28% by echocardiogram Other: Able to tolerate peripheral blood stem cell collection HIV negative Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception for at least 1 month prior to, during, and for 1 month after study participation PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: See Disease Characteristics No more than 1 prior course of chemotherapy on the Intergroup low/intermediate risk neuroblastoma study (P9641, A3961) Endocrine therapy: Not specified Radiotherapy: Prior localized emergency radiotherapy to sites of life-threatening or function-threatening disease allowed Surgery: Not specified Other No other prior systemic therapy

Ages Eligible for Study
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Maximum Age: 30 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (unpurged PBSC collection)<br>Induction-3 wks (cyclophosphamide day 0&1, doxorubicin hydrochloride & vincristine sulfate day 0-2 & filgrastim(G-CSF) day 3 crs 1,2,4 & 6.) Crs 3 & 5 (etoposide day 0-2, cisplatin day 0-3, G-CSF day 4). Pts undergo unpurged PBSC collection until the target cell count is reached. Surgical resection of the tumor after crs 5 of induct. CR, VGPR, PR after induct receive consolidation (melphalan day -7 to -5, carboplatin & etoposide day -7 to -4. purged peripheral blood stem cell transplantation infusion day 0, G-CSF 4 hrs post transplant. Day 66, isotretinoin 2x day/14 days. Isotretinoin every 4 wks 6 crs. After consol (28 days from stem cell infusion), radiation therapy 1x day/7 days. Not undergoing autologous bone marrow transplantation receive maintenance(cyclophosphamide 30 mins, topotecan hydrochloride days 0-4, G-CSF day 5). Maint every 3 wks/3 crs. Radiation therapy and Isotretinoin 2x day/14 days then every 4 wks for 6 crs. | Biological: filgrastim<br>* Given IV<br>* Other names: NSC 614629;Drug: carboplatin<br>* Given IV<br>* Other names: NSC #241240;Drug: cisplatin<br>* Given IV<br>* Other names: NSC #11987;Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC #026271;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: IND #7038;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: isotretinoin<br>* Given IV<br>* Other names: NSC 329481;Drug: melphalan<br>* Given IV<br>* Other names: NSC 008806;Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: NSC #609699;Drug: vincristine sulfate<br>* Given IV<br>* Other names: NSC #067574;Procedure: autologous bone marrow transplantation<br> <br> Procedure: bone marrow ablation with stem cell support<br> <br> Procedure: conventional surgery<br>* All patients undergo delayed surgical resection of the residual tumor after course 5 of induction chemotherapy<br>Procedure: peripheral blood stem cell transplantation<br> <br> Radiation: radiation therapy<br>* After completion of consolidation (at least 28 days from stem cell infusion), all patients receive local radiotherapy daily over 7 days<br>|
| Experimental: Arm II (unpurged PBSC collection)<br>Induction-3 wks (cyclophosphamide day 0&1, doxorubicin hydrochloride & vincristine sulfate day 0-2 & filgrastim(G-CSF) day 3 crs 1,2,4 & 6.) Crs 3 & 5 (etoposide day 0-2, cisplatin day 0-3, G-CSF day 4). Immunocytology + PBSC undergo purged autologous bone marrow collection or repeat purged or unpurged PBSC collection. Surgical resection of the tumor after crs 5 of induct. CR, VGPR, PR after induct receive consolidation (melphalan day -7 to -5, carboplatin & etoposide day -7 to -4. Unpurged peripheral blood stem cell transplantation infusion day 0, G-CSF 4 hrs post transplant. Day 66, isotretinoin 2x day/14 days. Isotretinoin every 4 wks 6 crs. After consol (28 days from stem cell infusion), radiation therapy 1x day/7 days. Not undergoing autologous bone marrow transplantation receive maintenance(cyclophosphamide 30 mins, topotecan hydrochloride days 0-4, G-CSF day 5). Maint every 3 wks/3 crs. Radiation therapy and Isotretinoin 2x day/14 days then every 4 wks for 6 crs. | Drug: carboplatin<br>* Given IV<br>* Other names: NSC #241240;Drug: cisplatin<br>* Given IV<br>* Other names: NSC #11987;Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC #026271;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: IND #7038;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: isotretinoin<br>* Given IV<br>* Other names: NSC 329481;Drug: melphalan<br>* Given IV<br>* Other names: NSC 008806;Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: NSC #609699;Drug: vincristine sulfate<br>* Given IV<br>* Other names: NSC #067574;Procedure: autologous bone marrow transplantation<br> <br> Procedure: bone marrow ablation with stem cell support<br> <br> Procedure: conventional surgery<br>* All patients undergo delayed surgical resection of the residual tumor after course 5 of induction chemotherapy<br>Procedure: peripheral blood stem cell transplantation<br> <br> Radiation: radiation therapy<br>* After completion of consolidation (at least 28 days from stem cell infusion), all patients receive local radiotherapy daily over 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival rate |  | Time from study registration until the time of the first occurrence of either relapse, progression, secondary malignancy, or death, or until the time of last contact with the patient if none of these events occurs, assessed up to 6 years | 
| Rate of occurrence of toxic (non disease-related) deaths where a toxic death will be counted if it occurs prior to the initiation of the immunotherapy |  | Up to day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to engraftment | Engraftment is defined as three consecutive measurements of ANC > 500. | Up to 6 years | 
| CD34 content |  | Up to 6 years | 
| Tumor content as measured by reverse transcriptase polymerase chain reaction |  | Up to 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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localized resectable neuroblastoma, regional neuroblastoma, disseminated neuroblastoma, stage 4S neuroblastoma, localized unresectable neuroblastoma