Phase III Study of Sequential Chemotherapy Regimens, Local Radiotherapy, and Marrow Chemoablation/Autologous Bone Marrow Rescue in Children and Adolescents Over 1 Year Old with Stage 4 or Stage 2B/3 N-myc-Amplified Neuroblastoma, with Investigational Window Study of CTX/TOPO in Stage 4 Patients
Basic Trial Information
|Phase III||Treatment||Closed||365 days to 20 years||NCI||POG-9340-42|
POG-9340, POG-9341, POG-9342
I. Evaluate the response rate and toxicity experienced by adolescents and children at least 365 days of age with previously untreated INSS Stage 4 neuroblastoma treated with 2 courses of cyclophosphamide/topotecan (CTX/TOPO) in an investigational window setting prior to Phase III therapy (POG-9340). II. Measure response rate, toxicity, event-free and overall survival, and patterns of failure among children and adolescents with INSS Stage 4 or N-myc amplified INSS Stage 2B/3 neuroblastoma treated sequentially with high-dose cisplatin/etoposide (CDDP/VP-16), CTX/doxorubicin/vincristine (CAV), ifosfamide/VP-16, carboplatin/VP-16, CDDP/VP-16, and CAV, local radiotherapy, and marrow chemoablation/autologous bone marrow rescue (ABMT) (POG-9341 and POG-9342). III. Measure these same endpoints in children and adolescents for whom ABMT is refused and who instead receive 5 additional courses of multiregimen chemotherapy followed by local radiotherapy (POG-9341). IV. Evaluate further the toxicity of ABMT using marrow-ablative CTX/VP-16/carboplatin following local radiotherapy (POG-9342). V. Measure event-free survival, overall survival, and patterns of failure among patients who achieve a complete, partial, or mixed response following induction chemotherapy and prior to ABMT. VI. Evaluate further the biologic parameters of neuroblastoma as required for POG-9047, and measure and correlate initial and subsequent P-glycoprotein levels in marrow or tumor tissue with clinical presentation at diagnosis, clinical course, response to therapy, and survival.
Newly diagnosed, histologically proven neuroblastoma Eligible stages according to International Staging System: Stage 4 with any N-myc number Stage 2B/3 with N-myc amplification (> 1 copy per haploid genome) Histologic verification waived for Stage 4 patients with either: Extensive disease with bone marrow positive for tumor and elevated urinary catecholamines OR Positive marrow aspirate and negative urinary catecholamines but with positive electron microscopic findings or neuron-specific enolase in the marrow and presence of a primary thoracic or abdominal lesion containing calcifications Stage 2B/3 patients must be entered from protocol POG-9244 after determination of N-myc status and after 1 course of OPEC (vincristine/cyclophosphamide/cisplatin/etoposide) on that protocol Direct entry to protocol POG-9341 allowed after POG-9244 closes Measurable disease required Concurrent registration on protocol POG-9047 required Concurrent registration on protocol POG-9280 (intergroup Neuroblastoma Epidemiology Study) strongly encouraged for Stage D patients
No prior therapy
Age: At least 365 days to under 21 years Performance status: Not specified Hematopoietic: Not specified Hepatic: Not specified Renal: Not specified
137 patients will be entered over 1.2 years to protocol POG-9341. If more than 5 transplant-related fatalities occur among the first 30 patients or if more than 10 occur prior to completion of accrual, the study may close early.
DIAGNOSTIC SURGERY is highly recommended, even in patients with positive bone marrow. PROTOCOL POG-9340: Stage 4 patients initially receive 2 courses of combination chemotherapy on Regimen A in an INVESTIGATIONAL WINDOW (in case of life-threatening disease or refusal of treatment on the Investigational Window, patients may begin Induction directly). PROTOCOL POG-9341: Stage 4 patients begin INDUCTION following Investigational Window, while Stage 2B/3 patients will have received 1 course of OPEC chemotherapy on protocol POG-9244 prior to starting Induction. Patients in clinical CR, PR, or MR who have a negative marrow following Induction undergo POST-INDUCTION SURGERY followed by INTERIM THERAPY and, if still eligible, ABMT on protocol POG-9342; responders not eligible for or refusing ABMT do not undergo surgery at this time and begin POST-INDUCTION CHEMOTHERAPY/RADIOTHERAPY, while patients with no response go off study. PROTOCOL POG-9342: MARROW ABLATION/AUTOLOGOUS RESCUE. The following acronyms are used: ABM Autologous bone marrow ABMT Autologous bone marrow transplantation CAV CTX/DOX/VCR CBDCA Carboplatin, NSC-241240 CDDP Cisplatin, NSC-119875 CTX Cyclophosphamide, NSC-26271 DOX Doxorubicin, NSC-123127 G-CSF Granulocyte Colony Stimulating Factor (Amgen), NSC-614629 GM-CSF Granulocyte-Macrophage Colony Stimulating Factor (Immunex), NSC-613795 HD CDDP High-dose CDDP IFF Ifosfamide, NSC-109724 Mesna Mercaptoethane sulfonate, NSC-113891 TOPO Topotecan, NSC-609699 VCR Vincristine, NSC-67574 VP-16 Etoposide, NSC-141540 DIAGNOSTIC SURGERY. Biopsy with tumor excision as indicated. PROTOCOL POG-9340. INVESTIGATIONAL WINDOW. Regimen A: 2-Drug Combination Chemotherapy. CTX/TOPO. PROTOCOL POG-9341. INDUCTION: 5 Sequential 2- and 3-Drug Combination Chemotherapy Regimens: CDDP/VP-16; followed by CAV; followed by IFF/VP-16; followed by CBDCA/VP-16; followed by CDDP/VP-16. POST-INDUCTION SURGERY (Patients clinically eligible for ABMT): Documentation of disease status, tumor resection as indicated. INTERIM THERAPY (Patients eligible for ABMT): 3-Drug Combination Chemotherapy followed by Radiotherapy. CAV; followed by tumor-bed irradiation with Co60 or accelerator beams of at least 4 MV. Marrow harvested between CAV and radiotherapy. POST-INDUCTION CHEMOTHERAPY/RADIOTHERAPY (Patients ineligible for or refusing ABMT): 5 Sequential 2- and 3-Drug Combination Chemotherapy Regimens followed, in selected patients, by Radiotherapy. IFF/VP-16; followed by CAV; followed by CDDP/VP-16; followed by CAV; followed by CBDCA/VP-16; followed, in patients refusing ABMT, by local irradiation as in INTERIM THERAPY. PROTOCOL POG-9342. MARROW ABLATION/AUTOLOGOUS RESCUE: 3-Drug Combination Ablative Chemotherapy followed by Autologous Bone Marrow Rescue followed by Hematopoietic Stimulation. VP-16/CBDCA/CTX; followed by ABM; followed by GM-CSF.
Zage PE, Kletzel M, Murray K, et al.: Outcomes of the POG 9340/9341/9342 trials for children with high-risk neuroblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 747-53, 2008.[PUBMED Abstract]
Kretschmar CS, Kletzel M, Murray K, et al.: Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a pediatric oncology group study. J Clin Oncol 22 (20): 4119-26, 2004.[PUBMED Abstract]
Cantos MF, Gerstle JT, Irwin MS, et al.: Surgical challenges associated with intensive treatment protocols for high-risk neuroblastoma. J Pediatr Surg 41 (5): 960-5, 2006.[PUBMED Abstract]
Trial Contact Information
Trial Lead Organizations
Pediatric Oncology Group
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.