Clinical trial NCT00410631: Observation, Combination Chemotherapy, Radiation Therapy, and/or Autologous Stem Cell Transplant in Treating Young Patients With Neuroblastoma
Official title: NB2004 Trial Protocol for Risk Adapted Treatment of Children With Neuroblastoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Neuroblastoma
Keywords: localized resectable neuroblastoma
localized unresectable neuroblastoma
regional neuroblastoma
stage 4S neuroblastoma
disseminated neuroblastoma
recurrent neuroblastoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-12-13
Enrollment: 642
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving combination chemotherapy may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. An autologous stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. This may allow more chemotherapy to be given so that more tumor cells are killed. Sometimes, after surgery, the tumor may not need more treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether observation is more effective than combination chemotherapy, radiation therapy, and/or autologous stem cell transplant in treating neuroblastoma.

PURPOSE: This randomized phase III and phase IV trial is studying observation, combination chemotherapy, radiation therapy, and/or autologous stem cell transplant to compare how well they work in treating young patients with neuroblastoma.

Detailed description: OBJECTIVES:

Primary

* Determine the event-free survival (EFS) of younger patients with newly diagnosed neuroblastoma categorized in the low-risk group (LRG) who undergo observation only or receive combination chemotherapy.
* Compare the EFS rate in patients with neuroblastoma categorized in the medium-risk group (MRG) treated with combination induction therapy, maintenance therapy, and consolidation therapy with that of a historical control group.
* Compare the EFS in patients with neuroblastoma categorized in the high-risk group (HRG) treated with standard vs experimental induction therapy followed by autologous stem cell transplantation and consolidation therapy.

Secondary

* Determine the locoregional EFS of patients in the LRG, MRG, or HRG.
* Determine the overall survival of these patients.
* Determine the extent of initial surgery, the extent or impact of best surgery, and surgery-related complications in these patients.
* Determine the time to transition to stage 4 disease in patients in the LRG or MRG.
* Determine the time to a locoregional event in patients in the LRG or HRG.
* Determine the time from diagnosis to an event in patients in the LRG.
* Determine the time from the beginning of regression to an adverse event in patients in the LRG.
* Determine the time to the beginning of primary tumor regression in patients in the LRG.
* Determine the time to the normalization of tumor markers in patients in the LRG.
* Determine the time to no evidence of disease in patients in the LRG with stage 4S disease.
* Assess the status of the primary tumor at 12 months and the best status of the primary tumor within 12 months in patients in the LRG.
* Determine the need for chemotherapy to control progression and the intensity of therapy required in patients in the LRG.
* Determine the acute and late side effects of external-beam radiotherapy in patients in the MRG or HRG.
* Determine the response to induction therapy in patients in the HRG.
* Assess early response after 2 courses of induction therapy in patients in the HRG.
* Determine the toxicity during induction courses 1 and 2 and the frequency of grade 3 or 4 toxicity during induction therapy in patients in the HRG.
* Assess the efficacy of iodine I 131 metaiodobenzylguanidine (MIBG) therapy, in terms of activity and whole body dose, in patients in the HRG.
* Assess molecular markers (e.g., chromosome 1p, chromosome 11q, neuroblastoma gene chip) in these patients.

OUTLINE: This is a prospective, historically controlled, randomized, open-label, multicenter study. Patients are stratified according to disease risk (low-risk vs medium-risk vs high-risk).

* Low-risk group: Patients undergo complete staging 3 months after initial surgery. Patients with no progression are observed for 12 months (for patients over 1 year of age) or until the end of the second year of life (for patients 1 year of age or younger). Patients with localized progression or threatening symptoms undergo N4 chemotherapy comprising doxorubicin hydrochloride IV over 30 minutes and vincristine IV on days 1, 3, and 5 and cyclophosphamide IV over 30 minutes on days 1-7. Treatment repeats every 21 days for up to 4 courses. Patients are reassessed after each course of N4 chemotherapy. Patients achieving stable disease or tumor regression at any point discontinue N4 chemotherapy and undergo observation. Patients with persistent progressive disease after 4 courses of N4 chemotherapy proceed to treatment as in the medium-risk group. Patients who progress to stage 4 disease after initial surgery proceed to treatment as in the medium-risk group (for patients 1 year of age or younger and no indication of stage 4S disease) or high-risk group (for patients over 1 year of age).
* Medium-risk group: Patients receive induction therapy followed by maintenance therapy and consolidation therapy.

  * Induction therapy: Patients\* receive N5 chemotherapy comprising cisplatin IV continuously over 96 hours and etoposide phosphate IV continuously over 96 hours on days 1-4, vindesine IV over 1 hour on day 1, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 9 and continuing until blood counts recover. Patients then receive N6 chemotherapy comprising vincristine IV over 1 hour on days 1 and 8, dacarbazine IV over 1 hour and ifosfamide IV continuously over 120 hours on days 1-5, doxorubicin hydrochloride IV over 4 hours on days 6 and 7, and G-CSF beginning on day 10 and continuing until blood counts recover. Treatment repeats every 21 days alternating between N5 and N6 chemotherapy for up to 6 total courses (3 courses of N5 and N6 each). Patients then proceed to maintenance therapy.

NOTE: \*Patients under 6 months of age receive up to 4 courses of N4 chemotherapy (as in the low-risk group) instead of N5/N6 chemotherapy until they reach 6 months of age.

Patients with active residual tumor after induction chemotherapy undergo external-beam radiotherapy (EBRT) for up to 25 fractions concurrently with maintenance chemotherapy. Secondary surgery for resection of the primary tumor is attempted after course 4 or 6 of the induction therapy and before EBRT.

* Maintenance therapy: Patients receive N7 chemotherapy comprising cyclophosphamide orally or IV over 1 hour on days 1-8. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
* Consolidation therapy: Beginning 21 days after completion of maintenance therapy, patients receive oral isotretinoin 2-3 times daily on days 1-14. Treatment repeats every 28 days for up to 6 courses in the absence of unacceptable toxicity. Patients then receive 3 additional courses after 3-months of rest.

  * High-risk group: Patients receive induction therapy followed by autologous stem cell transplantation (ASCT) and consolidation therapy.
* Induction therapy: Patients 1 year of age and over are randomized to 1 of 2 treatment arms. Patients under 1 year of age do not undergo randomization; instead they are assigned to arm I.

  * Arm I (standard): Patients\* receive N5 and N6 chemotherapy as in induction therapy for the medium-risk group.
  * Arm II (experimental): Patients receive N8 chemotherapy comprising topotecan hydrochloride IV continuously over 168 hours and cyclophosphamide IV over 1 hour on days 1-7, etoposide IV over 1 hour on days 8-10, and G-CSF SC beginning on day 12 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients then receive N5 and N6 chemotherapy as in induction therapy for the medium-risk group.

In both arms, patients with active residual primary tumor after 6 courses of induction therapy undergo iodine I 131 metaiodobenzylguanidine (MIBG)\*\* radiotherapy (before ASCT). Patients also undergo EBRT for up to 25 fractions after ASCT. Secondary surgery for resection of the primary tumor is attempted after course 4 or 6 of induction therapy and before radiotherapy.

NOTE: \*Patients under 6 months of age receive up to 4 courses of N4 chemotherapy (as in the low-risk group) instead of N5/N6 chemotherapy until they reach 6 months of age.

NOTE: \*\*Patients with MIBG-negative disease undergo EBRT only.

* Conditioning followed by ASCT: Patients receive melphalan IV over 30 minutes on days -8 to -5, etoposide phosphate IV over 4 hours on day -4, and carboplatin IV over 1 hour on days -4 to -2. Patients undergo ASCT on day 0. Patients receive G-CSF SC beginning on day 2 and continuing until blood counts recover.
* Consolidation therapy: Beginning 30 days after ASCT, patients receive isotretinoin\* as in consolidation therapy for the medium-risk group.

NOTE: \*Isotretinoin is discontinued during EBRT and restarted 1 week after completion of EBRT.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 642 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of neuroblastoma by histology using tumor tissue or as evidenced by the presence of distinct neuroblastoma cells in the bone marrow AND elevated catecholamine metabolites (i.e., homovanillic acid \[HVA\] and vanillylmandelic acid \[VMA\]) in blood or urine

  * Newly diagnosed disease (for patients in the low-risk group)
  * Diagnosis from tumor tissue (for patients in the medium-risk group)
* Meets criteria for 1 of the following risk groups:

  * Low-risk group

    * No MYCN amplification AND meets 1 of the following criteria:

      * Stage 1 disease
      * Stage 2 disease with no chromosome 1p deletion or imbalance
      * Stage 3 disease with no chromosome 1p deletion or imbalance (for patients \< 2 years of age)
      * Stage 4S disease (for patients \< 1 year of age)
  * Medium-risk group

    * No MYCN amplification AND meets 1 of the following criteria:

      * Stage 2 disease with chromosome 1p deletion or imbalance
      * Stage 3 disease with chromosome 1p deletion or imbalance

        * Any chromosome 1p status (for patients ≥ 2 years of age)
      * Stage 4 disease (for patients \< 1 year of age)
  * High-risk group, meeting 1 of the following criteria:

    * Any stage disease with MYCN amplification

      * Any MYCN status (for patients ≥ 1 year of age)

PATIENT CHARACTERISTICS:

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

* No prior nephrectomy or other mutilating surgery as initial surgery (for patients in the low-risk group)
* No other concurrent anticancer therapy

Primary outcomes:
measure: Event-free survival (EFS)
measure: Locoregional EFS
Secondary outcomes:
measure: Time from diagnosis to transition to stage 4 disease, to death from disease, or to the last follow-up (if no transition to stage 4 disease is observed)
measure: Overall survival
measure: Time to the beginning of primary tumor regression (in patients in the low-risk group [LRG])
measure: Time to the normalization of tumor markers HVA and VMA in urine
measure: Time to no evidence of disease (in patients in the LRG with stage 4S disease)
measure: Status of the primary tumor 12 months after diagnosis (LRG)
measure: Best status of the primary tumor within the first 12 months (LRG)
measure: Status of chromosome 1p (unblinded) and status of chromosome 11q (blinded)
measure: Comparison of the extent of initial surgery (incomplete resection vs macroscopic complete resection) (LRG)
measure: Comparison of the extent of best surgery during protocol treatment (incomplete resection vs macroscopic complete resection)
measure: Surgery-related complications (i.e., bleeding, infection, intestinal obstruction, or other)
measure: Disease progression and symptoms controlled after the first, second, third, and fourth N4 course (LRG)
measure: Disease progression and symptoms not controlled after four N4 courses (LRG)
measure: Transition to stage 4 disease at any time (LRG)
measure: Acute and late side effects of external-beam radiotherapy (medium-risk group [MRG] and high-risk group [HRG])
measure: Early response after 2 courses of induction therapy (N5 and N6 or two courses of N8) (HRG)
measure: Response to induction therapy prior to conditioning therapy or after 280 days (HRG)
measure: Grade of toxicity observed during induction therapy course 1 (N5 or N8) (HRG)
measure: Grade of toxicity observed during induction therapy course 2 (N6 or N8) (HRG)
measure: Frequency of grade 3 or 4 toxicity observed during the last 6 courses of induction therapy (3 courses of N5 and N6) (HRG)
measure: Activity and whole body dose of radiotherapy
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Kinderklinik - Universitaetsklinikum Aachen
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bamberg
country: Germany
facility: Klinikum am Bamberg
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: Helios Klinikum Berlin
city: Berlin
country: Germany
facility: Charite University Hospital - Campus Virchow Klinikum
city: Biefeld
country: Germany
facility: Evangelisches Krankenhauus Bielfeld
city: Bonn
country: Germany
facility: Kinderklinik der Universitaet Bonn
city: Braunschweig
country: Germany
facility: Staedtisches Klinikum - Howedestrase
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Celle
country: Germany
facility: Allgemeinen Krankenhaus Celle Kinderklinik
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Coburg
country: Germany
facility: Klinikum Coburg
city: Cologne
country: Germany
facility: Kliniken der Stadt Koeln gGmbH - Kinderkrankenhaus Riehl
city: Cologne
country: Germany
facility: Children's Hospital
city: Cottbus
country: Germany
facility: Carl - Thiem - Klinkum Cottbus
city: Datteln
country: Germany
facility: Vestische Kinderklinik
city: Detmold
country: Germany
facility: Klinikum Lippe - Detmold
city: Dortmund
country: Germany
facility: Klinikum Dortmund
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus
city: Duesseldorf
country: Germany
facility: Universitaets - Frauenklinik, Duesseldorf
city: Duisburg
country: Germany
facility: Klinikum Duisburg
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
city: Erlangen
country: Germany
facility: Universitaets - Kinderklinik
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Universitaetskinderklinik - Universitaetsklinikum Freiburg
city: Giessen
country: Germany
facility: Kinderklinik
city: Goettingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Greiswald
country: Germany
facility: Universitats - Kinderklinik
city: Halle
country: Germany
facility: Universitaetsklinikum Halle
city: Halle
country: Germany
facility: Krankenhaus St. Elisabeth und St. Barbara
city: Hamburg
country: Germany
facility: University Medical Center Hamburg - Eppendorf
city: Hannover
country: Germany
facility: Kinderkrankenhaus auf der Bult
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitaets-Kinderklinik Heidelberg
city: Heilbronn
country: Germany
facility: SLK - Kliniken Heilbronn GmbH - Klinikum am Gesundbrunnen
city: Herdecke
country: Germany
facility: Gemeinschaftskrankenhaus
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Jena
country: Germany
facility: Universitaets - Kinderklinik
city: Jena
country: Germany
facility: Universitaets - Kinderklinik
city: Karlsruhe
country: Germany
facility: Staedtisches Klinikum Karlsruhe gGmbH
city: Kassel
country: Germany
facility: Kinderkrankenhaus Park Schoenfeld
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Koblenz
country: Germany
facility: Klinikum Kemperhof Koblenz
city: Krefeld
country: Germany
facility: Klinikum Krefeld GmbH
city: Ludwigshafen
country: Germany
facility: St. Annastift Krankenhaus
city: Luebeck
country: Germany
facility: Universitaets - Kinderklinik - Luebeck
city: Magdeburg
country: Germany
facility: Universitatsklinikum der MA
city: Mainz
country: Germany
facility: Johannes Gutenberg University
city: Mannheim
country: Germany
facility: Staedtisches Klinik - Kinderklinik
city: Marburg
country: Germany
facility: Universitaets - Kinderklinik
city: Minden
country: Germany
facility: Klinikum Minden
city: Muenster
country: Germany
facility: University of Muenster
city: Munich
country: Germany
facility: Krankenhaus Muenchen Schwabing
city: Munich
country: Germany
facility: Dr. von Haunersches Kinderspital der Universitaet Muenchen
city: Munich
country: Germany
facility: Klinikum der Universitaet Muenchen - Grosshadern Campus
city: Munich
country: Germany
facility: Staedtisches Krankenhaus Muenchen - Harlaching
city: Neubrandenburg
country: Germany
facility: Klinikum Neubrandenburg
city: Neunkirchen
country: Germany
facility: Kinderklinik Kohlhof
city: Nuremberg
country: Germany
facility: Cnopf'sche Kinderklinik
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Regensburg
country: Germany
facility: Klinik St. Hedwig-Kinderklinik
city: Rostock
country: Germany
facility: Kinderklinik - Universitaetsklinikum Rostock
city: Siegen
country: Germany
facility: Kinderklink Siegen Deutsches Rotes Kreuz
city: St. Augustin
country: Germany
facility: Johanniter-Kinderklinik
city: Stuttgart
country: Germany
facility: Olgahospital
city: Trier
country: Germany
facility: Krankenanstalt Mutterhaus der Borromaerinnen
city: Tuebingen
country: Germany
facility: Universitaets-Kinderklinik
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Ulm
country: Germany
facility: Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
city: Wilhelmshaven
country: Germany
facility: Reinhard-Nieter-Krankenhaus
city: Wuerzburg
country: Germany
facility: Universitaets - Kinderklinik Wuerzburg
city: Wuppertal
country: Germany
facility: Helios Kliniken Wuppertal University Hospital
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Universitaets-Kinderspital beider Basel
city: Lucerne 16
country: Switzerland
facility: Kinderspital Luzern
city: St. Gallen
country: Switzerland
facility: Ostschweizer Kinderspital
city: Zurich
country: Switzerland
facility: University Children's Hospital
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Frank Berthold, MD
role: STUDY_CHAIR
References:
citation: Decarolis B, Simon T, Krug B, Leuschner I, Vokuhl C, Kaatsch P, von Schweinitz D, Klingebiel T, Mueller I, Schweigerer L, Berthold F, Hero B. Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed. BMC Cancer. 2016 Jul 27;16:542. doi: 10.1186/s12885-016-2513-9.