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Metronomic Treatment in Children and Adolescents With Recurrent or Progressive High Risk Neuroblastoma (METRO-NB2012)

Primary Purpose

Recurrent Neuroblastoma

Status
Recruiting
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
metronomic therapy
Sponsored by
University of Cologne
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Neuroblastoma focused on measuring Recurrent Neuroblastoma

Eligibility Criteria

2 Years - 20 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Newly diagnosed recurrence or progression of high risk neuroblastoma which progressed despite previous treatment (irrespective of the number of previous relapses/progressions).
  • Refractory and/or residual high-risk neuroblastoma with measurable or evaluable disease irrespective of preceding treatment (no Progression during the minimal interval as defined below)
  • Age: ≥ 2 years and < 21 years

  • Measurable or evaluable disease defined as

    • Presence of at least one measurable (recurrent or newly progressing) neuroblastoma lesion ≥ 10 mm by magnetic resonance imaging (MRI) or computed tomography (CT) or
    • Newly detected unambiguous scintigraphic (MIBG) avid bone and/or medullary lesions
    • presence of unambiguous bone marrow metastasis
  • Minimal interval between start of trial medication and preceding anti-cancer treatment is 4 weeks after chemotherapy, 6 weeks after radiotherapy, and 12 weeks after myeloablative therapy
  • Life expectancy > 3 months
  • Good to moderate general condition (performance scale ≥60)
  • No serious infection

  • Spontaneous recovering blood counts:

    • White blood cell count ≥ 1000/µL
    • Neutrophil count ≥ 500/µL
    • Platelet count ≥ 25 000/µL (unsupported)
  • Written informed consent of parents or legal guardian and/ or patient according to age and status of psycho-intellectual development.

Exclusion Criteria:

  • Minimal residual disease status (only) without unambiguous measurable or evaluable disease
  • Patients unable to swallow trial medication
  • Any concomitant anti-cancer treatment (e.g. other cytostatic drugs, "small molecules", antibodies, radiotherapy, surgery of tumor or metastases)
  • Treatment with medication that interact with study medication that cannot be discontinued at least one week prior to the start of trial medication and for the duration of the trial
  • Intake of antihypertensive drugs, e.g. calcium channel blockers
  • Established hypersensitivity to the active or one of the other constituents of the trial medication

  • Severe medical or psychosocial conditions preventing trial participate and/or any of the following

    • Peripheral neuropathy or constipation CTCAE grade 3 or 4
    • Cardiac arrhythmias (sinus bradycardia for age, sinus arrhythmia as 2.-3. grade atrioventricular block)
    • Pre-existing recurrent symptomatic bronchial asthma
    • Diabetes mellitus (propranolol covers symptoms of hypoglycemia)
    • Conditions with low blood pressure below age-dependent normal ranges
    • History of gastrointestinal ulcer or perforation
    • Known active hepatitis B virus (HBV), hepatitis C (HBC) virus or human immunodeficiency virus (HIV) infection
  • Concomitant participation in other clinical trials with investigational drugs or with competing interventions
  • Pregnancy, lactation
  • Sexually active patients not willing to use highly effective contraception

Sites / Locations

  • Children's University HospitalRecruiting
  • Marc HoembergRecruiting
  • Children's University HospitalRecruiting
  • Children's University HospitalRecruiting
  • Children's University HospitalRecruiting
  • Children's Hospital, Medizinische HochschuleRecruiting
  • Children's University HospitalRecruiting
  • Dr. von Haunersches KinderspitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

metronomic therapy

Arm Description

Treatment consists of eight alternating 28-day-cycles of propranolol, celecoxib, cyclophosphamide, vinblastine, etoposide (PCCVE) and of propranolol, celecoxib, cyclophosphamide, vinblastine (PCCV) followed by five cycles PCCV resulting in a total of 13 cycles (364 days of treatment)

Outcomes

Primary Outcome Measures

non-inferiority of EFS compared to historical control group
The primary trial objective is to demonstrate the non-inferiority of event free survival (EFS) in comparison to a historical control group. Event free survival (EFS) defined as time from start of treatment up to Progression (emerged from residual tumor, PD) or recurrence (developing from CR achieved by metronomic treatment), permanent discontinuation of treatment for unacceptable toxicity, secondary malignant neoplasm or death of any reason.

Secondary Outcome Measures

disease control rate at 6 months
Disease control rate at 6 months of metronomic treatment defined as number of patients achieving overall complete response (CR), partial response (PR) or stable disease (SD) related to all treated patients.
Overall survival
Overall survival defined as time from start of treatment until death of any reason or date of last information
hospitalization days
Any patient stay in hospital that includes at least one night from day 1 of metronomic treatment until 30 days after the end of treatment. Overall treatment time is 12 months.
number of transfusion days
The number of days with transfusion of platelets or packed red blood cells. Overall treatment time is 12 months.
drop-out rate
The number and rate of patients stopping metronomic treatment during treatment period due to patients and/or parents wish. Overall treatment time is 12 months.
disease control rate at 12 months
Disease control rate at 12 months of metronomic treatment defined as number of patients achieving overall complete response (CR), partial response (PR) or stable disease (SD) related to all treated patients.

Full Information

First Posted
December 15, 2015
Last Updated
November 3, 2022
Sponsor
University of Cologne
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1. Study Identification

Unique Protocol Identification Number
NCT02641314
Brief Title
Metronomic Treatment in Children and Adolescents With Recurrent or Progressive High Risk Neuroblastoma
Acronym
METRO-NB2012
Official Title
Phase 2 Trial of Metronomic Treatment in Children and Adolescents With Recurrent or Progressive Neuroblastoma (NB)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
December 22, 2016 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cologne

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Neuroblastoma is the second most frequent cause for death from cancer in childhood. Already one year after diagnosis of recurrence from high risk neuroblastoma, 75% of the patients experience further progression. Metronomic therapy is targeting not only the tumor cell, but also the tumor supplying vasculature and the interactions between Tumor and immune cells. The toxicity is expected to be low due to the low (but continuous) dosing of drugs. The study investigates the tolerance and the efficacy of a new combination of five drugs consisting of propranolol (antiangiogenetic, anti-neuroblastic), Celecoxib (modulating immune response, ant-neuroblastic), cyclophosphamide (antiangiogenetic, anti-neuroblastic), etoposide (antiangiogenetic, anti-neuroblastic), and vinblastin (antiangiogenetic, anti-neuroblastic). Vinblastin is scheduled every 14 days intravenously, all other drugs are applied daily throughout 365 days (except etoposide for 4x3 weeks). The efficacies of each of the drugs have been demonstrated in vitro and in vivo in animal studies. All drugs have been used in children for other conditions. From those experiences low toxicities and a favorable Quality of life are expected.
Detailed Description
Neuroblastoma relapses during or after intensive therapy most likely result from the presence of primary or acquired drug resistance. Therefore, new therapeutic modalities for salvage therapies are urgently needed. The historical Kaplan-Meier curves of 218 unselected high risk patients after the first recurrence (from CR) or after the first progression (from PR/SD) demonstrate a 1 year event free survival rate of 25.2 ± 2.9% and a 1 year overall survival rate of 42.7 ± 3.3%. Today cancer is widely considered as a multicomponent disease. One novel strategy likely to target the complexity of tumor cells and tumor environment is metronomic scheduling of anticancer treatment or "metronomic treatment" (MT). Low doses of chemotherapeutic drugs are continuously administered to cancer patients. The higher frequency and lower dose targets distinct aspects of cancer's functionality. Effects on tumor-angiogenesis, anti-cancer immunity and tumor stroma have been shown. Additionally low-dose metronomic treatment is often combined with modern antiinflammatory or antiangiogenic drugs, which specifically interact e.g. in tumor growth or angiogenesis pathways. The rationale of this trial is the efficacy of metronomic therapy in heavily pre-treated refractory neuroblastoma patients.This trial protocol proposes a metronomic schedule of low dose chemotherapy with cyclophosphamide, etoposide and vinblastine, in combination with propranolol, a non-selective blocker of β adrenergic receptors and celecoxib, a selective cyclooxygenase type 2 (COX-2) inhibitor. Patients enrolled in this study may benefit for two reasons. In the palliative situation, metronomic treatment may result in disease stabilization (SD) and a significant improvement of the quality of life (QOL) of patients e.g. by the decrease of pain through the treatment. For this reason, QOL including pain module is assessed as a separate secondary objective/ outcome measure. In the case of tumor response (PR, CR), the patients may qualify for a subsequent treatment approach aiming at further disease stabilization or even a long-term benefit.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Neuroblastoma
Keywords
Recurrent Neuroblastoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
26 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
metronomic therapy
Arm Type
Experimental
Arm Description
Treatment consists of eight alternating 28-day-cycles of propranolol, celecoxib, cyclophosphamide, vinblastine, etoposide (PCCVE) and of propranolol, celecoxib, cyclophosphamide, vinblastine (PCCV) followed by five cycles PCCV resulting in a total of 13 cycles (364 days of treatment)
Intervention Type
Drug
Intervention Name(s)
metronomic therapy
Other Intervention Name(s)
Dociton, Celebrex, Endoxan, Lastet, Vinblastinsulfat Teva
Intervention Description
Propranolol 0.5 mg/kgxd p.o. day 1, mg/kgxd p.o. day 2, mg/kgxd p.o. day 3-365 (maximum total daily dose: 120 mg) divided in 2 doses per day Celecoxib 400 mg/m2xd p.o.; day 1-365 (maximum total daily dose: 800 mg) divided in 2 doses per day Cyclophosphamide cycle 1, day1: loading dose: 500 mg/m2 intravenous 1-h-infusion, single dose day 2-365 25 mg/m2xd p.o (maximum total daily dose: 50 mg) as single daily dose Vinblastine 3 mg/m2xd i.v. (maximum total daily dose: 6 mg) administered day 1 and 15 (every two weeks) as single daily dose Etoposide 25 mg/m2xd p.o.; day 1-21 weeks 1-3, 9-11, 17-19, 25-27 (maximum total daily dose: 50 mg) as single daily dose
Primary Outcome Measure Information:
Title
non-inferiority of EFS compared to historical control group
Description
The primary trial objective is to demonstrate the non-inferiority of event free survival (EFS) in comparison to a historical control group. Event free survival (EFS) defined as time from start of treatment up to Progression (emerged from residual tumor, PD) or recurrence (developing from CR achieved by metronomic treatment), permanent discontinuation of treatment for unacceptable toxicity, secondary malignant neoplasm or death of any reason.
Time Frame
up to 12 months
Secondary Outcome Measure Information:
Title
disease control rate at 6 months
Description
Disease control rate at 6 months of metronomic treatment defined as number of patients achieving overall complete response (CR), partial response (PR) or stable disease (SD) related to all treated patients.
Time Frame
6 months after start of treatment
Title
Overall survival
Description
Overall survival defined as time from start of treatment until death of any reason or date of last information
Time Frame
up to 12 months
Title
hospitalization days
Description
Any patient stay in hospital that includes at least one night from day 1 of metronomic treatment until 30 days after the end of treatment. Overall treatment time is 12 months.
Time Frame
up to 395 days
Title
number of transfusion days
Description
The number of days with transfusion of platelets or packed red blood cells. Overall treatment time is 12 months.
Time Frame
up to 365 days
Title
drop-out rate
Description
The number and rate of patients stopping metronomic treatment during treatment period due to patients and/or parents wish. Overall treatment time is 12 months.
Time Frame
up to 12 months
Title
disease control rate at 12 months
Description
Disease control rate at 12 months of metronomic treatment defined as number of patients achieving overall complete response (CR), partial response (PR) or stable disease (SD) related to all treated patients.
Time Frame
12 months after start of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Newly diagnosed recurrence or progression of high risk neuroblastoma which progressed despite previous treatment (irrespective of the number of previous relapses/progressions). Refractory and/or residual high-risk neuroblastoma with measurable or evaluable disease irrespective of preceding treatment (no Progression during the minimal interval as defined below) Age: ≥ 2 years and < 21 years Measurable or evaluable disease defined as Presence of at least one measurable (recurrent or newly progressing) neuroblastoma lesion ≥ 10 mm by magnetic resonance imaging (MRI) or computed tomography (CT) or Newly detected unambiguous scintigraphic (MIBG) avid bone and/or medullary lesions presence of unambiguous bone marrow metastasis Minimal interval between start of trial medication and preceding anti-cancer treatment is 4 weeks after chemotherapy, 6 weeks after radiotherapy, and 12 weeks after myeloablative therapy Life expectancy > 3 months Good to moderate general condition (performance scale ≥60) No serious infection Spontaneous recovering blood counts: White blood cell count ≥ 1000/µL Neutrophil count ≥ 500/µL Platelet count ≥ 25 000/µL (unsupported) Written informed consent of parents or legal guardian and/ or patient according to age and status of psycho-intellectual development. Exclusion Criteria: Minimal residual disease status (only) without unambiguous measurable or evaluable disease Patients unable to swallow trial medication Any concomitant anti-cancer treatment (e.g. other cytostatic drugs, "small molecules", antibodies, radiotherapy, surgery of tumor or metastases) Treatment with medication that interact with study medication that cannot be discontinued at least one week prior to the start of trial medication and for the duration of the trial Intake of antihypertensive drugs, e.g. calcium channel blockers Established hypersensitivity to the active or one of the other constituents of the trial medication Severe medical or psychosocial conditions preventing trial participate and/or any of the following Peripheral neuropathy or constipation CTCAE grade 3 or 4 Cardiac arrhythmias (sinus bradycardia for age, sinus arrhythmia as 2.-3. grade atrioventricular block) Pre-existing recurrent symptomatic bronchial asthma Diabetes mellitus (propranolol covers symptoms of hypoglycemia) Conditions with low blood pressure below age-dependent normal ranges History of gastrointestinal ulcer or perforation Known active hepatitis B virus (HBV), hepatitis C (HBC) virus or human immunodeficiency virus (HIV) infection Concomitant participation in other clinical trials with investigational drugs or with competing interventions Pregnancy, lactation Sexually active patients not willing to use highly effective contraception
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marc Hoemberg, Dr.
Phone
x49 221 4786853
Ext
6853
Email
marc.hoemberg@uk-koeln.de
First Name & Middle Initial & Last Name or Official Title & Degree
Barbara Hero, Dr.
Phone
x49 221 4786853
Ext
6853
Email
barbara.hero@uk-koeln.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marc Hoemberg, Dr.
Organizational Affiliation
University of Cologne
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's University Hospital
City
Bonn
Country
Germany
Individual Site Status
Recruiting
Facility Name
Marc Hoemberg
City
Cologne
ZIP/Postal Code
50924
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marc Hoemberg, Dr.
Phone
00492214786853
Ext
6853
Email
marc.hoemberg@uk-koeln.de
First Name & Middle Initial & Last Name & Degree
Barbara Hero, Dr.
Phone
00492214786853
Ext
6853
Email
barbara.hero@uk-koeln.de
Facility Name
Children's University Hospital
City
Essen
Country
Germany
Individual Site Status
Recruiting
Facility Name
Children's University Hospital
City
Frankfurt
Country
Germany
Individual Site Status
Recruiting
Facility Name
Children's University Hospital
City
Freiburg
Country
Germany
Individual Site Status
Recruiting
Facility Name
Children's Hospital, Medizinische Hochschule
City
Hannover
Country
Germany
Individual Site Status
Recruiting
Facility Name
Children's University Hospital
City
Leipzig
Country
Germany
Individual Site Status
Recruiting
Facility Name
Dr. von Haunersches Kinderspital
City
Muenchen
Country
Germany
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
21298742
Citation
Simon T, Berthold F, Borkhardt A, Kremens B, De Carolis B, Hero B. Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: results of German trials. Pediatr Blood Cancer. 2011 Apr;56(4):578-83. doi: 10.1002/pbc.22693. Epub 2010 Dec 9.
Results Reference
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PubMed Identifier
10772661
Citation
Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 2000 Apr;105(8):R15-24. doi: 10.1172/JCI8829. Erratum In: J Clin Invest. 2006 Nov;116(11):3084. J Clin Invest. 2006 Oct;116(10):2827.
Results Reference
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PubMed Identifier
16960692
Citation
Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007 May;56(5):641-8. doi: 10.1007/s00262-006-0225-8. Epub 2006 Sep 8.
Results Reference
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PubMed Identifier
20501839
Citation
Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, Hu XB, Zheng MH, Liang L, Feng L, Liang YM, Han H. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010 Jun 15;70(12):4840-9. doi: 10.1158/0008-5472.CAN-10-0269. Epub 2010 May 25.
Results Reference
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PubMed Identifier
17289900
Citation
Ponthan F, Wickstrom M, Gleissman H, Fuskevag OM, Segerstrom L, Sveinbjornsson B, Redfern CP, Eksborg S, Kogner P, Johnsen JI. Celecoxib prevents neuroblastoma tumor development and potentiates the effect of chemotherapeutic drugs in vitro and in vivo. Clin Cancer Res. 2007 Feb 1;13(3):1036-44. doi: 10.1158/1078-0432.CCR-06-1908.
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PubMed Identifier
21730361
Citation
Nakanishi Y, Nakatsuji M, Seno H, Ishizu S, Akitake-Kawano R, Kanda K, Ueo T, Komekado H, Kawada M, Minami M, Chiba T. COX-2 inhibition alters the phenotype of tumor-associated macrophages from M2 to M1 in ApcMin/+ mouse polyps. Carcinogenesis. 2011 Sep;32(9):1333-9. doi: 10.1093/carcin/bgr128. Epub 2011 Jul 5.
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PubMed Identifier
22927533
Citation
Asgharzadeh S, Salo JA, Ji L, Oberthuer A, Fischer M, Berthold F, Hadjidaniel M, Liu CW, Metelitsa LS, Pique-Regi R, Wakamatsu P, Villablanca JG, Kreissman SG, Matthay KK, Shimada H, London WB, Sposto R, Seeger RC. Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma. J Clin Oncol. 2012 Oct 1;30(28):3525-32. doi: 10.1200/JCO.2011.40.9169. Epub 2012 Aug 27.
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PubMed Identifier
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Citation
Pasquier E, Street J, Pouchy C, Carre M, Gifford AJ, Murray J, Norris MD, Trahair T, Andre N, Kavallaris M. beta-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma. Br J Cancer. 2013 Jun 25;108(12):2485-94. doi: 10.1038/bjc.2013.205. Epub 2013 May 21.
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PubMed Identifier
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Citation
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PubMed Identifier
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Citation
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Results Reference
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Metronomic Treatment in Children and Adolescents With Recurrent or Progressive High Risk Neuroblastoma

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