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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02641314
Recruitment Status : Recruiting
First Posted : December 29, 2015
Last Update Posted : July 14, 2020
Sponsor:
Information provided by (Responsible Party):
Frank Berthold, University of Cologne

Tracking Information
First Submitted Date  ICMJE December 15, 2015
First Posted Date  ICMJE December 29, 2015
Last Update Posted Date July 14, 2020
Study Start Date  ICMJE October 2016
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 22, 2015)
non-inferiority of EFS compared to historical control group [ Time Frame: up to 12 months ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2018)
  • disease control rate at 6 months [ Time Frame: 6 months after start of treatment ]
    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 [ Time Frame: up to 12 months ]
    Overall survival defined as time from start of treatment until death of any reason or date of last information
  • hospitalization days [ Time Frame: up to 395 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 [ Time Frame: up to 365 days ]
    The number of days with transfusion of platelets or packed red blood cells. Overall treatment time is 12 months.
  • drop-out rate [ Time Frame: up to 12 months ]
    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 [ Time Frame: 12 months after start of treatment ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2015)
  • disease control rate at 6 months [ Time Frame: 6 months after start of treatment ]
    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 [ Time Frame: up to 12 months ]
    Overall survival defined as time from start of treatment until death of any reason or date of last information
  • Quality of life [ Time Frame: 3 months, 6 months, and 12 months after start of treatment ]
    Age-adjusted questionnaires applied after 3, 6, and 12 months of treatment.Overall treatment time is 12 months.
  • hospitalization days [ Time Frame: up to 395 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 [ Time Frame: up to 395 days ]
    The number of days with transfusion of platelets or packed red blood cells. Overall treatment time is 12 months.
  • drop-out rate [ Time Frame: up to 12 months ]
    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 [ Time Frame: 12 months after start of treatment ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Metronomic Treatment in Children and Adolescents With Recurrent or Progressive High Risk Neuroblastoma
Official Title  ICMJE Phase 2 Trial of Metronomic Treatment in Children and Adolescents With Recurrent or Progressive Neuroblastoma (NB)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Recurrent Neuroblastoma
Intervention  ICMJE Drug: metronomic therapy
  • Propranolol 0.5 mg/kgxd p.o. day 1,

    1. mg/kgxd p.o. day 2,
    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
Other Names:
  • Dociton
  • Celebrex
  • Endoxan
  • Lastet
  • Vinblastinsulfat Teva
Study Arms  ICMJE Experimental: metronomic therapy
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: Drug: metronomic therapy
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 22, 2015)
26
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 31, 2023
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ≥ 50 000/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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 20 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Frank Berthold, Prof. Dr. x49 221 4786853 ext 6853 frank.berthold@uk-koeln.de
Contact: Barbara Hero, Dr. x49 221 4786853 ext 6853 barbara.hero@uk-koeln.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02641314
Other Study ID Numbers  ICMJE Uni-Koeln-1495
2011-004593-29 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Frank Berthold, University of Cologne
Study Sponsor  ICMJE University of Cologne
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Frank Berthold, Prof. Dr. University of Cologne
Study Director: Marc Hoemberg, Dr. University of Cologne
PRS Account University of Cologne
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP