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.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

participants targeted

Target at below P25 for phase_2

Timeline

Completed

Started Dec 2016

Longer than P75 for phase_2

Geographic Reach

1 country

8 active sites

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

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Study Timeline

Key milestones and dates

6.5 years study duration

First Submitted

Initial submission to the registry

December 15, 2015

Completed

14 days until next milestone

First Posted

Study publicly available on registry

December 29, 2015

Completed

12 months until next milestone

Study Start

First participant enrolled

December 22, 2016

Completed

6.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

June 29, 2023

Completed

Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

June 29, 2023

Completed

Last Updated

May 10, 2024

Status Verified

May 1, 2024

Enrollment Period

6.5 years

First QC Date

December 15, 2015

Last Update Submit

May 8, 2024

Conditions

Recurrent Neuroblastoma

Keywords

Recurrent Neuroblastoma

Outcome Measures

Primary Outcomes (1)

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.
up to 12 months

Secondary Outcomes (6)

disease control rate at 6 months
6 months after start of treatment
Overall survival
up to 12 months
hospitalization days
up to 395 days
number of transfusion days
up to 365 days
drop-out rate
up to 12 months
+1 more secondary outcomes

Study Arms (1)

metronomic therapy

EXPERIMENTAL

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)

Drug: metronomic therapy

Interventions

metronomic therapyDRUG

* 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

Also known as: Dociton, Celebrex, Endoxan, Lastet, Vinblastinsulfat Teva

metronomic therapy

Eligibility Criteria

Age2 Years - 20 Years

Sexall

Healthy VolunteersNo

Age GroupsChild (0-17), Adult (18-64)

You may qualify if:

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)
+1 more criteria

You may not qualify if:

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
+2 more criteria

Contact the study team to confirm eligibility.