Metronomic Treatment in Children and Adolescents With Recurrent or Progressive High Risk Neuroblastoma (METRO-NB2012)
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|ClinicalTrials.gov Identifier: NCT02641314|
Recruitment Status : Recruiting
First Posted : December 29, 2015
Last Update Posted : July 14, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Recurrent Neuroblastoma||Drug: metronomic therapy||Phase 2|
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||26 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase 2 Trial of Metronomic Treatment in Children and Adolescents With Recurrent or Progressive Neuroblastoma (NB)|
|Study Start Date :||October 2016|
|Estimated Primary Completion Date :||December 31, 2022|
|Estimated Study Completion Date :||July 31, 2023|
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)
Drug: metronomic therapy
- 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.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02641314
|Contact: Frank Berthold, Prof. Dr.||x49 221 4786853 ext firstname.lastname@example.org|
|Contact: Barbara Hero, Dr.||x49 221 4786853 ext email@example.com|
|Principal Investigator:||Frank Berthold, Prof. Dr.||University of Cologne|
|Study Director:||Marc Hoemberg, Dr.||University of Cologne|