Clinical trial · Interventional
Metronomic Treatment in Children and Adolescents With Recurrent or Progressive High Risk Neuroblastoma
Phase 2 Trial of Metronomic Treatment in Children and Adolescents With Recurrent or Progressive Neuroblastoma (NB)
NCT02641314CI-TRIAL-00077039METRO-NB2012completedPhase 2ClinicalTrials.gov clinicaltrialsProvenance
- Source
- ClinicalTrials.gov
- Retrieved
- Sep 8, 2026
- Layer
- normalized (units and labels harmonized; values unchanged)
- Run
- ING-CLINICALTRIALS-20260908-000001
Summary
Brief summary (as posted)
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.
Conditions
Conditions (1)
Free-text conditions as registered, with the CancerIndex entity they were reconciled to and the match type.
| Condition (as posted) | Mapped entity | Match | Confidence |
|---|---|---|---|
| Recurrent Neuroblastoma | Neuroblastoma | CURATED_BROADER | 0.78 |
Interventions
Interventions (1)
| Intervention | Type | Mapped drug | Match |
|---|---|---|---|
| metronomic therapy | Drug | — | UNRESOLVED |
Design
Arms and outcomes
Arms (1)
- type
- EXPERIMENTAL
- label
- metronomic therapy
- 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)
- interventionNames
- Drug: metronomic therapy
Primary outcomes (1)
- measure
- non-inferiority of EFS compared to historical control group
- timeFrame
- up to 12 months
- 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.
Secondary outcomes (6)
Eligibility
Eligibility (as posted)
- Sex
- All
- Minimum age
- 2 Years
- Maximum age
- 20 Years
Show eligibility criteria text
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
References
Publications (10)
- BACKGROUNDSimon 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. PMID 21298742
- BACKGROUNDKlement 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. PMID 10772661
- BACKGROUNDGhiringhelli 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. PMID 16960692
- BACKGROUNDWang 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. PMID 20501839
- BACKGROUNDPonthan 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. PMID 17289900
- BACKGROUNDNakanishi 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.