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Study of a Propranolol (HEMANGIOL®) and Oral Metronomic Vinorelbine (NAVELBINE®) Combination for Children and Teenagers With Refractory/Relapsing Solid Tumors (PROVIN)

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ClinicalTrials.gov Identifier: NCT02897986
Recruitment Status : Not yet recruiting
First Posted : September 13, 2016
Last Update Posted : September 13, 2016
Sponsor:
Information provided by (Responsible Party):
Assistance Publique Hopitaux De Marseille

Study Description
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Brief Summary:

Cancer remains the first cause of death due to disease in children and adolescents despite important progress and 70% of the survivors present sequelae. It is therefore mandatory to generate new and preferably less toxic treatment strategies relying on new anticancer agents, and/or new combinations or schedules of administered compounds.

Metronomic chemotherapy (MC) consists in administrating low doses of anticancer agents on a daily/weekly basis. MC has been showed to be a safe and effective way to administer chemotherapy to obtain anti-cancer effects through anti-angiogenic and pro-imune effects.

Drug repositioning consist in using non-anticancer drug for which anti-cancer properties have been unveiled. Propranolol is a non selective beta-blocker initially used to treat hypertension but recently its anticancer properties have been discovered. The place of Betablockers as anticancer agents is supported by both preclinical and epidemiologic data. The investigators have showed that the use of betablockers could sensitize breast cancer, angiosarcoma and neuroblastoma to chemotherapy in vitro and in vivo at least in part via an anti-angiogenic mechanism. There are currently 12 clinical trials evaluating prospectively their potential in adults with cancer but none in children so far.

The Objective is to determine the Maximal Tolerated Dose (MTD) of a combination of oral metronomic vinorelbine and daily oral propranolol. This study is a phase I trial with a "rolling six" design and a dose escalation with thrice weekly oral vinorelbine only plus addition of daily oral propranolol after completion of the first cycle. PK analysis of vinorelbine and propranolol will be performed. Once the recommended dose of the combination established 4 extension cohorts of 9 patients will be added Potential biomarkers (such as beta-adrenergic receptors on the tumours, B-tubulin isotypes in the tumour) will also be evaluated.

This will provide a well tolerated, all oral combination for patients with refractory/relapsing tumours. This combination could also be then proposed as a maintenance for instance in patients with rhabdomyosarcoma or neuroblastoma.


Condition or disease Intervention/treatment Phase
Pediatric Cancer Drug: administration of a propranolol (HEMANGIOL®) and oral metronomic vinorelbine (NAVELBINE®) combination Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Study Start Date : January 2017
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: patients with refractory/relapsing solid tumors Drug: administration of a propranolol (HEMANGIOL®) and oral metronomic vinorelbine (NAVELBINE®) combination


Outcome Measures
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Primary Outcome Measures :
  1. number of patients with grade 3 toxicity [ Time Frame: 28 days ]

Eligibility Criteria
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Ages Eligible for Study:   4 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed malignant solid tumour and refractory low grade gliomas and desmoids tumours.
  • Relapsed or refractory tumours after at least one line of treatment (patients can have been previously treated with oral or IV vinorelbine with a weekly schedule)
  • Measurable targets
  • Lansky Score > 70 or score OMS < 2.
  • Life expectancy > 6 months.
  • Adequate haematological function: neutrophil count ≥ 1.0 x 109/L, platelet count ≥ 75 x 109/L
  • Creatinine< 1.5X normal value for the age or clearance >70 ml/mn/1.73 m2
  • Liver function: Bilirubin < 3N and ALAT and ASAT < 4 N).
  • Other organ toxicity < Grade 2 according to NCI-CTC version 4.0
  • No active infection

Exclusion Criteria:

  • Absence of a wash out period of:

    • 21 days in case of previous chemotherapy or targeted therapy (reduced to 2 weeks in case of treatment vincristine or prolonged to 6 weeks in case of treatment with nitrosurea agents)
    • 6 weeks in case of prior radiotherapy of the target lesions
  • Peripheral neuropathy > grade 2
  • contra-indication to Propranolol (i.e. asthma, bradycardia, hypotension, decreased SF, ECG-anomalies)
  • Pregnancy or breast feeding
Contacts and Locations
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Information from the National Library of Medicine

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): NCT02897986


Contacts
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Contact: Nicolas ANDRE, Professor nicolas.andre@ap-hm.fr

Locations
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France
Assistance Publique Hôpitaux de Marseille
Marseille, France, 13005
Contact: Nicolas ANDRE, Professor       nicolas.andre@ap-hm.fr   
Sponsors and Collaborators
Assistance Publique Hopitaux De Marseille
Investigators
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Study Director: Urielle Desalbres Assistance Publique Hôpitaux de Marseille
More Information
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Responsible Party: Assistance Publique Hopitaux De Marseille
ClinicalTrials.gov Identifier: NCT02897986    
Other Study ID Numbers: 2016-06
First Posted: September 13, 2016    Key Record Dates
Last Update Posted: September 13, 2016
Last Verified: September 2016
Additional relevant MeSH terms:
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Vinorelbine
Propranolol
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
 Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents