Efficacy and Safety of Sirolimus in Children and Adolescents With Juvenile Nasopharyngeal Angiofibroma (JNA)

Juvenile nasopharyngeal angiofibroma (JNA) is a pathologically benign yet locally aggressive and destructive tumor that develops in the choana and nasopharynx. Historical treatment of JNA has included embolization, surgical resection, and radiation. Inhibition of mTOR signaling proved to be an important point in inhibition of JNA growth and vascularization. Sirolimus (rapamun) is an mTOR inhibitor, still data on sirolimus efficacy and safety in JNA is limited to few clinical cases.

The main purpose of the study is to evaluate the efficacy and safety of sirolimus in children and adolescents with primary or recurrent JNA. Historical control will be used for comparison as standard treatment.

Due to limited experience of sirolimus in JNA in routine practice, study should be conducted in 2 phases: pilot and extended.

The duration of the pilot phase is 3 months. Decision regarding conducting of extended phase will be based on the response to treatment in pilot phase. Response to treatment defined as a reduction of the JNA volume or stable volume or an increase in volume \< 20% from the initial one.

In the extended period, duration of treatment for patients with primary JNA will be determined by the response to treatment. In case of the response to the therapy, treatment duration will be up to 9 months (3 courses by 3 months each). In case of JNA increase in volume more than 20% from the initial one (control time points 3 and 6 months), sirolimus therapy will be discontinued and surgical intervention to be provided (according to the investigator's decision). After completion of 9 months' treatment period, all patients with primary JNA will receive surgical treatment. The duration of follow up is 3 years In the group of patients with relapse or progression of JNA, therapy will continue up to 3 years or until loss of the response to the therapy (which the earliest).

Optimal individual dosage of sirolimus will be determined under control of concentration in blood serum. Sirolimus therapeutic concentration - 5-15 ng/ml. Blood samples will be collected until therapeutic concertation will be achieved in 2 consecutive samples, but no more than 4 samples (on the 4th, 7th, 10th, 14th days of sirolimus admission).

• The proportion of patients with JNA with positive dynamics [Срок оценки: 6 months from study enrollment]
• The proportion of patients with JNA with positive dynamics [Срок оценки: 9 months from study enrollment]
• proportion of patients with progression after sirolimus therapy initiation [Срок оценки: 3, 6, 9 months from study enrollment]
• The number and proportion (%) of patients receiving sirolimus without tumor progression in post-surgery catamnesis. [Срок оценки: 6, 12, 18, 24, 30, 36 months of post-surgery catamnesis.]
• Primary JNA: The number of the severe bleeding cases in the post-surgery period [Срок оценки: up to 6 days after surgery intervention]
• The blood loss volume in the surgical intervention and postoperative period [Срок оценки: up to 6 days after surgery intervention]
• Number and % of patients requiring hem transfusions in the surgical intervention and/or postoperative periods in patients receiving sirolimus and in the historical control group [Срок оценки: up to 6 days after surgery intervention]
• amount of patients required embolization and completeness of embolization in patients receiving sirolimus and in the historical control group. [Срок оценки: 1 day of surgery intervention]
• The proportion of patients (%) with complete and partial removal of JNA in patients treated with sirolimus and in the historical control group. [Срок оценки: 1 day of surgery intervention]
• Recurrent JNA: The number and proportion (%) of patients with tumor progression (tumor growth in the same location) [Срок оценки: 6, 9, 15, 21, 27 and 33 months of sirolimus therapy.]
• Recurrent JNA: The number and proportion (%) of patients with tumor recurrence (tumor growth in new location) treated with sirolimus and in the historical control group [Срок оценки: 6, 9, 15, 21, 27 and 33 months of sirolimus therapy.]
• Recurrent JNA: The number and proportion (%) of patients required surgery intervention or radiotherapy in patients received sirolimus and in the historical control group [Срок оценки: 33 months of sirolimus treatment]