RAPAMALYMPH protocol

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Lille

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Otorhinolaryngologic Diseases [C09]

Decision date (initial)

2024-11-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

CHU de Lille. PHRC 2012

External identifiers

EU CT number

2024-517769-17-00

EudraCT number

2013-002800-15

ClinicalTrials.gov

NCT03243019

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Pharmacokinetic

To determine the response rate to treatment with Rapamycin, by evaluating the reduction in volume of cervico-facial lymphatic malformations 3 months after obtaining the therapeutic plateau. A response will be considered positive if the reduction in volume is greater than 1/5th of the initial lesion volume.

Secondary objectives 5

1. Assessment of response kinetics
2. Assessment of the safety and side effects of Rapamycin used alone in this indication, according to the NCI-CTC 3.0 scale.
3. Assessment of improvement in clinical status and quality of life.
4. Evaluation of efficacy on the haemorrhagic component of mucosal forms
5. Biological evaluation of response to treatment

Conditions and MedDRA coding

Poor prognosis cervico-facial lymphatic malformations (Lymphangima)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Minor patients aged between 1 and 18 years, regardless of sex, with a cervico-facial lymphatic malformation of micro-cystic or mixed form with a unilateral or bilateral supra-hyoid location (class II, III and IV of the De Serres classification), or any form with mediastinal extension.
2. Presenting a chronic algic symptomatology, or functional symptomatology with respiratory discomfort or swallowing or phonatory disorders with a CDS score strictly below 8
3. For which curative treatment is not possible or presents a major functional or vital risk. Lesions corresponding to these definitions include extensions - exceeding half of the mobile hemi-tongue or half of the hemi-base of the tongue -infiltrating more than a third of the floor of the mouth -more than half of the jugal mucosa one-third of the hemipharynx -the larynx -the trachea -both recurrent spaces -the mediastinum -the infra-temporal fossa -the pterygoid muscles -the mandibular or maxillary bone intrastructures -conjunctivo-palpebral -intra-conical orbital structures
4. Karnofsky score (>10 years) or Lansky score (≤10 years) >50%
5. Biological functions with the following standards: -Neutrophil count ≥1.0 x 109/L -Platelet count ≥ 100 x 109/L -Haemoglobin ≥ 8 g/dL -Total bilirubin ≤ 1.5 ULN -Transaminases < 2.5 ULN -Serum albumin ≥ 2 g/dL. -LDL cholesterol <160 mg/dL -Triglycerides < 150 mg/dL -Glomerular filtration rate (GFR) calculated using the Schwartz formula (for creatinine expressed in mg/l): GFR (ml/min/1.73 m2) = [k x height (cm)] / [creatinine (mg/l) x 8.84] > 70 ml/min/1.73 m2 With : k = 29 for premature newborns k = 40 for full-term newborns and children under 1 year of age k = 49 for children aged 2 to 12 years k = 49 for girls aged 13 to 21 k = 62 for boys aged 13 to 21
6. Informed consent signed by both parents or the person(s) with parental authority
7. Negative pregnancy test if indicated
8. Person covered by a Social Security system
9. For patients who have undergone surgery or sclerotherapy: inclusion possible if they meet the above criteria and after a minimum of 2 months after the procedure. Surgical procedures that do not modify the target area, such as tracheostomy or gastrostomy, do not modify the inclusion delay

Exclusion criteria 17

1. Non-compliance with inclusion criteria
2. Other immunosuppressive treatment or long-term general corticosteroid therapy
3. Chronic renal failure
4. Chronic liver failure
5. Digestive disorders that may interfere with the absorption of Rapamycin: ulcerative gastritis, repeated vomiting, malabsorption syndrome, etc.
6. Severe uncontrolled infection
7. Patients requiring treatment that may induce CYP3A4 activity (rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin) or inhibit CYP3A4 activity (ketoconazole, voriconazole, itraconazole, telithromycin, clarithromycin, diltiazem, verapamil, nicardipine ; clotrimazole, fluconazole , troleandomycin , bromocriptine, cimetidine, danazol , protease inhibitors) due to changes in Rapamycin metabolism and consequent changes in Rapamycin plasma levels.
8. Patients already receiving treatment with an inhibitor of the mTOR pathway
9. Patients taking digestive motor stimulants such as cisapride and metoclopramide if they cannot be stopped since Pharmacokinetic interactions may be observed.
10. Known allergy to peanuts or soya
11. Inability to receive enlightened information
12. Not covered by the social security system
13. Refusal to sign the consent form
14. For patients of childbearing potential, contraception other than oral contraceptives should be offered during treatment. Although the results of a single-dose interaction study with an oral contraceptive suggest the absence of a pharmacokinetic interaction, the possibility of pharmacokinetic changes that may affect the efficacy of oral contraception during prolonged treatment with Rapamune® cannot be ruled out.
15. Pregnancy or breastfeeding
16. Patients, parents or legal guardians incapable of giving consent or benefiting from a legal protection regime (guardianship)
17. Refusal of the child to participate

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Assessment of the response in terms of lesion volume using volumetric MRI 3 months after the therapeutic plateau has been reached. A transient increase in lesion volume may be observed in the case of locoregional infections or direct trauma. In these situations, MRI may be delayed by one or two weeks to allow treatment of the intercurrent problem. A decrease in volume ≥ 1/5th will be considered a positive response.

Secondary endpoints 5

1. The kinetics of the response are assessed by MRI at 6 months and 1 year, in order to evaluate the evolution at the end of treatment and at 6 months after stopping treatment.
2. Known adverse reactions will be systematically investigated on a monthly basis.
3. Clinical evaluation of the extent of the lesion, with photographic and video recording of the pharyngolaryngeal fibroscopy, with assessment of the infiltrated areas, the macroscopic appearance and the haemorrhagic appearance of the lesions.
4. The scoring used the same scores as those used for the initial assessment, even if the patient changed age group during the study. This clinical assessment was carried out at 3 months, 6 months and 12 months. The assessment criterion is based on the change in scores between each examination.
5. To evaluate the effectiveness of mTOR pathway inhibition, we will assess the impact of Rapamycin on signaling proteins (pAKT, p70S6 kinase, pMEK, pERK) in cellular samples before and after treatment using Bioplex, a method for analyzing phosphorylated proteins. We will also measure circulating angiogenic factors (VEGF C, VEGFR3) in serum samples before and after treatment using ELISA.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Lille

Sponsor organisation

Centre Hospitalier Universitaire De Lille

Address

2 Avenue Oscar Lambret, Cs 70001 Cs 70001

City

Lille Cedex

Postcode

59037

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Lille

Contact name

Prof. Pierre FAYOUX

Public contact point

Organisation

Centre Hospitalier Universitaire De Lille

Contact name

Prof. Pierre FAYOUX

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications