Phase 2a non-commercial and non-randomized intervention study evaluating the efficacy of crizotinib in the treatment of children with severe type 2 neurofibromatosis, in particular those excluded from surgery and / or radiotherapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical University Of Warsaw

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jan 2024 → ongoing

Decision date (initial)

2024-08-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-516607-16-00

EudraCT number

2021-005770-26

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Radiological assessment of the change in the size of the selected target tumor as a result of the assessment of the effect of crizotinib in children with NF-2.

Secondary objectives 2

1. Evaluation of the safety and tolerability of crizotinib treatment in children with NF-2.
2. Radiographic evaluation of the persistence of crizotinib effect on the target tumor in children with NF-2 6 months after the end of treatment.

Conditions and MedDRA coding

Neurofibromatosis type 2 is a genetically determined primary malignancy resulting from a mutation that disables the function of the cell division control gene and leads to neoplasia such as benign peripheral nervous system tumors and various benign or locally malignant tumors of the central nervous system. Many complications occur in children more often than in adults and significantly shorten the survival period of affected children.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. children meeting the clinical criteria for the diagnosis of NF-2 (NIH/1991 criteria after the Manchester revision of 1992) with the presence of multifocal neoplastic lesions in the central and/or peripheral nervous system
2. children from 4 years of age to 15 years of age who are able to swallow the drug tablet whole
3. children with: 3a. volumetric magnetic resonance (MR) studies showed steady progression (>10% of tumor weight over 4 to 12 months) of at least one measurable multifocal or polycyclic tumor lesion to objectively assess imaging response using system assessment criteria RECIST 1.1 (response evaluation criteria in solid crowds) 3b. there were no contraindications to the use of crizotinib specified in the Summary of Product Characteristics 3c. the function of the hematopoietic system allows treatment in accordance with the current Summary of Product Characteristics (in particular, the absolute neutrophil count is >1,500/µl and platelets >100,000/µl) 3d. renal function allows treatment (creatinine level not exceeding 1 mg/ml in children up to 13 years of age and 1.5 mg/ml in older children, including boys) 3e. bilirubin is less than 1.5 times the upper limit of normal and transaminases and alkaline phosphatase are less than 2.5 times the upper limit of normal;
4. children about: 4a. expected survival of more than one year and Lansky/Karnofsky Pediatric Performance ≥ 60 4b. stabilized neurological status for at least a year, without complications of previous radiotherapy or chemotherapy (or biological therapies) found on the day of eligibility for the study,
5. children with excluded comorbidities causing the risk of complications of crizotinib treatment (see exclusion criteria)
6. children whose parents: 6a. will be able to take care of them, will be able to conduct therapy in accordance with the requirements of the treatment protocol and sign an informed consent for treatment, and have full parental rights 6b. will follow the dietary recommendations and the rules of drug administration, in particular they will avoid the use of grapefruit or grapefruit juice and preparations containing St. John's wort and other herbal preparations or marijuana derivatives (CBD oils) and dietary supplements not recommended by the researcher (unconventional therapies) 6c. each time in a situation necessitating the administration of any other drug, they will consult with the researchers the possibility of its use, knowing the possible drug interactions presented in a separate table attached to the parental copy of the written consent for treatment
7. the protocol assumes the exclusion of concomitant use of chemotherapy and other molecularly targeted drugs

Exclusion criteria 1

1. children who: 1a. they will not be able to swallow the medicine tablet whole 1b. are or during the last 4 months have been actively treated with chemotherapy or other biological therapies, are undergoing radiotherapy or have been treated with therapeutic irradiation (regardless of the method and source of radiotherapy) in the period from 4 to 10 months before qualifying for a clinical trial 1c. remain immediately or up to 6 months after neurosurgery, in particular with unstable intracranial hypertension (regardless of the cause) 1d. participate in another therapeutic clinical trial conducted for them for any reason (excluding observational studies) 1e. do not meet the inclusion criteria, in particular due to comorbidities causing the risk of complications of crizotinib treatment: uncontrolled or moderate and severe arterial hypertension, broadly defined arrhythmias requiring treatment, severe defects and/or heart failure requiring treatment, renal and/or liver failure above mild (for liver - above Child-Pugh class C), chronic lung disease with symptoms of respiratory failure (O2 saturation <95% at rest and at room temperature) 1f. are treated for diseases of the digestive system that cause intestinal absorption disorders (short intestine, uncontrolled celiac disease, chronic malnutrition/cachexia and anorexia, chronic diseases with nausea, vomiting and diarrhea, Crohn's disease and ulcerative colitis) 1g. require treatment with substances that are inhibitors or inducers of the following enzymes of the cytochrome system: o CYP3A4 (inhibitors such as atazanavir, ritonavir, cobicistat, itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin and erythromycin, as well as grapefruit and grapefruit juice) o CYP3A4 (strong and moderate inducers such as carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort and moderate inducers such as rifabutin, efavirenz) o CYP2B6 (e.g. bupropion, efavirenz) 1h. require concomitant use of drugs that interact pharmacologically with crizotinib listed in the SmPC o especially with CYP3A4 substrates with a low therapeutic index (midazolam, alfentanil, cisapride, cyclosporine, ergot derivatives, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) o drugs metabolized mainly by UDP-glucuronyltransferases: UGT1A1 (e.g. raltegravir, irinotecan) or UGT2B7 (e.g. morphine, naloxone) o drugs that slow the heart rate, drugs that prolong the QT interval and/or antiarrhythmic drugs that may prolong the QT interval or induce torsades de pointes (e.g. class IA antiarrhythmics such as quinidine, disopyramide or class III antiarrhythmics such as amiodarone, sotalol, dofetilide, ibutilide and methadone, cisapride, moxifloxacin, neuroleptics, etc.) or bradycardia-inducing drugs (e.g. non-dihydropyridine calcium channel blockers such as verapamil and diltiazem; beta blockers, clonidine, guanfacine, digoxin , mefloquine, cholinesterase inhibitors, ilocarpine). 1i. children with unstable malignancy or rapidly progressing malignant tumors of any origin, especially CNS tumors requiring emergency treatment for intracranial hypertension 1j. the patient's parents have limited custody of the child or family during the divorce proceedings 1k. pregnant or lactating patients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Stabilization or (desirable) regression of the primary tumor

Secondary endpoints 1

1. Stabilization or (desirable) regression of the patient's primary tumor and other tumors for at least 6 months after the end of treatment

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical University Of Warsaw

Sponsor organisation

Medical University Of Warsaw

Address

Ul. Zwirki I Wigury 61

City

Warsaw

Postcode

02-091

Country

Poland

Scientific contact point

Organisation

Medical University Of Warsaw

Contact name

Marek Karwacki

Public contact point

Organisation

Medical University Of Warsaw

Contact name

Marek Karwacki

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 6 files

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

Application history

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