Exceptional temporary use protocol for Birabresib for adult and paediatric patients with NUT carcinoma
NUT carcinomas are rare and aggressive tumours, for which no treatment has so far demonstrated significant efficacy. Birabresib is a targeted therapy directed against BET proteins (Bromodomain ExtraTerminal proteins), which are deregulated in certain tumour types, including NUT carcinomas. This drug was assessed in an early clinical trial, which showed responses in patients with NUT carcinoma, albeit transient. Until now, Birabresib was not available to patients with NUT carcinoma.
The implementation of an exceptional temporary use protocol, developed by the French National Agency for the Safety of Medicines and Health Products (ANSM) and Gustave Roussy, now authorises its use in France under secure and supervised conditions.
What are NUT cancers?
NUT cancers are very rare and aggressive. They are called "NUT" because they are linked to genetic abnormalities involving the NUTM1 gene. These cancers mainly affect the medial regions of the chest, head or neck, although they can develop in other parts of the body. NUT cancers are characterised by rapid growth and a strong propensity for metastatic dissemination, which explains their poor prognosis.
They occur at any age, but are more common in young adults and children, with an average age at diagnosis between 20 and 30 years.
The incidence of these cancers is estimated at a few hundred cases per year worldwide.
How is NUT cancer diagnosed?
Symptoms are not very specific and include severe fatigue, difficulty breathing or swallowing, chest pain, cough lasting more than two to three weeks, or unexplained swelling in the neck or face.
Diagnosis will be made after imaging, biopsy, and molecular testing to detect the NUT gene mutation. The results of this genetic test are essential to be able to make a firm diagnosis.
How are they treated?
The standard of care is surgery when the tumour is localised, high-dose chemotherapy and radiotherapy. However, to date, due to the aggressiveness of these cancers, their efficacy is not significant enough.
Why use Birabresib in NUT carcinomas?
BET proteins are a therapeutic vulnerability in NUT carcinomas, which can be targeted by Birabresib.
This drug has shown responses in an early clinical trial, as well as in a series of patients who received compassionate access.
BET inhibitors are currently no longer available in Europe, and can only be administered in the United States in clinical trials. This programme therefore makes it possible to offer a new therapeutic option to a disease that is currently orphan.
What is an exceptional temporary use protocol?
This protocol allows the provision, on an exceptional basis, of drugs that do not have marketing authorisation (MA) or access via a clinical trial, for the treatment of serious, rare or disabling diseases, when the available data suggest a potential benefit for the patient. It is administered under safe conditions, like a clinical trial.
For whom is the exceptional temporary use protocol intended?
The protocol is intended for adults, adolescents, and children with NUT carcinoma that has progressed after at least one line of systemic therapy. This protocol was approved by the French Cancer Society, and was developed jointly by ANSM and Gustave Roussy.
How can the drug be accessed?
All information and contacts can be found in 
the temporary use protocol.
The referring doctor sends the diagnosis and medical follow-up report to birabresib@gustaveroussy.fr
The file is then discussed in the molecular SPC, which issues a therapeutic recommendation based on the history of the disease, previous treatments and available molecular information. In the event of a favourable recommendation for the use of Birabresib, a written recommendation is sent to the referring oncologist who decides with the patient on the prescription of the treatment. In parallel with the discussion in the molecular SPC, additional analyses on the biopsy performed for diagnosis may be requested.
For patients in France:
The treatment initiation consultation is conducted at Gustave Roussy, while follow-up (and subsequent consultations) may be carried out by the patient's referring oncologist. The treatment will be available at the Gustave Roussy pharmacy for the first dispensing and then sent to the patient's usual hospital pharmacy for subsequent dispensing.
Clinical data to assess the efficacy of the treatment will be collected at Gustave Roussy as part of the STING protocol (NCT04932525) which will be offered to the patient.
For patients in countries with an S2 form:
A request for a consultation at the start of treatment at Gustave Roussy must be made with an S2 form. Treatment follow-up can then be carried out, in the country of origin, by the referring oncologist. Clinical data to assess the efficacy of the treatment will be collected at Gustave Roussy as part of the FRESH protocol which will be offered to the patient.
For patients in countries without an S2 form:
A request for a consultation at the start of treatment at Gustave Roussy must be sent via the Gustave Roussy International Department. Clinical data to assess the efficacy of the treatment will be collected at Gustave Roussy as part of the FRESH protocol which will be offered to the patient.
The first cycle of Birabresib is prescribed in consultation at the start of treatment, and the prescription is sent to the Gustave Roussy pharmacy. The patient then recovers their treatment to take it at home.
For subsequent treatment cycles, a request for the drug to be shipped to the hospital pharmacy of its reference centre may be made (for patients in France). The capsules are shipped within 5 working days after receipt of the prescription.
How is Birabresib administered and stored?
Birabresib comes in the form of capsules to be swallowed with a liquid, taken once a day, continuously, until the patient or their oncologist decides to stop taking them (in case of insufficient efficacy or adverse effects).
The dose should be taken on an empty stomach, without food. The capsules should be stored at room temperature.
How is Birabresib funded?
For patients in France, care is provided in full by the French health insurance system, as part of the compassionate protocol.
For foreign patients with an S2 form, the costs related to treatment and care are covered by the health system of the country of origin, in accordance with the provisions of the S2 form.
For foreign patients who do not have an S2 form, the cost of treatment is communicated on request.
What is the follow-up under the protocol?
The prescribing doctor for Birabresib is responsible for the clinical follow-up of the patient, with particular attention to pharmacovigilance aspects.
Follow-up data will be collected by the STING study (https://www.clinicaltrials.gov/study/NCT04932525), subject to patient acceptance and informed consent (https://www.gustaveroussy.fr/fr/igr-3196).
How is Birabresib made in the pharmacy of Gustave Roussy?
Birabresib capsules are specially prepared by the pharmacy of the Gustave Roussy Cancer Centre, as there is no equivalent medicine available.
The active substance used (birabresib) has been the subject of clinical trials in the past. Despite proven efficacy, its development has largely been stopped due to the very rare nature of NUT tumours. It is currently only available as an investigational chemical reagent.
Before its preparation, the hospital pharmacy checks this substance to ensure that it meets the expected quality, purity and safety criteria for human use.
The capsules are then manufactured and inspected by qualified hospital pharmacists, according to strict quality rules.
This treatment is offered only when no other treatment options are available.
The capsules produced are 20 mg birabresib, the basis for dose adjustments if necessary.
Capsule composition: for 20 mg birabresib, 20 mg hpmcas, 10 mg ac-di-sol, QS size 3 capsule with lactose.
The treatment can only be made available at a French hospital. Foreign patients must go to the Gustave Roussy Pharmacy.
