Centralized and secure access to the investigational drug ONC201 in France

Malignant midline brain tumors in children, adolescents, and adults

ONC201 is the first drug in a new class of anticancer agents that targets the energy metabolism of cancer cells. It is currently in clinical development exclusively in the United States for children and adults with relapsed midline malignant glioma. An accelerated marketing authorization for this indication is currently being prepared with the U.S. Food and Drug Administration. Until now, it has not been available in France, as CHIMERIX, the manufacturer, has not been able to supply the drug in Europe.

The implementation of a compassionate use protocol, developed by the French National Agency for Medicines and Health Products Safety (ANSM) and Gustave Roussy, now authorizes its use in France under safe and supervised conditions.

What We Already Know About the Drug

ONC201 has shown signs of efficacy in patients with relapsed midline malignant brain tumors harboring the H3K27M mutation, particularly in 30% of patients with thalamic tumors. It is possible that this drug may also be effective against tumors located in other regions of the brain, particularly in children with infiltrating brainstem gliomas harboring the H3K27M mutation, although the activity does not appear to be as significant as it is for thalamic tumors. Approximately 400 patients with all types of cancer have had access to ONC201 in the U.S. for over five years, which has allowed for the determination of the recommended dose and tolerability, as well as the observation of encouraging initial efficacy results in both children and adults with thalamic tumors.

While development of this drug continues in the U.S., the company does not have a program in Europe for patients with relapsed disease. The ONC201 compassionate use program addresses this need in France. The BIOMEDE 2.0 protocol, currently being developed with CHIMERIX in France and Europe, will compare the efficacy of ONC201 with that of everolimus combined with radiation therapy in pediatric, adolescent, and adult patients diagnosed with this type of glioma. BIOMEDE 2.0 will begin enrolling patients in early 2022.

Who is eligible for the compassionate use protocol?

Children, adolescents, or adults who have relapsed from a high-grade midline malignant glioma with an H3K27M mutation or another equivalent alteration. This alteration is identified in a tumor biopsy either through tumor DNA sequencing or an immunohistochemistry test. Sequencing helps identify other mutations that may affect the efficacy of the drug ONC201 and also opens up other therapeutic options currently in development as part of clinical trials. This compassionate use protocol has been approved by the two professional societies involved: the French Society for the Fight Against Childhood and Adolescent Cancers (SFCE) and the Association of French-Speaking Neuro-Oncologists (ANOCEF) for adults.

What is a compassionate use protocol?

A compassionate use protocol provides access to an experimental treatment when no other therapeutic option is available (an approved drug or one being evaluated in a clinical trial) and the available data on the drug suggest that it could benefit the patient.

How can you gain access to the compassionate use protocol?

All information and contact details are included in the compassionate use protocol on the ANSM website.

The physician treating the patient submits a request to the National Molecular Case Review Committee (RCP).  The neuropathological and molecular diagnosis is confirmed by the INCa RENOCLIP network before each medical case is discussed at the National Molecular Multidisciplinary Review Committee. During the committee meeting—composed of physicians, biologists, and neuro-oncologists—the patient’s medical history, the patient’s clinical status, prior treatments, and tumor sequencing results to determine the best possible treatment option(s) at the time of relapse. Tumor sequencing may indeed reveal other mutations that could be targeted by therapies—particularly combination therapies—currently being evaluated in a clinical trial. The various available treatment options are discussed and prioritized. The attending physician, who participates in the multidisciplinary team meeting (MDT), is informed of these recommendations and decides, together with the patient and their family, whether to prescribe ONC201 or another treatment. ONC201 will be available only to patients whose cases have been evaluated and approved by the national MDT.

How are ONC201 capsules obtained?

The patient’s referring oncologist prescribes the medication and sends the prescription through their own hospital pharmacy to the Gustave Roussy hospital pharmacy, which then ships the treatment back to the hospital where the patient is usually treated. The patient picks up the treatment there to take it at home. The capsules are shipped within 5 business days of receiving the prescription.

How is the medication administered and stored?

ONC201 comes in the form of capsules to be swallowed. It is available in two dosages, 25 mg and 100 mg, to allow the dosage to be adjusted according to the patient’s weight. It should be taken once a week, on an empty stomach and between meals. The capsules should be stored at room temperature.

How long should treatment continue?

There is no set duration; treatment should continue as long as it is well tolerated and effective. Available data indicate that it is well tolerated, apart from a few mild digestive symptoms that can be managed with additional treatment prescribed by the referring oncologist.

How is treatment with ONC201 funded?

There is no financial cost to the patient or their family. The treatment is fully covered by health insurance under the compassionate use protocol. As part of the BIOMEDE 2.0 trial, CHIMERIX will provide the medication free of charge.

What is the follow-up process under the compassionate use protocol?

Follow-up is conducted by the prescribing physician. Since this drug has not yet been approved for marketing, pharmacovigilance is of the utmost importance. For this reason, the follow-up data collected by the physician will be compiled by the SACHA study, provided that the patients, parents, or legal guardians do not object. The objective of the SACHA study is to assess the safety and efficacy of a new drug when it is prescribed off-label or on a compassionate-use basis. 

Will patients currently being treated with radiation therapy alone or with everolimus combined with radiation therapy (currently the best available treatment for all midline malignant tumors, as demonstrated in the BIOMEDE 1.0 trial) have access to ONC201?

ONC201 is a treatment option for any patient whose tumor progresses after an initial treatment regimen that included radiation therapy. Patients currently being treated with radiation therapy alone or with radiation therapy combined with everolimus may have access to ONC201 under the compassionate use protocol if their initial treatment becomes ineffective and the tumor progresses clinically or radiologically.

What about patients who have just been diagnosed and have not yet begun treatment?

Compassionate use of ONC201 is available only to patients whose tumor has progressed after at least one prior treatment regimen that included radiation therapy. This is the indication (thalamic tumors) for which a marketing application is currently being prepared in the U.S. There are no data authorizing or justifying the prescription of ONC201 at diagnosis, outside the context of a clinical trial. 

In 2022, the international BIOMEDE 2.0 trial, sponsored by Gustave Roussy, will open enrollment in France for children, adolescents, and adults newly diagnosed with a midline malignant glioma harboring the H3K27M mutation. The objective of this clinical trial will be to determine whether ONC201 plus radiation therapy is superior to the currently proven best treatment, everolimus plus radiation therapy. To this end, one of the two treatments will be randomly assigned to each patient. If the tumor progresses during treatment, patients who received everolimus may be treated with ONC201. Patients who received ONC201 may receive everolimus. They may also be offered the opportunity to participate in a therapeutic trial if they are eligible.

As with any clinical trial, participation in BIOMEDE 2.0 will be based on the physician’s recommendation and following the patient’s free and informed consent—or, for minor patients, the consent of both parents or legal guardians—who will have been informed in advance.

In the BIOMEDE 2.0 trial, scheduled to begin in 2022, the drug ONC201, manufactured by CHIMERIX, will be prescribed. Each patient participating in BIOMEDE 2.0 will therefore have access to ONC201 either at the time of diagnosis or upon tumor progression. Consequently, patients participating in BIOMEDE 2.0 will not be eligible for compassionate use of ONC201 upon tumor progression following radiation therapy.

Is testing for the H3K27M mutation essential?

Testing for the H3K27M mutation or an equivalent molecular alteration is essential because it confirms the malignancy of the tumor. Furthermore, the drug has not been shown to be effective when the tumor does not harbor this mutation.

Can the mutation be detected in a blood sample or in cerebrospinal fluid?

It is possible to test for the H3K27M mutation in cerebrospinal fluid, but there is a significant risk of failing to detect it even when it is present. There are currently no data on the presence of the mutation in circulating blood (liquid biopsy) that could serve as an alternative to tumor analysis. Furthermore, sequencing from a tissue biopsy will generate a large amount of additional information that is very important for discussion during the national molecular multidisciplinary team meeting (MDT).

This is why a tumor biopsy is required in order to prescribe ONC201.

How is it possible to manufacture the drug in the Gustave Roussy pharmacy?

A drug is patented and protected by the pharmaceutical company that markets it until generic versions become available. The active ingredient in its composition is a raw material—such as ONC201—that is not protected by a patent. French law allows hospital pharmacies to prepare compounded medications by purchasing this raw material and adhering to the rules of good hospital compounding practices to best meet patients’ therapeutic needs when no suitable treatment or formulation is commercially available.

To prepare compounded formulations of ONC201 under the compassionate use protocol, the Gustave Roussy Pharmacy team and the ANSM first identified a supplier of the active ingredient. Subsequently, pharmaceutical qualification was conducted in collaboration with the ANSM. Mass spectrometry and nuclear magnetic resonance analyses confirmed that the substance was indeed ONC201 in its active form and that its purity was 99.5%. Generally, by law, active ingredients in marketed drugs must have a purity greater than 98%. The Gustave Roussy Pharmacy prepares the ONC201 capsules and ships them to the pharmacies of healthcare facilities where patients are being treated.

For more information:

• Contact your treating physician
• Review the therapeutic use protocol on the ANSM website