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2,4,6,7,8,9-Hexahydro-4-((2-Methylphenyl)Methyl)-7-(Phenylmethyl)Imidazo(1,2-A)Pyrido(3,4-E)Pyrimidin-5(1H)-One

This article discusses recent clinical trials investigating the use of ONC201, a novel drug also known as 2,4,6,7,8,9-Hexahydro-4-((2-Methylphenyl)Methyl)-7-(Phenylmethyl)Imidazo(1,2-A)Pyrido(3,4-E)Pyrimidin-5(1H)-One, in the treatment of diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs). These aggressive brain tumors, particularly challenging in children and young adults, have limited treatment options. The trials aim to evaluate the safety and effectiveness of ONC201 alone or in combination with other therapies, offering new hope for patients with these devastating cancers.

Table of Contents

Introduction

ONC201, also known as dordaviprone, is an investigational drug being studied for the treatment of certain types of brain tumors, particularly diffuse midline gliomas (DMGs) including diffuse intrinsic pontine gliomas (DIPGs). These are aggressive brain tumors that are difficult to treat with current therapies. In this article, we’ll explore what ONC201 is, how it works, and its potential benefits for patients with these challenging conditions.[1][2][3]

What is ONC201?

ONC201 is a small molecule drug developed by Chimerix, Inc. Its chemical name is 2,4,6,7,8,9-hexahydro-4-((2-methylphenyl)methyl)-7-(phenylmethyl)imidazo(1,2-a)pyrido(3,4-e)pyrimidin-5(1H)-one. It is also known by other names such as TIC-10 and ONC-201. ONC201 is administered orally in the form of capsules.[1][3]

Target Conditions

ONC201 is being investigated primarily for the treatment of:

  • Diffuse Midline Gliomas (DMGs): A type of aggressive brain tumor that occurs in the midline structures of the brain.
  • Diffuse Intrinsic Pontine Gliomas (DIPGs): A specific type of DMG that occurs in the brainstem, particularly in children.
  • H3 K27M-mutant gliomas: A subtype of DMG characterized by a specific genetic mutation.

These tumors are often difficult to treat due to their location in critical areas of the brain and their resistance to conventional therapies.[1][2][3]

Mechanism of Action

ONC201 works by targeting specific proteins in cancer cells:

  • It acts as an antagonist (blocker) of DRD2 and DRD3 receptors. These are proteins that can promote cancer cell growth and survival.
  • By blocking these receptors, ONC201 may help stop the growth of cancer cells and potentially cause them to die.

This unique mechanism of action makes ONC201 different from traditional chemotherapy drugs and potentially more targeted in its effects on cancer cells.[3]

Clinical Trials

Several clinical trials are currently underway to evaluate the safety and effectiveness of ONC201 in patients with DMGs and DIPGs:

  • The ACTION Study: This is a Phase 3 randomized, double-blind, placebo-controlled study evaluating ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma patients who have completed radiation therapy.[1]
  • BIOMEDE 2.0 Study: This study is comparing ONC201 to another drug called everolimus in combination with radiotherapy for newly diagnosed DMGs.[2]
  • PNOC022 Study: This is an adaptive platform trial testing ONC201 in combination with other novel agents for children and young adults with DMGs at various stages of treatment.[3]

These trials aim to determine if ONC201 can improve outcomes such as progression-free survival (time without tumor growth) and overall survival in patients with these challenging brain tumors.

Dosage and Administration

The dosage of ONC201 can vary depending on the specific trial and patient characteristics:

  • In some trials, patients weighing 52.5 kg or more receive 625 mg of ONC201 (5 x 125-mg capsules) on dosing days.
  • For patients weighing less than 52.5 kg, the dose is scaled based on body weight.
  • ONC201 is typically given orally (by mouth) on a weekly or twice-weekly schedule.
  • The minimum body weight for receiving ONC201 is typically 10 kg.

It’s important to note that these dosages are still being studied and may be adjusted based on ongoing research findings.[1][2][3]

Potential Benefits

While research is still ongoing, ONC201 shows promise in several areas:

  • It may help slow or stop the growth of DMGs and DIPGs, which are often resistant to other treatments.
  • ONC201 is taken orally, which may be more convenient for patients compared to intravenous treatments.
  • Its targeted mechanism of action may lead to fewer side effects compared to traditional chemotherapy.
  • Early studies suggest it may improve survival rates in some patients with these aggressive brain tumors.

However, it’s important to remember that these potential benefits are still being evaluated in clinical trials.[1][2][3]

Side Effects and Safety

As with any medication, ONC201 may cause side effects. The full safety profile is still being determined through clinical trials, but some potential side effects and safety considerations include:

  • Changes in liver function tests
  • Gastrointestinal effects such as diarrhea
  • Potential interactions with other medications, particularly those that affect certain liver enzymes (CYP3A4/5 inhibitors or inducers)
  • Monitoring of heart function, as some trials exclude patients with certain cardiac conditions

Patients in clinical trials are closely monitored for any adverse effects. It’s crucial for patients to discuss all potential risks and benefits with their healthcare team.[1][2][3]

Conclusion

ONC201 represents a promising new approach in the treatment of diffuse midline gliomas, including DIPGs. Its unique mechanism of action and early clinical results offer hope for patients with these challenging brain tumors. However, it’s important to remember that ONC201 is still an investigational drug, and more research is needed to fully understand its efficacy and safety profile. Patients and families interested in ONC201 should discuss the potential risks and benefits with their healthcare providers and consider participation in clinical trials if appropriate.

Trial Name Primary Objective Patient Population Key Endpoints ONC201 Dosing
The ACTION Study Evaluate efficacy of ONC201 after radiotherapy in H3 K27M-mutant diffuse glioma Newly diagnosed H3 K27M-mutant diffuse glioma patients Overall survival, Progression-free survival 625 mg twice weekly for patients ≥52.5 kg; weight-based dosing for <52.5 kg
BIOMEDE 2.0 Assess efficacy of ONC201 + everolimus combination in DMG patients Newly diagnosed and recurrent DMG patients Progression-free survival at 6 months, Overall survival at 7 months 375 mg/m2 daily (specifics not provided)
PNOC022 Evaluate efficacy of ONC201 combinations in DMG patients at various stages Newly diagnosed, post-radiation, and recurrent DMG patients aged 2-39 years Progression-free survival at 6 months, Overall survival at 7 months Up to 625 mg daily (weight-based dosing)

FAQ

  • What is ONC201 and how does it work? ONC201 is a novel drug that works by antagonizing (blocking) certain receptors in cancer cells called DRD2 and D3D3. It's being studied for its potential to fight aggressive brain tumors, particularly diffuse midline gliomas.
  • What types of brain tumors are being targeted in these clinical trials? The clinical trials are focusing on diffuse midline gliomas (DMGs), including a specific type called diffuse intrinsic pontine gliomas (DIPGs). These are aggressive brain tumors that are particularly challenging to treat, especially in children and young adults.
  • Who is eligible to participate in these clinical trials? Eligibility varies by trial, but generally includes patients aged 2 to 39 years with newly diagnosed or recurrent DMGs, including DIPGs. Specific criteria regarding tumor type, previous treatments, and overall health status apply. It's important to consult with a healthcare provider for individual eligibility.
  • What are the main goals of these clinical trials? The primary goals are to assess the safety and effectiveness of ONC201, either alone or in combination with other treatments. The trials aim to measure outcomes such as progression-free survival, overall survival, and quality of life in patients with these challenging brain tumors.
  • Are there any side effects or risks associated with ONC201? As with any experimental treatment, there may be potential side effects or risks. The clinical trials are designed to monitor and assess these carefully. Patients are closely observed for any adverse events, and the trials include specific criteria to ensure patient safety throughout the study.

Ongoing Clinical Trials on 2,4,6,7,8,9-Hexahydro-4-((2-Methylphenyl)Methyl)-7-(Phenylmethyl)Imidazo(1,2-A)Pyrido(3,4-E)Pyrimidin-5(1H)-One

  • Study of ONC201 for Patients with Newly Diagnosed H3 K27M-mutant Diffuse Glioma After Radiotherapy

    Recruiting

    3 1
    Investigated drugs:
    Austria Denmark Germany Italy The Netherlands Spain

  • Study on ONC201 and Everolimus with Radiotherapy for Newly Diagnosed Diffuse Intrinsic Pontine Glioma and Other Diffuse Midline Gliomas in Children, Adolescents, and Adults

    Recruiting

    3 1 1 1
    Investigated diseases:
    Investigated drugs:
    Denmark France Spain Sweden

Glossary

  • Diffuse Midline Glioma (DMG): A type of aggressive brain tumor that occurs in the midline structures of the brain, including the thalamus, brain stem, and spinal cord. It's characterized by specific genetic mutations and is particularly difficult to treat.
  • Diffuse Intrinsic Pontine Glioma (DIPG): A specific type of diffuse midline glioma that occurs in the pons, a part of the brain stem. DIPG is one of the most challenging pediatric cancers to treat due to its location and aggressive nature.
  • H3K27M mutation: A specific genetic mutation found in many diffuse midline gliomas. This mutation affects histone proteins, which are important in DNA packaging and gene expression, and is associated with more aggressive tumor behavior.
  • Progression-free survival (PFS): The length of time during and after treatment that a patient lives with the disease but it does not get worse. In these trials, PFS6 refers to the percentage of patients who are alive and without disease progression 6 months after starting treatment.
  • Overall survival (OS): The length of time from either the date of diagnosis or the start of treatment that patients are still alive. In one of the trials, OS7 refers to the percentage of patients still alive 7 months after starting treatment.
  • Karnofsky/Lansky Performance Status: Scales used to measure a patient's ability to perform ordinary tasks. These are used to determine a patient's prognosis and fitness for specific therapies. A score of 50 or higher is often required for clinical trial participation.
  • QTc interval: A measurement on an electrocardiogram (ECG) that represents the time it takes for the heart's electrical system to fire an impulse through the ventricles and then recharge. It's important in assessing heart health and potential side effects of some medications.
  • CYP3A4/5 inhibitors/inducers: Substances that can affect the activity of certain liver enzymes responsible for metabolizing many medications. Inhibitors can increase drug levels in the body, while inducers can decrease them, potentially affecting treatment efficacy or side effects.

References

  1. http://clinicaltrials.eu/trial/study-of-onc201-for-patients-with-newly-diagnosed-h3-k27m-mutant-diffuse-glioma-after-radiotherapy/
  2. http://clinicaltrials.eu/trial/study-on-onc201-and-everolimus-with-radiotherapy-for-newly-diagnosed-diffuse-intrinsic-pontine-glioma-and-other-diffuse-midline-gliomas-in-children-adolescents-and-adults/
  3. http://clinicaltrials.eu/trial/study-on-onc201-and-paxalisib-for-children-and-young-adults-with-diffuse-midline-gliomas-including-diffuse-intrinsic-pontine-gliomas/