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Dordaviprone

Dordaviprone, also known as ONC201, is an innovative drug being studied in various clinical trials for its potential in treating different types of cancer. This article explores the ongoing research on dordaviprone, focusing on its use in gliomas, endometrial cancer, and colorectal cancer prevention. We’ll examine the drug’s mechanism of action, its administration in different trials, and the preliminary findings from these studies.

Table of Contents

What is Dordaviprone?

Dordaviprone, also known as ONC201 or TIC10, is an experimental drug currently being studied for its potential in treating various types of cancer and preventing colorectal cancer[1][2][3]. This medication is part of a new class of drugs that work in unique ways to target cancer cells.

How Does Dordaviprone Work?

Dordaviprone works through multiple mechanisms to fight cancer cells:

  • ClpP agonist: It activates a protein called ClpP, which helps to break down other proteins in cancer cells[1].
  • DRD2 antagonist: It blocks a receptor called DRD2, which is involved in cancer cell growth[1].
  • Akt/ERK inhibitor: It blocks enzymes called Akt and ERK, which are important for cancer cell survival and growth[3].
  • TRAIL inducer: It increases the production of a protein called TRAIL, which can cause cancer cells to die[3].

These combined actions may help to stop the growth of tumor cells and potentially kill them.

Conditions Treated with Dordaviprone

Dordaviprone is being studied for several types of cancer and precancerous conditions:

  • Gliomas: These are tumors that occur in the brain and spinal cord. Dordaviprone is particularly being studied for a specific type called H3 K27M-mutant glioma[1][2].
  • Colorectal Cancer Prevention: It’s being tested to see if it can prevent colorectal cancer in people at high risk, such as those with familial adenomatous polyposis (FAP) or multiple polyps[3].

Clinical Trials and Research

Several clinical trials are currently underway to study dordaviprone:

  1. Expanded Access for Glioma Patients: This program provides dordaviprone to patients with H3 K27M-mutant and/or midline gliomas who can’t access the drug through other clinical trials[1].
  2. The ACTION Study: This is a large Phase 3 trial testing dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma. It’s looking at whether the drug can extend overall survival and progression-free survival when given after radiotherapy[2].
  3. Colorectal Cancer Prevention Trial: This Phase 1 trial is testing dordaviprone’s safety and effectiveness in preventing colorectal cancer in high-risk individuals[3].

Dosage and Administration

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

  • In the ACTION study, patients weighing 52.5 kg or more receive 625 mg (5 x 125-mg capsules) on dosing days. Patients weighing less than 52.5 kg receive a dose scaled to their body weight[2].
  • The drug is typically taken orally (by mouth) either once weekly or once every 3 weeks[3].

It’s important to note that as dordaviprone is still in clinical trials, the optimal dosage may not yet be established and could change based on research findings.

Potential Side Effects

As dordaviprone is still in clinical trials, all of its potential side effects are not yet fully known. The ongoing studies are closely monitoring for any adverse events. Some areas being specifically watched include:

  • Changes in laboratory test results[2]
  • Effects on corticosteroid use[2]
  • Changes in performance status (a measure of a patient’s ability to perform daily activities)[2]
  • Changes in prolactin levels (a hormone) in the blood[3]

Patients in clinical trials are closely monitored for any side effects or adverse events. If you’re considering participating in a clinical trial for dordaviprone, it’s important to discuss potential risks and benefits with your healthcare provider.

Aspect Details
Drug Name Dordaviprone (ONC201)
Mechanism of Action ClpP agonist and DRD2 antagonist
Main Cancer Types Studied Gliomas (especially H3 K27M-mutant), DIPG, Endometrial Cancer, Colorectal Cancer Prevention
Administration Oral (capsules), various dosing schedules (weekly, twice weekly)
Key Outcomes Measured Progression-free survival, Overall survival, Tumor response, Safety and tolerability
Notable Trial Phases Phase 1, Phase 2, Phase 3
Special Populations Pediatric patients, Adults with specific mutations or cancer types
Biomarkers of Interest H3 K27M mutation, TRAIL expression

FAQ

  • What is dordaviprone (ONC201)? Dordaviprone, also known as ONC201, is a brain-penetrant, small-molecule drug that acts as a mitochondrial caseinolytic protease P (ClpP) agonist and a dopamine receptor D2 (DRD2) antagonist. It is being studied for its potential to treat various types of cancer, particularly gliomas and other solid tumors.
  • What types of cancer is dordaviprone being tested for? Dordaviprone is being tested in clinical trials for several types of cancer, including gliomas (especially those with H3 K27M mutations), diffuse intrinsic pontine glioma (DIPG), endometrial cancer, and for the prevention of colorectal cancer in high-risk individuals.
  • How is dordaviprone administered in clinical trials? In most trials, dordaviprone is administered orally, typically as capsules. The dosing schedules vary between trials, with some using weekly dosing (e.g., 625 mg once per week) and others using more frequent dosing (e.g., twice weekly on consecutive days).
  • What are the primary outcomes being measured in dordaviprone trials? The primary outcomes vary depending on the trial, but commonly include progression-free survival, overall survival, tumor response rates, and determination of the recommended Phase 2 dose (RP2D). Safety and tolerability are also key considerations in all trials.
  • Are there any notable side effects or safety concerns with dordaviprone? While specific safety data is not provided in the trial summaries, all studies include monitoring for adverse events, vital signs, electrocardiograms, and clinical laboratory results. It's important to note that in some trials, the decision to terminate the study was not related to any safety concerns with dordaviprone.

Ongoing Clinical Trials on Dordaviprone

  • Study on ONC201 and Paxalisib for Children and Young Adults with Diffuse Midline Gliomas, Including Diffuse Intrinsic Pontine Gliomas

    Not yet recruiting

    2 1 1
    Investigated diseases:
    Investigated drugs:
    The Netherlands

Glossary

  • Glioma: A type of tumor that occurs in the brain and spinal cord, arising from glial cells that support and protect nerve cells.
  • H3 K27M mutation: A specific genetic mutation found in some gliomas, particularly in children and young adults, which is associated with a poor prognosis.
  • Diffuse Intrinsic Pontine Glioma (DIPG): A rare and aggressive type of brain tumor that occurs in the brainstem, primarily affecting children.
  • 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.
  • Overall Survival (OS): The length of time from either the date of diagnosis or the start of treatment for a disease that patients are still alive.
  • Recommended Phase 2 Dose (RP2D): The dose of a drug determined in Phase 1 trials to be appropriate for further testing in Phase 2 trials, balancing efficacy and safety.
  • RANO-HGG criteria: Response Assessment in Neuro-Oncology High-Grade Glioma criteria, used to evaluate the response to treatment in brain tumors.
  • Endometrial Cancer: A type of cancer that begins in the lining of the uterus (endometrium).
  • Familial Adenomatous Polyposis (FAP): An inherited disorder characterized by the growth of numerous polyps in the large intestine and rectum, which can lead to colorectal cancer if left untreated.
  • TRAIL: Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, a protein that can induce cell death in tumor cells.

References

  1. https://clinicaltrials.gov/study/NCT04617002
  2. https://clinicaltrials.eu/trial/study-of-onc201-for-patients-with-newly-diagnosed-h3-k27m-mutant-diffuse-glioma-after-radiotherapy/
  3. https://clinicaltrials.gov/study/NCT05630794