Dordaviprone (Monograph)

Brand name: Modeyso
Drug class: Antineoplastic Agents

Introduction

Dordaviprone hydrochloride, a protease activator of the mitochondrial caseinolytic protease P (ClpP), is an antineoplastic agent.

Uses for Dordaviprone

Dordaviprone has the following uses:

Dordaviprone is indicated for the treatment of adults and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy.

This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Dordaviprone Dosage and Administration

General

Dordaviprone hydrochloride is available in the following dosage form(s) and strength(s):

• Capsules: 125 mg of dordaviprone

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Select patients for treatment with dordaviprone based on the presence of an H3 K27M mutation from tumor specimens.

Monitor ECG and electrolytes before starting dordaviprone and periodically during treatment as clinically indicated.

Take dordaviprone orally once weekly on an empty stomach (at least 1 hour before or 3 hours after food intake).

Adults

Dosage

• The recommended dosage of dordaviprone in adult patients is 625 mg orally once weekly.

• Continue dordaviprone until disease progression or unacceptable toxicity occurs.

• See Full Prescribing Information for dosage modification recommendations for adverse reactions and concomitant use with CYP3A4 inhibitors.

Pediatric Patients

Dosage

• The recommended dosage of dordaviprone in pediatric patients 1 year of age and older weighing ≥10 kg is based on body weight as follows:

  Body weight 10 kg to <12.5 kg: 125 mg once weekly

  Body weight 12.5 kg to <27.5 kg: 250 mg once weekly

  Body weight 27.5 kg to <42.5 kg: 375 mg once weekly

  Body weight 42.5 kg to <52.5 kg: 500 mg once weekly

  Body weight 52.5 kg: 625 mg once weekly

• Continue dordaviprone until disease progression or unacceptable toxicity occurs.

• See Full Prescribing Information for dosage modification recommendations for adverse reactions and concomitant use with CYP3A4 inhibitors.

Cautions for Dordaviprone

Contraindications

None.

Warnings/Precautions

Hypersensitivity

Dordaviprone can cause severe hypersensitivity reactions.

In the pooled safety population Grade 3 hypersensitivity reactions occurred in 0.3% of patients receiving dordaviprone. Signs and symptoms of hypersensitivity may include rash, hives, fever, low blood pressure, wheezing, or swelling of the face or throat.

Inform patients about the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical attention if symptoms occur.

If clinically significant hypersensitivity or anaphylaxis occur, immediately interrupt dordaviprone and initiate appropriate medical treatment and supportive care. Based on the severity of the adverse reaction, temporarily interrupt or permanently discontinue dordaviprone.

QTc Interval Prolongation

Dordaviprone causes a concentration-dependent QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death.

In the pooled safety population, of the 82 patients who underwent at least one post-baseline ECG assessment, 6% experienced an increase in QTc of >60 msec compared to baseline after receiving dordaviprone and 1.2% had an increase in QTc to >500 msec.

Monitor ECGs and electrolytes prior to starting dordaviprone and then periodically during treatment as clinically indicated.

Significant prolongation of the QT interval may occur when dordaviprone is taken concomitantly with other products that have a known potential to prolong the QT interval. Avoid concomitant use of dordaviprone with products known to prolong the QT interval. If concomitant use cannot be avoided, separate administration of dordaviprone and the QT-prolonging product.

Increase the frequency of monitoring when administering dordaviprone to patients taking other products that have a known potential to prolong the QT interval and in patients with congenital long QT syndrome, existing QTc prolongation, a history of ventricular arrhythmias, electrolyte abnormalities, heart failure, or who are taking strong or moderate CYP3A4 inhibitors. Interrupt or reduce the dose of dordaviprone in patients who develop QT prolongation, and permanently discontinue the drug in patients with signs of life-threatening arrhythmias.

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, dordaviprone can cause fetal harm when administered to a pregnant woman. In embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended dose.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with dordaviprone and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with dordaviprone and for 1 month after the last dose.

Specific Populations

Pregnancy

Based on findings from animal studies and its mechanism of action, dordaviprone can cause fetal harm when administered to a pregnant woman. There are no available data on dordaviprone use in pregnant women to inform a drug-associated risk.

In animal embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during the period of organogenesis caused embryofetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended dose. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of dordaviprone or its metabolites in human milk, their effects on a breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children from dordaviprone, advise women not to breastfeed during treatment with dordaviprone and for 1 week after the last dose.

Females and Males of Reproductive Potential

Dordaviprone can cause fetal harm when administered to a pregnant woman.

Verify pregnancy status of females of reproductive potential prior to initiating dordaviprone.

Advise females of reproductive potential to use effective contraception during treatment with dordaviprone and for 1 month after the last dose.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with dordaviprone and for 1 month after the last dose.

Based on the mechanism of action of dordaviprone (dopamine D2 receptor inhibition and alterations to mitochondrial function), treatment with dordaviprone may adversely impact fertility in males and females.

Pediatric Use

The safety and effectiveness of dordaviprone has been established in pediatric patients 1 year of age and older for the treatment of diffuse midline glioma harboring an H3 K27M mutation.

The efficacy of dordaviprone was evaluated in 4 pediatric patients 9 to 17 years of age with diffuse midline glioma harboring an H3 K27M mutation. Safety was evaluated in 154 pediatric patients with glioma aged 3 to 17 years who received dordaviprone at the recommended dose across four open-label clinical studies (ONC006, ONC013, ONC014, and ONC018). Of these 154 patients, 73% were 3 to 11 years of age and 27% were 12 to 17 years of age. No additional safety signals were observed in pediatric patients.

The exposure of dordaviprone in pediatric patients weighing 10 kg and higher is predicted to be within the range of exposures predicted in adults at the recommended dosage.

The safety and effectiveness of dordaviprone have not been established in pediatric patients less than 1 year of age.

Geriatric Use

Of the 376 patients with glioma who received dordaviprone at the recommended dose across four open-label clinical studies (ONC006, ONC013, ONC014, and ONC018), 3.7% of patients were ≥65 years of age and 0.5% were ≥75 years of age. Clinical studies of dordaviprone did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently than younger patients.

Common Adverse Effects

The most common (≥20%) adverse reactions are fatigue, headache, vomiting, nausea, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities are decreased lymphocytes, decreased calcium, and increased alanine aminotransferase.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• CYP3A4 Inhibitors: Avoid concomitant use of strong and moderate CYP3A4 inhibitors with dordaviprone. If concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the dose of dordaviprone as recommended.

• CYP3A4 Inducers: Avoid concomitant use of strong and moderate CYP3A4 inducers with dordaviprone.

• Drugs Known to Prolong QTc Interval: Avoid concomitant use of dordaviprone with products known to prolong the QTc interval. If concomitant use cannot be avoided, separate administration of dordaviprone and the QT-prolonging product.

Actions

Mechanism of Action

Dordaviprone is a protease activator of the mitochondrial caseinolytic protease P (ClpP). Dordaviprone also inhibits the dopamine D2 receptor.

Diffuse midline gliomas harboring an H3 K27M mutation are associated with the loss of H3 K27 trimethylation. In-vitro, dordaviprone activated the integrated stress response, induced apoptosis, and altered mitochondrial metabolism leading to restored histone H3 K27 trimethylation in H3 K27M-mutant diffuse glioma models.

Dordaviprone exhibited antitumor activity in cell-based assays and in vivo models of H3 K27M-mutant diffuse glioma.

Advice to Patients

• Advise the patient and caregiver to read the FDA-approved patient labeling.

• Advise patients that dordaviprone can cause hypersensitivity. Inform patients about the signs and symptoms of hypersensitivity reactions and instruct patients or caregivers to seek immediate medical attention if symptoms occur.

• Advise patients that dordaviprone can cause QTc interval prolongation. Inform patients of the signs and symptoms of QTc prolongation and instruct patients or caregivers to seek immediate medical attention if symptoms occur.

• Inform patients that dordaviprone may interact with some drugs. Advise patients to inform their healthcare provider about all medications they are taking, including prescription and over-the-counter drugs, vitamins, and herbal products. Additionally, patients should consult their healthcare provider before starting or stopping any prescription drug, nonprescription drug, or supplement.

• Instruct patients and caregivers to read the Instructions for Use before taking dordaviprone, and each time the patient gets a refill as there may be new information they need to know.

• Patients should take dordaviprone orally once weekly on an empty stomach (no food intake at least 1 hour prior to or 3 hours after taking dordaviprone). Take the prescribed dose at the same time on the same day of the week.

• Instruct patients to swallow capsules whole. For patients unable to swallow capsules whole, instruct patients to open capsules and mix contents with approximately 15 to 30 mL of liquid (sports drink, apple juice, lemonade, or water). Instruct patients to drink the mixture. After drinking the mixture, instruct patients to add another 15 to 30 mL of the liquid to the container, swirl to dissolve any remaining medication, and then drink the remaining contents.

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

• Advise females to inform their healthcare provider of a known or suspected pregnancy.

• Advise females of reproductive potential to use effective contraception during treatment with dordaviprone and for 1 month after the last dose.

• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with dordaviprone and for 1 month after the last dose.

• Advise women not to breastfeed during treatment with dordaviprone and for 1 week after the last dose.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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