Dordaviprone

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.

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 MODEYSO, advise women not to breastfeed during treatment with dordaviprone and for 1 week after the last dose.

Carcinogenesis

Carcinogenicity studies with dordaviprone were not conducted.

Mutagenesis

Dordaviprone was not genotoxic in in vitro (Ames and micronucleus assay) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

Dedicated fertility studies were not conducted with dordaviprone.

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in WARNINGS AND PRECAUTIONS and below reflects exposure to dordaviprone at the recommended weight-based dose taken until disease progression or unacceptable toxicity in 376 adult and pediatric patients with glioma across four open-label clinical studies (ONC006, ONC013, ONC014, and ONC018).

Of the 376 patients who received dordaviprone, 35% were exposed for 6 months, and 17% were exposed for 1 year.

The median age was 23 years (range: 3 to 80): 30% were 2 to 11 years old, 11% were 12 to 17 years old, 55% were 18 to 64 years old, and 3.7% were 65 years or older. Fifty-two percent (52%) were female; 74% White, 10% unknown race or race not reported, 9% Black or African American, 4% Asian, 2.9% other or multiple races; and 13% were of Hispanic or Latino ethnicity. Karnofsky/Lansky Performance Status (KPS/LPS) score was 80 to 100 in 66% of patients, 60 to 70 in 27%, and <60 in 7%.

Relevant disease characteristics included primary tumor locations in the midline (91%) and non-midline regions (9%); 33% had diffuse intrinsic pontine glioma (DIPG); 30% had multifocal disease; 79% had an H3 K27M mutation; 75% had recurrent disease.

Serious adverse reactions occurred in 33% of patients who received dordaviprone. Serious adverse reactions in >2% of patients included hydrocephalus (5%), vomiting (4.3%), headache (3.2%), seizure (2.4%), and muscular weakness (2.1%). Fatal adverse reactions occurred in 1% of patients who received dordaviprone, including cardiac arrest (0.5%), intracranial hemorrhage (0.3%), and encephalopathy (0.3%).

Permanent discontinuation of dordaviprone due to an adverse reaction occurred in 2.1% of patients. Adverse reactions which resulted in permanent discontinuation of dordaviprone in >1 patient included confusional state.

Dosage interruptions of dordaviprone due to an adverse reaction occurred in 6% of patients. Adverse reactions which required dosage interruption in >1 patient included increased alanine aminotransferase, increased aspartate aminotransferase, decreased lymphocyte count, muscular weakness, and aspiration pneumonia.

Dose reductions of dordaviprone due to an adverse reaction occurred in 2.7% of patients. Adverse reactions which required dose reductions in >1 patient included decreased neutrophil count and increased alanine aminotransferase.

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

Adverse reactions that occurred in at least 10% of patients treated with dordaviprone are presented in Table 1.

Table 1. Adverse Reactions (≥10%) in Patients with Glioma Who Received Dordaviprone in ONC006, ONC013, ONC014, and ONC018:

^a Includes asthenia.
^b Includes head discomfort and sinus headache.
^c Includes accessory nerve disorder, auditory nerve disorder, facial nerve disorder, facial paralysis, facial paresis, glossopharyngeal nerve disorder, hypoglossal nerve disorder, IIIrd nerve disorder, IIIrd nerve paralysis, IVth nerve disorder, IVth nerve paralysis, tongue paralysis, trigeminal nerve disorder, trigeminal neuralgia, VIth nerve disorder, VIth nerve paralysis, and VIth nerve paresis.
^d Includes back pain, pain in extremity, arthralgia, neck pain, non-cardiac chest pain, myalgia, bone pain, musculoskeletal chest pain, musculoskeletal stiffness, and spinal pain.
^e Includes dermatitis, dermatitis acneiform, dermatitis bullous, eczema, erythema multiforme, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

Other clinically important adverse reactions observed in less than 10% of patients treated with dordaviprone were peripheral neuropathy, seizure, diarrhea, tremor, and venous thromboembolic events.

Selected laboratory abnormalities that occurred in at least 10% of patients treated with dordaviprone are presented in Table 2.

Table 2. Select Laboratory Abnormalities (≥10%) that Worsened from Baseline in Patients with Glioma Receiving Dordaviprone in ONC006, ONC013, ONC014, and ONC018:

^a Severity as defined by the National Cancer Institute CTCAE Version 5.0.
^b The denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 325 to 330 patients.