Modeyso Drug Information

MODEYSO is indicated for the treatment of adult 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 overall 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).

Patient Selection

Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens. An FDA-approved test for the detection of this mutation is not currently available.

Recommended Testing Before Starting MODEYSO

Monitor electrocardiograms (ECG) and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated.

Recommended Dosage and Administration Take MODEYSO on an empty stomach, at least 1 hour before or 3 hours after food intake. Adults The recommended dosage of MODEYSO is 625 mg orally once weekly. A recommended dosage of MODEYSO has not been established in pediatric patients who weigh less than 10 kg.

Table 1: Recommended Body Weight-Based Dosage for Pediatric Patients Continue MODEYSO until disease progression or unacceptable toxicity. Swallow capsules whole. For patients unable to swallow capsules whole, open each capsule, mix contents with approximately 15 to 30 mL of liquid (sports drink, apple juice, lemonade, or water) before administration, and administer orally as a liquid.

Once mixed, administer within 2 hours of preparation, or discard and mix a new dose. Vomiting If vomiting occurs after taking a dose, do not take an additional dose and take the next dose at the regularly scheduled time. Missed Dose If a dose is missed within 2 days, take the missed dose as soon as possible.

If a dose is missed by more than 2 days, skip the missed dose and take the next dose at the scheduled time.

Dosage Modifications for Adverse Reactions

The recommended dosage reductions for adverse reactions for MODEYSO are provided in Table 2. Table 2: The recommended dosage modifications for adverse reactions are provided in Table 3. Table 3: a.

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. b. See Table 2 for recommended dosage reductions.

Dosage Modifications for CYP3A4 Inhibitors

Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. • If concomitant use of a strong CYP3A4 inhibitor cannot be avoided for adult and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO from 625 mg to 375 mg once weekly. • If concomitant use of a moderate CYP3A4 inhibitor cannot be avoided for adult and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO from 625 mg to 500 mg once weekly. • The recommended dosage for pediatric patients weighing less than 52.5 kg who are receiving strong or moderate CYP3A4 inhibitors has not been established. Upon discontinuation of the CYP3A4 inhibitor, wait for 3 to 5 plasma half-lives of the CYP3A4 inhibitor, then increase MODEYSO to the dose that was taken before starting the CYP3A4 inhibitor.

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 MODEYSO 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). Karnofsky/Lansky Performance Status (KPS/LPS) score was 80 to 100 in 66% of patients, Serious adverse reactions occurred in 33% of patients who received MODEYSO.

Permanent discontinuation of MODEYSO due to an adverse reaction occurred in 2.1% of patients. Adverse reactions which resulted in permanent discontinuation of MODEYSO in >1 patient included confusional state. Dosage interruptions of MODEYSO 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 MODEYSO 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 MODEYSO are presented in Table 4.

Table 4: Adverse Reactions (≥10%) in Patients with Glioma Who Received MODEYSO in ONC006, ONC0 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 MODEYSO were peripheral neuropathy, seizure, diarrhea, tremor, and venous thromboembolic events. Selected laboratory abnormalities that occurred in at least 10% of patients treated with MODEYSO are presented in Table 5. Table 5: Select Laboratory Abnormalities (≥10%) that Worsened from Baseline in Patients with Glioma Receiving MODEYSO in ONC006, ONC0 7 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.

Effect of Other Drugs on MODEYSO Table 6 describes drug interactions where concomitant use of another drug affects MODEYSO. Table 6: Effect of Other Drugs on MODEYSO Strong and Moderate CYP3A4 Inhibitors Prevention or Management • Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. • If concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the MODEYSO dose as recommended. Mechanism and Clinical Effects • Dordaviprone is a CYP3A4 substrate. • Strong and moderate CYP3A4 inhibitors increase dordaviprone exposure, which may increase the risk of MODEYSO‑related adverse reactions.

Mechanism and Clinical Effects • Dordaviprone is a CYP3A4 substrate. • Strong and moderate CYP3A4 inducers decrease dordaviprone exposure, which may reduce the anti-tumor activity of MODEYSO.

Drugs Known to Prolong QTc Interval Table 7 describes drug interactions associated with QTc interval prolongation when used concomitantly with MODEYSO. Table 7: Products that Prolong QTc Interval Products that Prolong QTc Interval Prevention or Management • Avoid concomitant use of MODEYSO with products known to prolong the QTc interval. • If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product. Clinical Impact • MODEYSO causes concentration dependent QTc interval prolongation. • Concomitant use of MODEYSO with other QT-prolonging products may increase the risk of QTc-associated arrhythmias.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, MODEYSO can cause fetal harm when administered to a pregnant woman. There are no available data on MODEYSO 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 (see Data ).

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 respectively. Dordaviprone caused maternal mortality, pre-implantation loss, and embryo-fetal toxicity of absent eye and small renal papillae at the 125 mg/kg/day dose (≥2 times the human recommended doses based on body surface area).

In an embryo-fetal development study, dordaviprone was administered orally to pregnant rabbits during the period of organogenesis from gestation days 7 to 19 at doses of mg/kg/day. Dordaviprone caused maternal mortality, embryo‑fetal mortality, lower fetal weights, and structural malformations of the face, limbs, vessels, brain, and heart at doses of ≥10 mg/kg/day (≥0.4 times the human exposure at the highest recommended dose based on C max ).

Pediatric Use The safety and effectiveness of MODEYSO has been established in pediatric patients aged 1 year and older for the treatment of diffuse midline glioma harboring an H3 K27M mutation. The efficacy of MODEYSO was evaluated in 4 pediatric patients aged 9 to 17 years 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 MODEYSO at the recommended dose across four open‑label clinical studies (ONC006, ONC013, ONC014, and ONC018).

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 MODEYSO have not been established in pediatric patients less than 1 year of age.