Relapsed or Refractory Acute Leukemia

REVUFORJ is indicated for the treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year and older.

2.1 Patient Selection

Select patients for the treatment of acute leukemia with REVUFORJ based on the presence of a KMT2A translocation in bone marrow cells [see Clinical Studies (14.1)]. An FDA-approved companion diagnostic for the detection of a KMT2A translocation is not currently available.

2.2 Recommended Dosage

The recommended dosage of REVUFORJ varies by patient weight and concomitant use of strong CYP3A4 inhibitors. See Table 1 for the recommended dosage for patients 1 year and older. Do not start REVUFORJ until the WBC is reduced to less than 25 Gi/L. Continue REVUFORJ until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.

• If the strong CYP3A4 inhibitor is discontinued, increase the REVUFORJ dose after at least 5 half-lives of the strong CYP3A4 inhibitor to the recommended dosage without strong CYP3A4 inhibitors (Table 1).
• Concurrent use of standard intrathecal chemotherapy prophylaxis is recommended for patients with risk of central nervous system relapse.

Administration:

• Administer REVUFORJ twice daily fasted or with a low-fat meal (e.g., meals with approximately 400 calories, 25% or less fat).
• Administer REVUFORJ orally around the same time each day.
• Advise patients to swallow tablets whole and to not cut or chew tablets. If patients are unable to swallow tablets, they may be crushed and dispersed in water and taken within 2 hours of preparation [see Instructions for Use].
• If a dose of REVUFORJ is missed or not taken at the usual time, administer the dose as soon as possible on the same day and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.

2.3 Dosage Modifications for Adverse Reactions

Assess blood counts, electrolytes, and liver enzymes prior to the initiation of REVUFORJ and monthly thereafter. Perform an electrocardiogram (ECG) prior to the initiation of REVUFORJ, at least once a week for the first 4 weeks, and at least monthly thereafter. Monitor for QTc interval prolongation and manage any abnormalities promptly [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Interrupt dosing or reduce dose for adverse reactions as per Table 3. Dose levels for dose reductions are listed in Table 4, Table 5, and Table 6.

Tablets:

• 25 mg of revumenib: Pink modified oval film-coated tablet debossed with “S” on one side and “25” on the other side.
• 110 mg of revumenib: Beige modified oval film-coated tablet debossed with “S” on one side and “110” on the other side.
• 160 mg of revumenib: Purple modified oval film-coated tablet debossed with “S” on one side and “160” on the other side.

5.1 Differentiation Syndrome

REVUFORJ can cause fatal or life-threatening differentiation syndrome (DS). Symptoms of differentiation syndrome, including those seen in patients treated with REVUFORJ, include fever, dyspnea, hypoxia, peripheral edema, pleuropericardial effusion, acute renal failure, and/or hypotension.

In clinical trials, DS occurred in 39 (29%) of 135 patients treated with REVUFORJ at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation, including 32% of patients with acute myeloid leukemia (AML), 25% of patients with mixed-phenotype acute leukemia (MPAL), and 14% of patients with acute lymphoblastic leukemia (ALL). DS was Grade 3 or 4 in 13% and fatal in one patient. The median time to onset was 10 days (range 3-41 days). Some patients experienced more than 1 DS event. Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1% [see Adverse Reactions (6.1)].

Reduce the white blood cell count (WBC) to less than 25 Gi/L prior to starting REVUFORJ. If DS is suspected, immediately initiate treatment with systemic corticosteroids (e.g., dexamethasone 10 mg intravenously every 12 hours in adults or dexamethasone 0.25 mg/kg/dose intravenously every 12 hours in pediatric patients weighing less than 40 kg) for a minimum of 3 days and until resolution of signs and symptoms. Institute supportive measures and hemodynamic monitoring until improvement. Interrupt REVUFORJ if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier if life-threatening symptoms occur such as pulmonary symptoms requiring ventilator support. Restart steroids promptly if DS recurs after tapering corticosteroids [see Dosage and Administration (2.3)].

5.2 QTc Interval Prolongation

REVUFORJ can cause QT (QTc) interval prolongation [see Clinical Pharmacology (12.2)]. In the clinical trials, QTc interval prolongation was reported as an adverse reaction in 39 (29%) of 135 patients treated with REVUFORJ at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation; QTc interval prolongation was Grade 3 in 12%. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 8%, and the increase from baseline QTcF was greater than 60 msec in 18%. REVUFORJ dose reduction was required for 5% due to QTc interval prolongation [see Adverse Reactions (6.1)]. QTc prolongation occurred in 16% of the 31 patients less than 17 years old, 33% of the 88 patients 17 years to less than 65 years old, and in 50% of the 16 patients 65 years or older.

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with REVUFORJ. Perform an ECG prior to initiation of treatment with REVUFORJ, and do not initiate REVUFORJ in patients with QTcF > 450 msec. Perform an ECG at least once a week for the first 4 weeks on treatment, and at least monthly thereafter [see Dosage and Administration (2.3)]. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use of REVUFORJ with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation [see Drug Interactions (7.1), Clinical Pharmacology (12.2)].

Interrupt REVUFORJ if QTcF increases to greater than 480 msec and less than 500 msec, and restart REVUFORJ at the same dose twice daily after the QTcF interval returns to less than or equal to 480 msec. Interrupt REVUFORJ if QTcF increases to greater than 500 msec or by > 60 msec from baseline, and restart REVUFORJ twice daily at the lower dose level after the QTcF interval returns to less than or equal to 480 msec. Permanently discontinue REVUFORJ in patients with ventricular arrhythmias and in those who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia [see Dosage and Administration (2.3)].

5.3 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, REVUFORJ can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of revumenib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, malformations, and altered fetal growth at maternal exposures approximately 0.5 times the human exposure (AUC) at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.3)].

6.1 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.

Relapsed or Refractory Acute Leukemia with KMT2A translocation

The safety of REVUFORJ reflects exposure in 135 patients (104 adult and 31 pediatric patients) with relapsed or refractory (R/R) acute leukemia with KMT2A translocation treated with REVUFORJ at a dose approximately equivalent to 160 mg in adults orally twice daily with a strong CYP3A4 inhibitor [see Clinical Studies (14.1)]. The median duration of exposure to REVUFORJ was 2.3 months (range < 1 to 23 months), and 3% of patients were exposed for more than 6 months.

Fatal adverse reactions occurred in 4 (3%) patients who received REVUFORJ, including 2 with differentiation syndrome, 1 with hemorrhage, and 1 with sudden death. Serious adverse reactions were reported in 99 (73%) patients. The most frequent serious adverse reactions (≥ 5%) were infection (24%), febrile neutropenia (19%), bacterial infection (17%), differentiation syndrome (12%), hemorrhage (9%), and thrombosis (5%).

Adverse reactions leading to dose interruption occurred in 42% of patients. The most common adverse reactions (≥ 5%) leading to dose interruption were electrocardiogram QT prolonged, febrile neutropenia, differentiation syndrome, infection, hypokalemia, and nausea. Adverse reactions leading to dose reduction occurred in 10% of patients who received REVUFORJ. Adverse reactions leading to a dose reduction (> 1%) included electrocardiogram QT prolonged. Adverse reactions leading to permanent discontinuation occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation (> 1%) included infection and respiratory failure.

The most common (≥ 20%) adverse reactions were hemorrhage, nausea, phosphate increased, musculoskeletal pain, infection, aspartate aminotransferase increased, febrile neutropenia, alanine aminotransferase increased, parathyroid hormone intact increased, bacterial infection, diarrhea, differentiation syndrome, electrocardiogram QT prolonged, phosphate decreased, triglycerides increased, potassium decreased, decreased appetite, constipation, edema, viral infection, fatigue, and alkaline phosphatase increased.

The common adverse reactions are summarised in Table 7.

Clinically relevant adverse reactions in less than 20% of patients who received REVUFORJ include:

Cardiac disorders: Cardiac failure, pericardial effusion, ventricular tachycardia, cardiac arrest

Endocrine disorders: Hyperparathyroidism

Eye disorders: Cataract

Gastrointestinal disorders: Abdominal pain

General disorders and administration site conditions: Sudden death

Immune system disorders: Drug hypersensitivity

Metabolism and nutrition disorders: Hyponatremia, hyperkalemia

Nervous system disorders: Taste disorder, syncope, headache, paresthesia

Renal disorders: Renal impairment

Skin and subcutaneous disorders: Rash

Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory acute leukemia with KMT2A translocation are shown in Table 8.

7.1 Effect of Other Drugs on REVUFORJ

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of REVUFORJ have been established in pediatric patients 1 year and older with relapsed or refractory acute leukemia with a KMT2A translocation. Use of REVUFORJ for this indication is supported by evidence from adequate and well-controlled trials in adults and pediatric patients [see Clinical Studies (14.1)] and additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. The patients included 13 infants (age < 2 years), 41 children (age 2 to < 12 years) and 16 adolescents (age 12 to < 17 years). The recommended dosage in patients weighing less than 40 kg is BSA-based.

The safety and efficacy of REVUFORJ in pediatric patients less than 1 year old have not been established.

Animal Data

In a repeat dose toxicity study in 6-7 week-old rats treated with revumenib at 75, 150, or 300 mg/kg/day for 13 weeks, an irreversible increase in femur growth plate closure was observed at revumenib exposures approximately 2 times the human exposure (AUC) at the recommended dose.

Based on the findings in animals, monitor bone growth and development in pediatric patients.

8.5 Geriatric Use

Of the 135 patients with relapsed or refractory acute leukemia with a KMT2A translocation in clinical studies of REVUFORJ, 16 (12%) patients were 65 years of age and older and 3 (2%) patients were 75 years of age and older [see Clinical Studies (14.1)].

No overall differences were observed in the effectiveness of REVUFORJ between patients who were 65 years and older and younger patients [see Clinical Studies (14.1) and Clinical Pharmacology (12.3)]. Compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older [see Warnings and Precautions (5.2)].

12.1 Mechanism of Action

Revumenib is a menin inhibitor and blocks the interaction of both wild-type lysine methyltransferase 2A (KMT2A) and KMT2A fusion proteins with menin. The binding of KMT2A fusion proteins with menin is involved in KMT2A-rearranged (KMT2Ar) acute leukemias through activation of a leukemogenic transcriptional pathway. In nonclinical studies using cells that express KMT2A fusions, inhibition of the menin-KMT2A interaction with revumenib altered the transcription of multiple genes including differentiation markers.

In nonclinical in vitro and in vivo studies, revumenib demonstrated antiproliferative and antitumor activity in leukemia cells harboring KMT2A fusion proteins.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of revumenib were characterized in patients with relapsed or refractory acute leukemia following single and multiple oral administration of revumenib with or without strong CYP3A4 inhibitors. Steady-state pharmacokinetic parameters are presented as geometric mean [coefficient of variation (%CV)] unless otherwise specified.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with revumenib. In a repeat dose toxicity study in rats treated with revumenib for 13 weeks, lymphoma was observed in multiple organs in one animal.

Revumenib was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, or an in vivo rat peripheral blood reticulocyte micronucleus assay.

Fertility studies in animals have not been conducted with revumenib.

In a repeat dose toxicity study in dogs treated with revumenib at 12.5, 25 or 40 mg/kg/day for 13 weeks, microscopic findings in the testes and epididymis consisted of depletion of germ cells and decreased sperm at ≥12.5 mg/kg/day. In females, microscopic changes of atrophy in the mammary glands, uterus, and vagina and decreased number of corpora lutea in the ovaries were observed at ≥12.5 mg/kg/day. At the end of the 13-week recovery period, the findings in the female reproductive organs were reversed at all doses, and the testicular and epididymal effects were reversed at 12.5 mg/kg/day. At the dose of 12.5 mg/kg/day in dogs, exposures (AUC) were approximately 1.3 times the human exposure (AUC) at the recommended dose.

13.2 Animal Toxicology and/or Pharmacology

In a repeat dose toxicity study in dogs treated with revumenib at 12.5, 25, or 40 mg/kg/day for 13 weeks, microscopic findings of nerve fiber degeneration in the brain, sciatic nerves, and spinal cord segments were observed at ≥ 12.5 mg/kg/day and were not reversed at the end of a 13-week recovery period.

In a repeat dose toxicity study in rats treated with revumenib at 75, 150, 300 mg/kg/day for 13 weeks, dose dependent ocular findings of lens opacities were observed at ≥ 75 mg/kg/day; the findings progressed during the dosing and recovery periods and were not reversed.

Hyperplasia was observed in multiple organs including the testes, mammary gland, uterus, pancreas, and kidney in rats treated at ≥ 75 mg/kg/day for up to 13 weeks. The findings were irreversible in the testes, mammary gland, and pancreas. Revumenib exposures at 75 mg/kg/day in rats are approximately 2 times the human exposure (AUC) at the recommended dose.

14.1 Relapsed or Refractory Acute Leukemia with a KMT2A Translocation

SNDX-5613-0700

The efficacy of REVUFORJ was evaluated in a single-arm cohort of an open-label, multicenter trial (SNDX-5613-0700, NCT04065399; AUGMENT-101) in adult and pediatric patients at least 30 days old with relapsed or refractory (R/R) acute leukemia with a KMT2A translocation. Patients with an 11q23 partial tandem duplication were excluded. Eligibility required a QTcF < 450 msec at study baseline. Treatment consisted of REVUFORJ at a dose approximately equivalent to 160 mg in adults orally twice daily with a strong CYP3A4 inhibitor until disease progression, unacceptable toxicity, failure to achieve morphological leukemia-free state by 4 cycles of treatment, or hematopoietic stem cell transplantation (HSCT).

The baseline demographic and disease characteristics of the 104 treated patients are shown in Table 10. Twenty-four (23%) patients underwent HSCT following treatment with REVUFORJ.

Efficacy was established on the basis of the rate of complete remission (CR) plus CR with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The median follow-up was 5.73 months (range, 0.3 to 28.9 months). The efficacy results are shown in Table 11. On subgroup analysis, CR+CRh was achieved by 18/86 (21%) of patients with AML, 3/16 (19%) of patients with ALL, and 1/2 (50%) of patients with MPAL.

Of the 22 patients who achieved a CR or CRh, the median time to CR or CRh was 1.9 months (range: 0.9, 5.6 months).
Among the 83 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 12 (14%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 21 patients who were independent of both RBC and platelet transfusions at baseline, 10 (48%) remained transfusion independent during any 56-day post-baseline period.

25 mg: Pink modified oval film-coated tablet debossed with “S” on one side and “25” on the other side.

• 30-count bottles with a desiccant and child resistant closure (NDC 73555-500-00)

110 mg: Beige modified oval film-coated tablet debossed with “S” on one side and “110” on the other side.

• 30-count bottles with a desiccant and child resistant closure (NDC 73555-501-00)

160 mg: Purple modified oval film-coated tablet debossed with “S” on one side and “160” on the other side.

• 30-count bottles with a desiccant and child resistant closure (NDC 73555-502-00)

Differentiation Syndrome

Advise patients of the risks of developing differentiation syndrome as early as 1 day after the start of therapy and during treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, low blood pressure, rapid weight gain, swelling of their arms or legs, or decreased urinary output, to their healthcare provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1)].

Prolonged QT Interval

Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia. Advise patients with a history of hypokalemia or hypomagnesemia of the importance of monitoring their electrolytes [see Warnings and Precautions (5.2)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with REVUFORJ and for 4 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with REVUFORJ and for 1 week after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of reproductive potential of the potential for impaired fertility from REVUFORJ [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant products, including over-the counter products and supplements [see Drug Interactions (7.1)].

Dosing Instructions

Advise patients to swallow tablets whole with a cup of water and not to cut or chew tablets. If patients are unable to swallow the tablets, they may be crushed and dispersed in water [see Instructions for Use]. Instruct patients that, if they miss a dose of REVUFORJ, to take it as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose, and return to the normal schedule the following day [see Dosage and Administration (2.2)].