REVUFORJ Film-coated tablet Ref.[116086] Active ingredients: Revumenib

Revumenib exposure-response relationships have not been fully characterized and the time course of pharmacodynamic response is unknown.

Cardiac Electrophysiology

The effect of REVUFORJ on the QTc interval was evaluated across a dose range of 113 mg to 339 mg twice daily (1.2 times the highest adult approved recommended dosage) with and without strong CYP3A4 inhibitors in patients with relapsed or refractory acute leukemia with a KMT2A translocation or an NPM1 mutation.

The increase in QTc interval was concentration dependent with an increase in QTc predicted to be 23 msec (upper bound of 90% confidence interval: 25 msec) at the mean steady-state maximum concentration (C_max) observed in patients at the highest approved recommended dosage without strong CYP3A4 inhibitors. The increase in QTc interval was predicted to be 20 msec (upper bound of 90% confidence interval: 21 msec) at steady-state C_max after administration of 160 mg twice daily with strong CYP3A4 inhibitors [see Warnings and Precautions (5.2)].

The pharmacokinetics of revumenib were characterized in patients with relapsed or refractory acute leukemia with a KMT2A translocation or an NPM1 mutation 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.

Table 9. Revumenib Pharmacokinetics in Patients with R/R Acute Leukemia with a KMT2A translocation or an NPM1 mutation:

Abbreviations: C_max = maximum plasma concentration; AUC = area under the time concentration curve; T_max = time to peak concentration
^a - Steady-state
^b - Dosage range of 113 mg to 339 mg (1.26 times the highest adult approved recommended dosage)
^c - Approximately 400-500 calories, 25% of calories from fat
^d - Independent of concentration
^e - M1 contributes to revumenib's clinically significant effects on QTc [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)] but does not contribute to its efficacy at the approved recommended dosage
^f - A single dose of radiolabeled revumenib 276 mg (1.02 times the highest adult approved recommended dosage) to adult patients with relapsed/refractory acute leukemia

Specific Populations

No clinically significant differences in the pharmacokinetics of revumenib were observed based on age (1 to 84 years), race (67% White, 7% Asian, 8% Black), sex, mild to moderate (CLcr 30 to 89 mL/min) renal impairment, and mild (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. The effect of severe renal impairment (CLcr less than 30 mL/min), end-stage renal disease (CLcr less than 15 mL/min), or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment is unknown.

Body weight (6-151 kg) has a significant effect on the pharmacokinetics of revumenib, with higher revumenib exposures in patients with lower body weight (less than 40 kg). This supports the use of BSA-based dosage in patients weighing less than 40 kg.

Pediatric Patients

Revumenib geometric mean (CV%) steady-state C_max was 3137 (39%) ng/mL and AUC_0-tau was 14,630 (55%) ng·hr/mL following 95 mg/m² twice daily with strong CYP3A4 inhibitors.

Revumenib predicted geometric mean (%CV) steady-state C_max was 1597 (70%) ng/mL and AUC_0-tau was 12,570 (56%) ng·hr/mL following 160 mg/m² twice daily without strong CYP3A4 inhibitors.

Drug Interaction Studies

Clinical Studies

Strong CYP3A4 Inhibitors: Revumenib AUC and C_max is increased by 2-fold following concomitant use of multiple doses of revumenib with certain azole antifungals that are strong CYP3A4 inhibitors (i.e., posaconazole, itraconazole, and voriconazole). Similarly, revumenib AUC and C_max is increased by 2.5-fold following concomitant use of multiple doses of revumenib with cobicistat (strong CYP3A4 inhibitor).

Strong and Moderate CYP3A4 Inducers: Revumenib exposure is expected to decrease and M1 exposure is expected to increase with strong and moderate CYP3A4 inducers.

Other Drugs: No clinically significant differences in revumenib pharmacokinetics were observed when used concomitantly with fluconazole (moderate CYP3A4 inhibitor), isavuconazole (moderate CYP3A4 inhibitor).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Revumenib inhibits CYP3A4, but does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.

Revumenib does not induce CYP1A2, CYP2B6, and CYP3A4.

Transporter Systems: Revumenib is a substrate of OCT1, OCT2, OAT1, OAT3, and MATE1, but is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, MATE2-K, or BSEP. M1 is a substrate of OATP1B1, but is not a substrate of P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B3, MATE1, or MATE2-K.

Revumenib inhibits MATE1, but does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, and MATE2-K. M1 inhibits MATE1, but does not inhibit OAT1, OAT3, OCT2, OATP1B1, OATP1B3, and MATE2-K.

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.

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 by local testing, including karyotyping. Patients with an 11q23 partial tandem duplication were excluded. Eligibility required a QTcF <450 msec, estimated glomerular filtration rate ≥60 mL/min/1.73 m², total bilirubin <1.5 x the upper limit of normal (ULN), aminotransferases <3 x ULN, and ejection fraction ≥50% at study baseline. Eastern Cooperative Oncology Group performance status score was to be 0–2 if ≥18 years old, Karnofsky Performance Scale score ≥50 (if 16 to <18 years old, and Lansky Performance score ≥50 if <16 years old). 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.

Table 10. Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory Acute Leukemia with KMT2A translocation (Study SNDX-5613-0700):

¹ One patient did not have a translocation type reported.

Efficacy was established on the basis of the rate of complete remission (CR) plus CR with partial hematological recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The median follow-up was 5.7 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 ½ (50%) of patients with MPAL.

Table 11. Efficacy Results in Patients with Relapsed or Refractory Acute Leukemia with KMT2A translocation (Study SNDX-5613-0700):

CI: confidence interval; NE = not estimable; DOCR = duration of CR; DOCRh = duration of CRh.
¹ CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 10⁹/L and platelet count ≥100 × 10⁹/L.
² CRh is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; residual neutropenia (>0.5 × 10⁹/L) and thrombocytopenia (>50 × 10⁹/L), but the count recovery criteria for CR are not met.
³ Duration of CR+CRh is defined as the time from first CR or CRh to the first documented relapse or death, whichever occurs first.
⁴ Duration of CR is defined as the time from first CR to the first documented relapse or death, whichever occurs first.
⁵ Duration of CRh is defined as the time from first CRh to the first documented relapse or death, whichever occurs first.
⁶ The 95% CI of the response rate is derived using the exact method based on binomial distribution. The median of the response duration is derived using Kaplan-Meier method.

For 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).

Of 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.

14.2 Relapsed or Refractory Acute Myeloid Leukemia with an NPM1 Mutation

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) described above [see Clinical Studies (14.1)]. A susceptible mutation was confirmed in enrolled patients using next generation sequencing or polymerase chain reaction (PCR) of the last exon of NPM1. The baseline demographic and disease characteristics of the 65 patients in the pivotal cohort are shown in Table 12. Seven patients (11%) underwent HSCT following treatment with REVUFORJ.

Table 12. Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory Acute Myeloid Leukemia with an NPM1 Mutation (Study SNDX-5613-0700):

Efficacy was established on the basis of the rate of complete remission (CR) plus CR with partial hematological recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The median follow-up was 3.8 months (range, 0.1 to 29.9) months. The efficacy results are shown in Table 13.

Table 13. Efficacy Results in Patients with Relapsed or Refractory Acute Myeloid Leukemia with an NPM1 mutation (Study SNDX-5613-0700):

CI: confidence interval; NE = not estimable; DOCR = duration of CR; DOCRh = duration of CRh.
¹ CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullarydisease; ANC ≥1.0 × 10⁹/L and platelet count ≥100 × 10⁹/L.
² CRh is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullarydisease; residual neutropenia (>0.5 × 10⁹/L) and thrombocytopenia (>50 × 10⁹/L), but the count recovery criteria for CR are not met.
³ Duration of CR+CRh is defined as the time from first CR or CRh to the first documented relapse or death, whichever occurs first.
⁴ Duration of CR is defined as the time from first CR to the first documented relapse or death, whichever occurs first.
⁵ Duration of CRh is defined as the time from first CRh to the first documented relapse or death, whichever occurs first.
⁶ The 95% CI of the response rate is derived using the exact method based on binomial distribution. The median of the response duration is derived using Kaplan-Meier method.

For the 15 patients who achieved a CR or CRh, the median time to response was 2.8 months (range: 1.8, 9.6 months).

Of the 46 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 8 (17%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 19 patients who were independent of both RBC and platelet transfusions at baseline, 13 (68%) remained transfusion independent during any 56-day post-baseline period.