A phase 1/1b trial evaluated the safety and effectiveness of the oral smoothened inhibitor sonidegib (LDE225) in combination with azacitidine in 63 patients with myeloid malignancies; the first analysis of the final study results was reported at ASH 2017.
Eligible patients could have untreated and relapsed/refractory (R/R) disease and acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), myelodysplastic syndromes (MDS), MDS/myeloproliferative neoplasms overlap, or myelofibrosis (MF) diagnoses. In the phase 1 (3 + 3) dose-escalation portion of the study, oral sonidegib was started at 400 mg daily continuously (28-day cycle) and azacitidine at 75 mg/m2 for 7 days, with dose adjustment per label. The primary end point of the study was to determine the maximum tolerated dose (MTD) and best overall response of sonidegib plus azacitidine. Dose-limiting toxicity (DLT) in phase 1 was assessed after 42 days at steady-state concentrations of sonidegib.
A total of 62 patients were enrolled (phase 1, 10 patients; phase 1b, 52 patients); of these, 28 (45%) patients were newly diagnosed and 34 (55%) had R/R disease. Among the 62 enrolled patients, 38 (61%) had AML, 18 (29%) had MDS, 4 (6.5%) had CMML, and 2 (3.5%) had MF. Among the 38 AML patients, 15 had untreated AML and 23 had R/R AML; 21 patients had intermediate risk, and 16 patients had unfavorable cytogenetics. The median age of the total study population was 72.5 years (range, 39-86 years) and the majority (66%) were male.
At the sonidegib 400-mg daily dose level (n = 6), 1 DLT of creatine phosphokinase elevation was reported. At a follow-up of 14.5 months, 218 cycles have been administered of the MTD dose of sonidegib 200 mg (n = 56). Dose adjustments were needed in 12.5% of sonidegib-treated patients and in 18% of azacitidine-treated patients; at least once, dose omissions were needed in 71.4% and 18%, respectively.
At the MTD sonidegib dose of 200 mg (n = 56), all patients experienced ≥1 grade 3 adverse events (AEs), which were mostly hematologic in nature and included thrombocytopenia (n = 45), neutropenia (n = 42), anemia (n = 39), and leukopenia (n = 38). The most common nonhematologic grade 1/2 AEs included fatigue (n = 43), constipation (n = 27), nausea (n = 21), cough (n = 18), insomnia (n = 14), diarrhea (n = 16), and abdominal pain (n = 16). Six deaths occurred in the study—4 due to cancer, 2 from cardiac arrest, and 2, sudden death.
At a median follow-up of 14.5 months, the best response (complete response + partial response + morphologic leukemia-free state) was achieved by 2 patients with untreated AML and 2 with R/R AML. Notably, 16 of the 21 (76%) patients with R/R AML had stable disease. Median overall survival was 6.4 months (95% confidence interval [CI], 4.2-10.9) and progression-free survival was 5.3 months (95% CI, 4.0-10.7) in patients with AML.
These results suggest that combination therapy with sonidegib plus azacitidine was associated with a high disease control rate and lack of disease progression, particularly in the R/R AML patient cohort.
Tibes R, et al. 2017 ASH. Abstract 2629.
