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Clinical Trial
. 2018 Nov;93(11):1301-1310.
doi: 10.1002/ajh.25238. Epub 2018 Sep 9.

Glasdegib in Combination With Cytarabine and Daunorubicin in Patients With AML or High-Risk MDS: Phase 2 Study Results

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Free PMC article
Clinical Trial

Glasdegib in Combination With Cytarabine and Daunorubicin in Patients With AML or High-Risk MDS: Phase 2 Study Results

Jorge E Cortes et al. Am J Hematol. .
Free PMC article

Abstract

Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/m2 on days 1-7 and daunorubicin 60 mg/m2 on days 1-3. Patients in remission then received consolidation therapy (2-4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27-75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7-54.1) achieved investigator-reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9-48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4-19.3) months, with 12-month survival probability 66.6% (80% CI 58.5-73.4). The most common treatment-related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high-risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.

Figures

Figure 1
Figure 1
A, Kaplan‐Meier plot of OS in all patients; B, patients with AML by cytogenetic risk and C, patients aged ≥55 years with and without censoring for patients receiving a transplant. Adv, adverse; AML, acute myeloid leukemia; CI, confidence interval; NE, not evaluable; Fav, favorable; Int, intermediate; OS, overall survival [Color figure can be viewed at http://wileyonlinelibrary.com]

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