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Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results
Author(s) -
Cortes Jorge E.,
Douglas Smith B.,
Wang Eunice S.,
Merchant Akil,
Oehler Vivian G.,
Arellano Martha,
DeAngelo Daniel J.,
Pollyea Daniel A.,
Sekeres Mikkael A.,
Robak Tadeusz,
Ma Weidong Wendy,
Zeremski Mirjana,
Naveed Shaik M.,
Douglas Laird A.,
O'Connell Ashleigh,
Chan Geoffrey,
Schroeder Mark A.
Publication year - 2018
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.25238
Subject(s) - medicine , cytarabine , daunorubicin , adverse effect , gastroenterology , nausea , myeloid leukemia , leukemia
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/m 2 on days 1‐7 and daunorubicin 60 mg/m 2 on days 1‐3. Patients in remission then received consolidation therapy (2‐4 cycles of cytarabine 1 g/m 2 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.