Phase 1/1b study of azacitidine and hedgehog pathway inhibitor sonidegib in patients with myeloid neoplasms

• Published in: Cancer Vol. 129; no. 15; pp. 2321 - 2330
• Main Authors: Tibes, Raoul, Kosiorek, Heidi E., Dueck, Amylou C., Palmer, Jeanne, Sproat, Lisa, Bogenberger, James, Hashmi, Shahrukh, Mesa, Ruben, Hogan, William, Litzow, Mark R., Al‐Kali, Aref
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2023
• Subjects: Acute myeloid leukemia; AML; azacitidine; Chronic myelomonocytic leukemia; Constipation; Cough; Diarrhea; hedgehog inhibitor; Hedgehog protein; Inhibitors; Insomnia; Leukemia; Malignancy; MDS; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelofibrosis; Neoplasms; Oncology; Patients; Remission; Side effects; Sleep disorders; sonidegib; Stem cells; Survival; Tumors; AML; hedgehog inhibitor; sonidegib; MDS; azacitidine
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.34800

Background Myeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice. Methods Sonidegib (SON), an oral HHi, was tested in this phase 1/1b trial in combination with azacitidine (AZA, 75 mg/m2 days ×7) in patients with newly diagnosed and relapsed/refractory (r/r) chronic MN or acute myeloid leukemia (AML). Results Sixty‐two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose‐finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1–28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia‐free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia‐free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment. Conclusions Our study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms. Combining sonidegib with azacitidine is safe in patients with myeloid neoplasms. Although outcome was not high for frontline therapy, in the relapsed setting, extended survival was seen.