Astellas Pharma Inc has announced dosing of the first patient in a randomized phase 3 registration trial of gilteritinib (ASP2215) versus salvage chemotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The primary endpoint of the trial is overall survival (OS).

Gilteritinib is a receptor tyrosine kinase inhibitor of FLT3 and AXL, which are involved in the growth of cancer cells. Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in up to one third of patients with AML.

The gilteritinib phase 3 trial follows a phase 1/2 trial, which evaluated doses from 20 to 450 mg once daily. A parallel multi-dose expansion cohort was initiated based on the efficacy seen in the dose escalation phase. Preliminary data from the phase 1/2 trial presented at the 2015 American Society of Clinical Oncology annual meeting demonstrated a 57.5 per cent overall response rate and a 47.2 per cent composite Complete Response (CR) rate (CR + CR with incomplete platelet recovery + CR with incomplete hematologic recovery) in 106 patients with FLT3 mutations who received 80 mg and higher doses. Median duration of response was 18 weeks across all doses and median OS was approximately 27 weeks at 80 mg and above in FLT3 mutation positive patients. Common drug-related adverse events (> 10 per cent) observed in the study were diarrhea (13.4 per cent), fatigue (12.4 per cent) and AST increase (11.3 per cent). At the 450 mg dose, two patients reached dose-limiting toxicity (grade 3 diarrhea and ALT/AST elevation) and the maximum tolerated dose was determined to be 300 mg.

On October 27, 2015, the Japanese Ministry of Health, Labor and Welfare (MHLW) announced the selection of gilteritinib as one of the first products designated for Sakigake.

The phase 3 trial is an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in patients with AML. The study will enroll 369 patients with FLT3 activating mutation in bone marrow or whole blood, as determined by central lab, AML who are refractory to or have relapsed after first-line AML therapy. Subjects will be randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy consisting of LoDAC (low-dose cytarabine), azacitidine, MEC (mitoxantrone, etoposide, and intermediate-dose cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin). The primary endpoint of the trial is OS.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialise gilteritinib.

AML is a cancer that impacts the blood and bone marrow and most commonly experienced in older adults. According to the American Cancer Society, in 2015, there will be an estimated 20,830 new cases of AML diagnosed in the United States, and about 10,460 cases will result in death.