Background: AS703569 is a novel, orally bioavailable, potent ATP-competitive, small molecule that inhibits all three aurora kinase isoforms (A, B, and C), and shows inhibitory activity across other kinases involved in cell proliferation and survival, including FLT3, ABL1, ABL1 (mut. T315I), JAK-2, and FGFR3. AS703569 has been tested as a single agent and in combination with standard-of-care anticancer agents in leukemia cell lines, freshly isolated leukemic cells, and tumor xenograft models. The strong inhibition of proliferation and the triggering of apoptosis induced by AS703569 lead to significant anti tumor activity resulting in tumor regression or growth delay, and prolongation of animal survival. AS703569 is currently being tested in phase I studies as a single agent and in combination; the main objectives are to establish the MTD (based on dose-limiting toxicities [DLTs]) and evaluate the safety and PK/PD effects of different regimens.Study design: This is an open-label, phase I, two-arm, dose-escalation study in patients (pts) with AML, CML, MDS, and MPD. Patients were sequentially assigned to one of two AS703569 dosing regimens: Regimen 1: once daily (QD), days 1–3 and 8–10 of a 21-day cycle; Regimen 2: QD, days 1–6 of a 21-day cycle. In both treatment arms, AS703569 was administered at escalating dose levels (DL; 3, 6, 10, 15, 21, 28, and 47 mg/m2/day) using a 3+3 cohort design. Repeated cycles were permitted until disease progression or unacceptable toxicity.Patient characteristics: Pt characteristics are summarized in the Table. Pts had primary AML (n=20), secondary AML (n=13), CML (n=6), MDS (n=5), and MPD (n=1). Pts were heavily pretreated and had failed previous chemotherapy.Safety: The median number of AS703569 cycles received per pt was 2 for Regimen 1 (range 1–7) and 1 for Regimen 2 (range 1–6). In Regimen 1, at DL 7 (47 mg/m2/day, n=3), 2 subjects reported DLTs: 1 case of grade 3 diarrhea with hyponatremia and sepsis with a fatal outcome, and 1 case of grade 3 diarrhea with GI bleeding. In Regimen 2, at DL 7 (n=5), 3 subjects reported DLTs: 2 cases of grade 4 mucositis and 1 case of neutropenic infection. Consequently, the dose was de-escalated to 37 mg/m2/day for both regimens and enrollment is ongoing at this DL to confirm the MTD. Grade ≥3 toxicities reported throughout the study mainly included infections (18 pts), neutropenia and febrile neutropenia (17 pts), thrombocytopenia (15 pts), anemia (11 pts), and GI disorders including mucositis, diarrhea and GI bleeding (8 pts). Alopecia was reported in some pts.PK: Preliminary data for 37 pts (DL 1–6) show an increased exposure with dose, a Tmax of 2–4 h (range 0.5–8 h), and an effective half-life of ~10–20 h.Activity (preliminary data): In Regimen 1, 1 pt with refractory CML (mut. T315I) has received 7 treatment cycles and shown a hematological and cytogenetic response; 5 pts with AML received 5–7 cycles, 3 achieved reduction in BM and/or peripheral blasts. In Regimen 2, 1 pt with MDS received 6 cycles and achieved a PR; 2 pts with AML received 3 cycles and did not progress.Conclusions: These data indicate that AS703569, QD, days 1–3 and 8–10 every 21 days or on days 1–6 every 21 days is generally well tolerated in pts with advanced hematological malignancies. Most grade 3/4 toxicities are commonly seen in pts with advanced hematological malignancies and are in part linked to the underlying disease. A DL with an unacceptable frequency of DLTs was reached and enrollment continues at a lower DL to confirm the MTD. Early evidence of activity was observed in pts with CML, AML, and MDS.Regimen 1Regimen 2N2421Median (range) age, years69.5 (48–83)71 (49–82)Sex, M/F15/912/9ECOG PS, 0-1-25-12-73-12-6Median (range) previous lines of therapy3 (1–6)2 (1–6)
Read full abstract
Feb 10, 2023
Ajit Singh + 4
Open Access
